Case Reports

Amyloidosis consists of approximately 30 protein-folding disorders sharing the common feature of abnormal extracellular amyloid deposition. In each condition, a specific soluble precursor protein aggregates to form the insoluble fibrils of amyloid, characterized by the beta-pleated sheet structure.¹ Amyloidosis occurs as either a systemic or localized process. Insulin-derived (AIns) amyloidosis, a localized process occurring at insulin injection sites, was first reported in 1983.² There were fewer than 20 reported cases until 2014, when 57 additional cases were reported by just 2 institutions,^3,4 indicating that AIns amyloidosis may be more common than previously thought.^3,5

Despite the increasing prevalence of diabetes mellitus and insulin use, there is a paucity of published cases of AIns amyloidosis. The lack of awareness of this condition among both dermatologists and general practitioners may be in part due to its variable clinical manifestations. We describe 2 patients with unique presentations of localized amyloidosis at repeated insulin injection sites.

Case Reports

Patient 1
A 39-year-old man with a history of type 1 diabetes mellitus presented with 4 asymptomatic nodules on the lateral thighs in areas of previous insulin injection. He first noticed the lesions 9 months prior to presentation and subsequently switched the injection site to the abdomen without development of new nodules. Despite being compliant with his insulin regimen, he had a long history of irregular glucose control, including frequent hypoglycemic episodes. The patient was using regular and neutral protamine hagedorn insulin.

On physical examination, 2 soft, nontender, exophytic nodules were noted on each upper thigh with surrounding hyperpigmented and hyperkeratotic collarettes (Figure 1). The nodules ranged in size from 2 to 3.5 cm in diameter.

Patient 2
A 53-year-old woman with a history of type 2 diabetes mellitus presented with painful subcutaneous nodules on the lower abdomen at sites of previous insulin injections. The nodules developed approximately 1 month after she started treatment with neutral protamine hagedorn insulin and had been slowly enlarging over the past year. She tried switching injection sites after noticing the lesions, but the nodules persisted. The patient had a long history of poor glucose control with chronically elevated glycohemoglobin and blood glucose levels.

On physical examination, 2 hyperpigmented, exophytic, smooth nodules were noted on the right and left lower abdomen, ranging in size from 2.5 to 5.5 cm in diameter (Figure 4).

Comment

Insulin is the suspected precursor protein in AIns amyloidosis, but the exact pathogenesis is unknown. The protein that is derived from insulin in these tumors is now identified as AIns amyloidosis.^5,6 It is hypothesized that insulin accumulates locally and is converted to amyloid by an unknown mechanism.⁷ Other potential contributory factors include chronic inflammation and foreign body reactions developing around amyloid deposits, as well as repeated trauma from injections into a single site.^4,5 It appears that lesions may derive from a wide range of insulin types and occur after variable time periods.

A majority of cases of iatrogenic amyloid have been described as single, firm, subcutaneous masses at an injection site that commonly are misdiagnosed as lipomas or lipohypertrophy.^7-11 To our knowledge, none of the reported cases resembled the multiple, discrete, exophytic nodules seen in our patients.^3,4 The surrounding hyperkeratosis noted in patient 1 is another uncommon feature of AIns amyloidosis (Figures 1 and 2). Only 3 AIns amyloidosis cases described lesions with acanthosis nigricans–like changes, only 1 of which provided a clinical image.^6,7,12The mechanism for the acanthosis nigricans–like changes may have been due to the high levels of insulin at the injection site. It has been suggested that the activation of insulinlike growth factor receptor by insulin leads to the proliferation of keratinocytes and fibroblasts.⁶ Histologic examination of AIns amyloidosis lesions generally demonstrates deposition of homogenous eosinophilic material consistent with amyloid, as well as positive Congo red staining with green birefringence by polarization. Immunohistologic staining with insulin antibody with or without proteomic analysis of the amyloid deposits can confirm the diagnosis. In both of our patients’ specimens, liquid chromatography–tandem mass spectrometry was performed for proteomic analysis, and results were consistent with AIns amyloidosis.

Reports in the literature have suggested that the deposition of amyloid at insulin injection sites has the potential to interfere with insulin absorption, leading to poor glucose control.^4,11,13 Hence, injection site rotation is a crucial aspect of treatment and prevention of AIns amyloidosis. In their study of 4 patients, Nagase et al⁴ compared serum insulin levels after insulin injection into amyloid nodules vs insulin levels after injection into normal skin. Insulin absorption at the amyloid sites was 34% of that at normal sites. Given these results, patients should be instructed to inject away from the amyloid deposit once it is identified.⁶ Glucose levels should be monitored closely when patients first inject away from the amyloid mass, as injection of the same dosage to an area of normal skin can lead to increased insulin absorption and hypoglycemia.^4,6 It is possible that the frequent hypoglycemic episodes noted in patient 1 were due to increased insulin sensitivity after switching to injection sites away from amyloid lesions.

Conclusion

Our patients demonstrate unique presentations of localized cutaneous amyloidosis at repeated insulin injection sites. We report these cases to complement the current data of iatrogenic amyloidosis and provide insight into this likely underreported phenomenon.

Amyloidosis consists of approximately 30 protein-folding disorders sharing the common feature of abnormal extracellular amyloid deposition. In each condition, a specific soluble precursor protein aggregates to form the insoluble fibrils of amyloid, characterized by the beta-pleated sheet structure.¹ Amyloidosis occurs as either a systemic or localized process. Insulin-derived (AIns) amyloidosis, a localized process occurring at insulin injection sites, was first reported in 1983.² There were fewer than 20 reported cases until 2014, when 57 additional cases were reported by just 2 institutions,^3,4 indicating that AIns amyloidosis may be more common than previously thought.^3,5

Despite the increasing prevalence of diabetes mellitus and insulin use, there is a paucity of published cases of AIns amyloidosis. The lack of awareness of this condition among both dermatologists and general practitioners may be in part due to its variable clinical manifestations. We describe 2 patients with unique presentations of localized amyloidosis at repeated insulin injection sites.

Case Reports

Patient 1
A 39-year-old man with a history of type 1 diabetes mellitus presented with 4 asymptomatic nodules on the lateral thighs in areas of previous insulin injection. He first noticed the lesions 9 months prior to presentation and subsequently switched the injection site to the abdomen without development of new nodules. Despite being compliant with his insulin regimen, he had a long history of irregular glucose control, including frequent hypoglycemic episodes. The patient was using regular and neutral protamine hagedorn insulin.

On physical examination, 2 soft, nontender, exophytic nodules were noted on each upper thigh with surrounding hyperpigmented and hyperkeratotic collarettes (Figure 1). The nodules ranged in size from 2 to 3.5 cm in diameter.

Patient 2
A 53-year-old woman with a history of type 2 diabetes mellitus presented with painful subcutaneous nodules on the lower abdomen at sites of previous insulin injections. The nodules developed approximately 1 month after she started treatment with neutral protamine hagedorn insulin and had been slowly enlarging over the past year. She tried switching injection sites after noticing the lesions, but the nodules persisted. The patient had a long history of poor glucose control with chronically elevated glycohemoglobin and blood glucose levels.

On physical examination, 2 hyperpigmented, exophytic, smooth nodules were noted on the right and left lower abdomen, ranging in size from 2.5 to 5.5 cm in diameter (Figure 4).

Comment

Insulin is the suspected precursor protein in AIns amyloidosis, but the exact pathogenesis is unknown. The protein that is derived from insulin in these tumors is now identified as AIns amyloidosis.^5,6 It is hypothesized that insulin accumulates locally and is converted to amyloid by an unknown mechanism.⁷ Other potential contributory factors include chronic inflammation and foreign body reactions developing around amyloid deposits, as well as repeated trauma from injections into a single site.^4,5 It appears that lesions may derive from a wide range of insulin types and occur after variable time periods.

A majority of cases of iatrogenic amyloid have been described as single, firm, subcutaneous masses at an injection site that commonly are misdiagnosed as lipomas or lipohypertrophy.^7-11 To our knowledge, none of the reported cases resembled the multiple, discrete, exophytic nodules seen in our patients.^3,4 The surrounding hyperkeratosis noted in patient 1 is another uncommon feature of AIns amyloidosis (Figures 1 and 2). Only 3 AIns amyloidosis cases described lesions with acanthosis nigricans–like changes, only 1 of which provided a clinical image.^6,7,12The mechanism for the acanthosis nigricans–like changes may have been due to the high levels of insulin at the injection site. It has been suggested that the activation of insulinlike growth factor receptor by insulin leads to the proliferation of keratinocytes and fibroblasts.⁶ Histologic examination of AIns amyloidosis lesions generally demonstrates deposition of homogenous eosinophilic material consistent with amyloid, as well as positive Congo red staining with green birefringence by polarization. Immunohistologic staining with insulin antibody with or without proteomic analysis of the amyloid deposits can confirm the diagnosis. In both of our patients’ specimens, liquid chromatography–tandem mass spectrometry was performed for proteomic analysis, and results were consistent with AIns amyloidosis.

Reports in the literature have suggested that the deposition of amyloid at insulin injection sites has the potential to interfere with insulin absorption, leading to poor glucose control.^4,11,13 Hence, injection site rotation is a crucial aspect of treatment and prevention of AIns amyloidosis. In their study of 4 patients, Nagase et al⁴ compared serum insulin levels after insulin injection into amyloid nodules vs insulin levels after injection into normal skin. Insulin absorption at the amyloid sites was 34% of that at normal sites. Given these results, patients should be instructed to inject away from the amyloid deposit once it is identified.⁶ Glucose levels should be monitored closely when patients first inject away from the amyloid mass, as injection of the same dosage to an area of normal skin can lead to increased insulin absorption and hypoglycemia.^4,6 It is possible that the frequent hypoglycemic episodes noted in patient 1 were due to increased insulin sensitivity after switching to injection sites away from amyloid lesions.

Conclusion

Our patients demonstrate unique presentations of localized cutaneous amyloidosis at repeated insulin injection sites. We report these cases to complement the current data of iatrogenic amyloidosis and provide insight into this likely underreported phenomenon.

Amyloidosis consists of approximately 30 protein-folding disorders sharing the common feature of abnormal extracellular amyloid deposition. In each condition, a specific soluble precursor protein aggregates to form the insoluble fibrils of amyloid, characterized by the beta-pleated sheet structure.¹ Amyloidosis occurs as either a systemic or localized process. Insulin-derived (AIns) amyloidosis, a localized process occurring at insulin injection sites, was first reported in 1983.² There were fewer than 20 reported cases until 2014, when 57 additional cases were reported by just 2 institutions,^3,4 indicating that AIns amyloidosis may be more common than previously thought.^3,5

Despite the increasing prevalence of diabetes mellitus and insulin use, there is a paucity of published cases of AIns amyloidosis. The lack of awareness of this condition among both dermatologists and general practitioners may be in part due to its variable clinical manifestations. We describe 2 patients with unique presentations of localized amyloidosis at repeated insulin injection sites.

Case Reports

Patient 1
A 39-year-old man with a history of type 1 diabetes mellitus presented with 4 asymptomatic nodules on the lateral thighs in areas of previous insulin injection. He first noticed the lesions 9 months prior to presentation and subsequently switched the injection site to the abdomen without development of new nodules. Despite being compliant with his insulin regimen, he had a long history of irregular glucose control, including frequent hypoglycemic episodes. The patient was using regular and neutral protamine hagedorn insulin.

On physical examination, 2 soft, nontender, exophytic nodules were noted on each upper thigh with surrounding hyperpigmented and hyperkeratotic collarettes (Figure 1). The nodules ranged in size from 2 to 3.5 cm in diameter.

Patient 2
A 53-year-old woman with a history of type 2 diabetes mellitus presented with painful subcutaneous nodules on the lower abdomen at sites of previous insulin injections. The nodules developed approximately 1 month after she started treatment with neutral protamine hagedorn insulin and had been slowly enlarging over the past year. She tried switching injection sites after noticing the lesions, but the nodules persisted. The patient had a long history of poor glucose control with chronically elevated glycohemoglobin and blood glucose levels.

On physical examination, 2 hyperpigmented, exophytic, smooth nodules were noted on the right and left lower abdomen, ranging in size from 2.5 to 5.5 cm in diameter (Figure 4).

Comment

Insulin is the suspected precursor protein in AIns amyloidosis, but the exact pathogenesis is unknown. The protein that is derived from insulin in these tumors is now identified as AIns amyloidosis.^5,6 It is hypothesized that insulin accumulates locally and is converted to amyloid by an unknown mechanism.⁷ Other potential contributory factors include chronic inflammation and foreign body reactions developing around amyloid deposits, as well as repeated trauma from injections into a single site.^4,5 It appears that lesions may derive from a wide range of insulin types and occur after variable time periods.

A majority of cases of iatrogenic amyloid have been described as single, firm, subcutaneous masses at an injection site that commonly are misdiagnosed as lipomas or lipohypertrophy.^7-11 To our knowledge, none of the reported cases resembled the multiple, discrete, exophytic nodules seen in our patients.^3,4 The surrounding hyperkeratosis noted in patient 1 is another uncommon feature of AIns amyloidosis (Figures 1 and 2). Only 3 AIns amyloidosis cases described lesions with acanthosis nigricans–like changes, only 1 of which provided a clinical image.^6,7,12The mechanism for the acanthosis nigricans–like changes may have been due to the high levels of insulin at the injection site. It has been suggested that the activation of insulinlike growth factor receptor by insulin leads to the proliferation of keratinocytes and fibroblasts.⁶ Histologic examination of AIns amyloidosis lesions generally demonstrates deposition of homogenous eosinophilic material consistent with amyloid, as well as positive Congo red staining with green birefringence by polarization. Immunohistologic staining with insulin antibody with or without proteomic analysis of the amyloid deposits can confirm the diagnosis. In both of our patients’ specimens, liquid chromatography–tandem mass spectrometry was performed for proteomic analysis, and results were consistent with AIns amyloidosis.

Reports in the literature have suggested that the deposition of amyloid at insulin injection sites has the potential to interfere with insulin absorption, leading to poor glucose control.^4,11,13 Hence, injection site rotation is a crucial aspect of treatment and prevention of AIns amyloidosis. In their study of 4 patients, Nagase et al⁴ compared serum insulin levels after insulin injection into amyloid nodules vs insulin levels after injection into normal skin. Insulin absorption at the amyloid sites was 34% of that at normal sites. Given these results, patients should be instructed to inject away from the amyloid deposit once it is identified.⁶ Glucose levels should be monitored closely when patients first inject away from the amyloid mass, as injection of the same dosage to an area of normal skin can lead to increased insulin absorption and hypoglycemia.^4,6 It is possible that the frequent hypoglycemic episodes noted in patient 1 were due to increased insulin sensitivity after switching to injection sites away from amyloid lesions.

Conclusion

Our patients demonstrate unique presentations of localized cutaneous amyloidosis at repeated insulin injection sites. We report these cases to complement the current data of iatrogenic amyloidosis and provide insight into this likely underreported phenomenon.

Nearly 20,000 patients are diagnosed with acute myeloid leukemia (AML) in the US annually.¹ Despite the use of aggressive chemotherapeutic agents, the prognosis remains poor, with a mean 5-year survival of 28.3%.² Fortunately, with the refinement of next-generation sequencing (NGS) hematology panels and development of systemic targeted therapies, the treatment landscape for eligible patients has improved, both in frontline and relapsed or refractory (R/R) patients.

Specifically, investigations into alterations within the FMS-like tyrosine kinase (FLT3) and isocitrate dehydrogenase (IDH) genes have led to the discovery of a number of targeted treatments. Midostaurin is US Food and Drug Administration (FDA)-approved for use in combination with induction chemotherapy for patients with internal tandem duplication of the FLT3 (FLT3-ITD) gene or mutations within the tyrosine kinase domain (FLT3-TKD).³ Ivosidenib is indicated for frontline treatment for those who are poor candidates for induction chemotherapy, and R/R patients who have an R132H mutation in IDH1.^4,5 Enasidenib is FDA-approved for R/R patients with R140Q, R172S, and R172K mutations in IDH2.⁶

The optimal treatment for patients with AML with ≥ 2 clinically actionable mutations has not been established. In this article we describe a geriatric patient who initially was diagnosed with AML with concurrent FLT3-TKD and IDH1 mutations and received targeted, sequential management. We detail changes in disease phenotype and mutational status by repeating an NGS hematology panel and cytogenetic studies after each stage of therapy. Lastly, we discuss the clonal evolution apparent within leukemic cells with use of ≥ 1 or more targeted agents.

Case Presentation

A 68-year-old man presented to the Emergency Department at The Durham Veterans Affairs Medical Center in North Carolina with fatigue and light-headedness. Because of his symptoms and pancytopenia, a bone marrow aspiration and trephine biopsy were performed, which showed 57% myeloblasts, 12% promyelocytes/myelocytes, and 2% metamyelocytes in 20 to 30% cellular bone marrow. Flow cytometry confirmed a blast population consistent with AML. A LeukoVantage (Quest Diagnostics) hematologic NGS panel revealed the presence of FLT3-TKD, IDH1, RUNX1, BCOR-E1477, and SF3B1 mutations (Table). Initial fluorescence in situ hybridization (FISH) results showed a normal pattern of hybridization with no translocations. His disease was deemed to be intermediate-high risk because of the presence of FLT3-TKD and RUNX1 mutations, despite the normal cytogenetic profile and absence of additional clinical features.

Induction chemotherapy was started with idarubicin, 12 mg/m², on days 1 to 3 and cytarabine, 200 mg/m², on days 1 to 7. Because of the presence of a FLT3-TKD mutation, midostaurin was planned for days 8 to 21. After induction chemotherapy, a bone marrow biopsy on day 14 revealed an acellular marrow with no observed myeloblasts. A bone marrow biopsy conducted before initiating consolidation therapy, revealed 30% cellularity with morphologic remission. However, flow cytometry found 5% myeloblasts expressing CD34, CD117, CD13, CD38, and HLA-DR, consistent with measurable residual disease. He received 2 cycles of consolidation therapy with high-dose cytarabine combined with midostaurin. After the patient's second cycle of consolidation, he continued to experience transfusion-dependent cytopenias. Another bone marrow evaluation demonstrated 10% cellularity with nearly all cells appearing to be myeloblasts. A repeat LeukoVantage NGS panel demonstrated undetectable FLT3-TKD mutation and persistent IDH1-R123C mutation. FISH studies revealed a complex karyotype with monosomy of chromosomes 5 and 7 and trisomy of chromosome 8.

We discussed with the patient and his family the options available, which included initiating targeted therapy for his IDH1 mutation, administering hypomethylation therapy with or without venetoclax, or pursuing palliative measures. We collectively decided to pursue therapy with single-agent oral ivosidenib, 500 mg daily. After 1 month of treatment, our patient developed worsening fatigue. His white blood cell count had increased to > 43 k/cm², raising concern for differentiation syndrome.

A review of the peripheral smear showed a wide-spectrum of maturing granulocytes, with a large percentage of blasts. Peripheral flow cytometry confirmed a blast population of 15%. After a short period of symptom improvement with steroids, the patient developed worsening confusion. Brain imaging identified 2 subdural hemorrhages. Because of a significant peripheral blast population and the development of these hemorrhages, palliative measures were pursued, and the patient was discharged to an inpatient hospice facility. A final NGS panel performed from peripheral blood detected mutations in IDH1, RUNX1, PTPN11, NRAS, BCOR-E1443, and SF3B1 genes.

Discussion

To our knowledge, this is the first reported case of a patient who sequentially received targeted treatments directed against both FLT3 and IDH1 mutations. Initial management with midostaurin and cytarabine resulted in sustained remission of his FLT3-TKD mutation. However, despite receiving prompt standard of care with combination induction chemotherapy and targeted therapy, the patient experienced unfavorable clonal evolution based upon his molecular and cytogenetic testing. Addition of ivosidenib as a second targeting agent for his IDH1 mutation did not achieve a second remission.

Clonal evolution is a well-described phenomenon in hematology. Indolent conditions, such as clonal hematopoiesis of intermediate potential, or malignancies, such as myelodysplastic syndromes and myeloproliferative neoplasms, could transform into acute leukemia through the accumulation of driver mutations and/or cytogenetic abnormalities. Clonal evolution often is viewed as the culprit in patients with AML whose disease relapses after remission with initial chemotherapy.^7-10 With the increasing availability of commercial NGS panels designed to assess mutations among patients experiencing hematologic malignancies, patterns of relapse, and, models of clonal evolution could be observed closely in patients with AML.

We were able to monitor molecular changes within our patient’s predominant clonal populations by repeating peripheral comprehensive NGS panels after lines of targeted therapies. The repeated sequencing revealed that clones with FLT3-TKD mutations responded to midostaurin with first-line chemotherapy whereas it was unclear whether clones with IDH1 mutation responded to ivosidenib. Development of complex cytogenetic findings along with the clonal expansion of BCOR mutation-harboring cells likely contributed to our patient’s acutely worsening condition. Several studies have found that the presence of a BCOR mutation in adults with AML leads to lower overall survival and relapse-free survival.^11,12 As of now, there are no treatments specifically targeting BCOR mutations.

Conclusions

For our patient with AML, sequential targeted management of FLT3-TKD and IDH1 mutations was not beneficial. Higher-risk disease features, such as the development of a complex karyotype, likely contributed to our patient’s poor response to second-line ivosidenib. The sequential NGS malignant hematology panels allowed us to closely monitor changes to the molecular structure of our patient’s AML after each line of targeted therapy. Future investigations of combining targeted agents for patients with AML with concurrent actionable mutations would provide insight into outcomes of treating multiple clonal populations simultaneously.

Nearly 20,000 patients are diagnosed with acute myeloid leukemia (AML) in the US annually.¹ Despite the use of aggressive chemotherapeutic agents, the prognosis remains poor, with a mean 5-year survival of 28.3%.² Fortunately, with the refinement of next-generation sequencing (NGS) hematology panels and development of systemic targeted therapies, the treatment landscape for eligible patients has improved, both in frontline and relapsed or refractory (R/R) patients.

Specifically, investigations into alterations within the FMS-like tyrosine kinase (FLT3) and isocitrate dehydrogenase (IDH) genes have led to the discovery of a number of targeted treatments. Midostaurin is US Food and Drug Administration (FDA)-approved for use in combination with induction chemotherapy for patients with internal tandem duplication of the FLT3 (FLT3-ITD) gene or mutations within the tyrosine kinase domain (FLT3-TKD).³ Ivosidenib is indicated for frontline treatment for those who are poor candidates for induction chemotherapy, and R/R patients who have an R132H mutation in IDH1.^4,5 Enasidenib is FDA-approved for R/R patients with R140Q, R172S, and R172K mutations in IDH2.⁶

The optimal treatment for patients with AML with ≥ 2 clinically actionable mutations has not been established. In this article we describe a geriatric patient who initially was diagnosed with AML with concurrent FLT3-TKD and IDH1 mutations and received targeted, sequential management. We detail changes in disease phenotype and mutational status by repeating an NGS hematology panel and cytogenetic studies after each stage of therapy. Lastly, we discuss the clonal evolution apparent within leukemic cells with use of ≥ 1 or more targeted agents.

Case Presentation

A 68-year-old man presented to the Emergency Department at The Durham Veterans Affairs Medical Center in North Carolina with fatigue and light-headedness. Because of his symptoms and pancytopenia, a bone marrow aspiration and trephine biopsy were performed, which showed 57% myeloblasts, 12% promyelocytes/myelocytes, and 2% metamyelocytes in 20 to 30% cellular bone marrow. Flow cytometry confirmed a blast population consistent with AML. A LeukoVantage (Quest Diagnostics) hematologic NGS panel revealed the presence of FLT3-TKD, IDH1, RUNX1, BCOR-E1477, and SF3B1 mutations (Table). Initial fluorescence in situ hybridization (FISH) results showed a normal pattern of hybridization with no translocations. His disease was deemed to be intermediate-high risk because of the presence of FLT3-TKD and RUNX1 mutations, despite the normal cytogenetic profile and absence of additional clinical features.

Induction chemotherapy was started with idarubicin, 12 mg/m², on days 1 to 3 and cytarabine, 200 mg/m², on days 1 to 7. Because of the presence of a FLT3-TKD mutation, midostaurin was planned for days 8 to 21. After induction chemotherapy, a bone marrow biopsy on day 14 revealed an acellular marrow with no observed myeloblasts. A bone marrow biopsy conducted before initiating consolidation therapy, revealed 30% cellularity with morphologic remission. However, flow cytometry found 5% myeloblasts expressing CD34, CD117, CD13, CD38, and HLA-DR, consistent with measurable residual disease. He received 2 cycles of consolidation therapy with high-dose cytarabine combined with midostaurin. After the patient's second cycle of consolidation, he continued to experience transfusion-dependent cytopenias. Another bone marrow evaluation demonstrated 10% cellularity with nearly all cells appearing to be myeloblasts. A repeat LeukoVantage NGS panel demonstrated undetectable FLT3-TKD mutation and persistent IDH1-R123C mutation. FISH studies revealed a complex karyotype with monosomy of chromosomes 5 and 7 and trisomy of chromosome 8.

We discussed with the patient and his family the options available, which included initiating targeted therapy for his IDH1 mutation, administering hypomethylation therapy with or without venetoclax, or pursuing palliative measures. We collectively decided to pursue therapy with single-agent oral ivosidenib, 500 mg daily. After 1 month of treatment, our patient developed worsening fatigue. His white blood cell count had increased to > 43 k/cm², raising concern for differentiation syndrome.

A review of the peripheral smear showed a wide-spectrum of maturing granulocytes, with a large percentage of blasts. Peripheral flow cytometry confirmed a blast population of 15%. After a short period of symptom improvement with steroids, the patient developed worsening confusion. Brain imaging identified 2 subdural hemorrhages. Because of a significant peripheral blast population and the development of these hemorrhages, palliative measures were pursued, and the patient was discharged to an inpatient hospice facility. A final NGS panel performed from peripheral blood detected mutations in IDH1, RUNX1, PTPN11, NRAS, BCOR-E1443, and SF3B1 genes.

Discussion

To our knowledge, this is the first reported case of a patient who sequentially received targeted treatments directed against both FLT3 and IDH1 mutations. Initial management with midostaurin and cytarabine resulted in sustained remission of his FLT3-TKD mutation. However, despite receiving prompt standard of care with combination induction chemotherapy and targeted therapy, the patient experienced unfavorable clonal evolution based upon his molecular and cytogenetic testing. Addition of ivosidenib as a second targeting agent for his IDH1 mutation did not achieve a second remission.

Clonal evolution is a well-described phenomenon in hematology. Indolent conditions, such as clonal hematopoiesis of intermediate potential, or malignancies, such as myelodysplastic syndromes and myeloproliferative neoplasms, could transform into acute leukemia through the accumulation of driver mutations and/or cytogenetic abnormalities. Clonal evolution often is viewed as the culprit in patients with AML whose disease relapses after remission with initial chemotherapy.^7-10 With the increasing availability of commercial NGS panels designed to assess mutations among patients experiencing hematologic malignancies, patterns of relapse, and, models of clonal evolution could be observed closely in patients with AML.

We were able to monitor molecular changes within our patient’s predominant clonal populations by repeating peripheral comprehensive NGS panels after lines of targeted therapies. The repeated sequencing revealed that clones with FLT3-TKD mutations responded to midostaurin with first-line chemotherapy whereas it was unclear whether clones with IDH1 mutation responded to ivosidenib. Development of complex cytogenetic findings along with the clonal expansion of BCOR mutation-harboring cells likely contributed to our patient’s acutely worsening condition. Several studies have found that the presence of a BCOR mutation in adults with AML leads to lower overall survival and relapse-free survival.^11,12 As of now, there are no treatments specifically targeting BCOR mutations.

Conclusions

For our patient with AML, sequential targeted management of FLT3-TKD and IDH1 mutations was not beneficial. Higher-risk disease features, such as the development of a complex karyotype, likely contributed to our patient’s poor response to second-line ivosidenib. The sequential NGS malignant hematology panels allowed us to closely monitor changes to the molecular structure of our patient’s AML after each line of targeted therapy. Future investigations of combining targeted agents for patients with AML with concurrent actionable mutations would provide insight into outcomes of treating multiple clonal populations simultaneously.

Nearly 20,000 patients are diagnosed with acute myeloid leukemia (AML) in the US annually.¹ Despite the use of aggressive chemotherapeutic agents, the prognosis remains poor, with a mean 5-year survival of 28.3%.² Fortunately, with the refinement of next-generation sequencing (NGS) hematology panels and development of systemic targeted therapies, the treatment landscape for eligible patients has improved, both in frontline and relapsed or refractory (R/R) patients.

Specifically, investigations into alterations within the FMS-like tyrosine kinase (FLT3) and isocitrate dehydrogenase (IDH) genes have led to the discovery of a number of targeted treatments. Midostaurin is US Food and Drug Administration (FDA)-approved for use in combination with induction chemotherapy for patients with internal tandem duplication of the FLT3 (FLT3-ITD) gene or mutations within the tyrosine kinase domain (FLT3-TKD).³ Ivosidenib is indicated for frontline treatment for those who are poor candidates for induction chemotherapy, and R/R patients who have an R132H mutation in IDH1.^4,5 Enasidenib is FDA-approved for R/R patients with R140Q, R172S, and R172K mutations in IDH2.⁶

The optimal treatment for patients with AML with ≥ 2 clinically actionable mutations has not been established. In this article we describe a geriatric patient who initially was diagnosed with AML with concurrent FLT3-TKD and IDH1 mutations and received targeted, sequential management. We detail changes in disease phenotype and mutational status by repeating an NGS hematology panel and cytogenetic studies after each stage of therapy. Lastly, we discuss the clonal evolution apparent within leukemic cells with use of ≥ 1 or more targeted agents.

Case Presentation

A 68-year-old man presented to the Emergency Department at The Durham Veterans Affairs Medical Center in North Carolina with fatigue and light-headedness. Because of his symptoms and pancytopenia, a bone marrow aspiration and trephine biopsy were performed, which showed 57% myeloblasts, 12% promyelocytes/myelocytes, and 2% metamyelocytes in 20 to 30% cellular bone marrow. Flow cytometry confirmed a blast population consistent with AML. A LeukoVantage (Quest Diagnostics) hematologic NGS panel revealed the presence of FLT3-TKD, IDH1, RUNX1, BCOR-E1477, and SF3B1 mutations (Table). Initial fluorescence in situ hybridization (FISH) results showed a normal pattern of hybridization with no translocations. His disease was deemed to be intermediate-high risk because of the presence of FLT3-TKD and RUNX1 mutations, despite the normal cytogenetic profile and absence of additional clinical features.

Induction chemotherapy was started with idarubicin, 12 mg/m², on days 1 to 3 and cytarabine, 200 mg/m², on days 1 to 7. Because of the presence of a FLT3-TKD mutation, midostaurin was planned for days 8 to 21. After induction chemotherapy, a bone marrow biopsy on day 14 revealed an acellular marrow with no observed myeloblasts. A bone marrow biopsy conducted before initiating consolidation therapy, revealed 30% cellularity with morphologic remission. However, flow cytometry found 5% myeloblasts expressing CD34, CD117, CD13, CD38, and HLA-DR, consistent with measurable residual disease. He received 2 cycles of consolidation therapy with high-dose cytarabine combined with midostaurin. After the patient's second cycle of consolidation, he continued to experience transfusion-dependent cytopenias. Another bone marrow evaluation demonstrated 10% cellularity with nearly all cells appearing to be myeloblasts. A repeat LeukoVantage NGS panel demonstrated undetectable FLT3-TKD mutation and persistent IDH1-R123C mutation. FISH studies revealed a complex karyotype with monosomy of chromosomes 5 and 7 and trisomy of chromosome 8.

We discussed with the patient and his family the options available, which included initiating targeted therapy for his IDH1 mutation, administering hypomethylation therapy with or without venetoclax, or pursuing palliative measures. We collectively decided to pursue therapy with single-agent oral ivosidenib, 500 mg daily. After 1 month of treatment, our patient developed worsening fatigue. His white blood cell count had increased to > 43 k/cm², raising concern for differentiation syndrome.

A review of the peripheral smear showed a wide-spectrum of maturing granulocytes, with a large percentage of blasts. Peripheral flow cytometry confirmed a blast population of 15%. After a short period of symptom improvement with steroids, the patient developed worsening confusion. Brain imaging identified 2 subdural hemorrhages. Because of a significant peripheral blast population and the development of these hemorrhages, palliative measures were pursued, and the patient was discharged to an inpatient hospice facility. A final NGS panel performed from peripheral blood detected mutations in IDH1, RUNX1, PTPN11, NRAS, BCOR-E1443, and SF3B1 genes.

Discussion

To our knowledge, this is the first reported case of a patient who sequentially received targeted treatments directed against both FLT3 and IDH1 mutations. Initial management with midostaurin and cytarabine resulted in sustained remission of his FLT3-TKD mutation. However, despite receiving prompt standard of care with combination induction chemotherapy and targeted therapy, the patient experienced unfavorable clonal evolution based upon his molecular and cytogenetic testing. Addition of ivosidenib as a second targeting agent for his IDH1 mutation did not achieve a second remission.

Clonal evolution is a well-described phenomenon in hematology. Indolent conditions, such as clonal hematopoiesis of intermediate potential, or malignancies, such as myelodysplastic syndromes and myeloproliferative neoplasms, could transform into acute leukemia through the accumulation of driver mutations and/or cytogenetic abnormalities. Clonal evolution often is viewed as the culprit in patients with AML whose disease relapses after remission with initial chemotherapy.^7-10 With the increasing availability of commercial NGS panels designed to assess mutations among patients experiencing hematologic malignancies, patterns of relapse, and, models of clonal evolution could be observed closely in patients with AML.

We were able to monitor molecular changes within our patient’s predominant clonal populations by repeating peripheral comprehensive NGS panels after lines of targeted therapies. The repeated sequencing revealed that clones with FLT3-TKD mutations responded to midostaurin with first-line chemotherapy whereas it was unclear whether clones with IDH1 mutation responded to ivosidenib. Development of complex cytogenetic findings along with the clonal expansion of BCOR mutation-harboring cells likely contributed to our patient’s acutely worsening condition. Several studies have found that the presence of a BCOR mutation in adults with AML leads to lower overall survival and relapse-free survival.^11,12 As of now, there are no treatments specifically targeting BCOR mutations.

Conclusions

For our patient with AML, sequential targeted management of FLT3-TKD and IDH1 mutations was not beneficial. Higher-risk disease features, such as the development of a complex karyotype, likely contributed to our patient’s poor response to second-line ivosidenib. The sequential NGS malignant hematology panels allowed us to closely monitor changes to the molecular structure of our patient’s AML after each line of targeted therapy. Future investigations of combining targeted agents for patients with AML with concurrent actionable mutations would provide insight into outcomes of treating multiple clonal populations simultaneously.

Mastocytosis is a rare disease that causes allergic and anaphylactic symptoms due to chronic or episodic, excessive mast cell degranulation as well as mast cell infiltration of the skin or other organs.¹ Mast cells aid in innate immunity by generation of a vasodilatory and inflammatory response and are significant contributors to allergic reactions. Cutaneous mastocytosis is defined by isolated skin involvement. Systemic mastocytosis (SM) is characterized by mast cell infiltration of extracutaneous organs, most often bone marrow.²

Background

SM is divided into distinct subtypes (Table 1). Nonadvanced SM subtypes include indolent SM and smoldering SM. These are the most common forms and tend to have more slowly progressing courses without evidence of organ tissue dysfunction, a myelodysplastic syndrome, or of a myeloproliferative disorder.³ Advanced SM is less common and is associated with organ tissue dysfunction. It also may be associated with myeloproliferative, myelodysplastic, or lymphoproliferative hematologic neoplasms, and subtypes include aggressive SM, SM with an associated hematologic neoplasm, and mast cell leukemia (Table 2).⁴

Treatment options approved by the US Food and Drug Administration (FDA) for advanced SM include disease-altering medications, such as tyrosine kinase inhibitors (eg, imatinib), but the approved treatment options for nonadvanced SM are generally aimed at managing only symptoms (Table 3). Although not approved by the FDA for the treatment of SM, omalizumab may aid in the prevention of anaphylaxis, the reduction of disease burden, and the improvement in quality of life for patients with SM.⁵ Omalizumab is a humanized monoclonal antibody against the Fc portion of immunoglobulin E (IgE). It is approved by the FDA for treatment of asthma as well as chronic idiopathic urticaria.⁶

Case Presentation

A 32-year-old female initially presented to Womack Army Medical Center at Fort Bragg, North Carolina, for evaluation due to recurrent episodes of anaphylaxis occurring 1 to 2 times per month as well as chronic skin rashes that progressed over the previous 5 years (Figure). She initially was diagnosed with idiopathic anaphylaxis and subsequently had multiple emergency department (ED) and clinic visits for vasovagal syncope, unexplained allergic reactions, dizziness, giddiness, and shortness of breath. More recently, she was diagnosed with idiopathic urticaria.

The patient reported at least 12 episodes in the previous year involving facial flushing that proceeded inferiorly, chest tightness, shortness of breath, labored breathing, crampy abdominal pain, and nausea without urticaria or significant pruritus. These bouts often were accompanied by mild facial angioedema, acute sinus pressure, vomiting, tachycardia, and lightheadedness. She reported experiencing brief losses of consciousness with at least 4 of these episodes. Home and ED blood pressure measurements revealed hypotension on several occasions with systolic readings in the 80s. She also developed nonpruritic freckles on her upper chest initially with subsequent increase in number and spread to involve her entire trunk, proximal extremities, and eventually distal extremities.

Discussion

Mast cell overactivation and degranulation in mastocytosis is largely driven by the IgE antibody, which plays a significant role in atopic conditions, immediate hypersensitivity reactions, and anaphylaxis, as well as in the immunologic response to parasitic infections. The severity of atopic disease seems to be associated with serum IgE levels in many patients.⁷ IgE binding to surface receptors on mast cells and eosinophils prompts the release of toxic mediators, incites inflammation, and induces allergic symptoms.⁸ Activation of mast cells is classically elicited by IgE binding to the high-affinity Fcε RI receptor, the expression of which correlates with IgE levels.⁹

The anti-IgE, recombinant, humanized immunoglobulin G monoclonal antibody, omalizumab, decreases mastocytic and eosinophilic symptoms by binding and inhibiting IgE. This diminishes free IgE levels, inhibits IgE binding to the Fcε RI receptor, and affects downregulation of this high-affinity receptor on mast cells and basophils.⁶ Omalizumab is currently FDA approved only for the treatment of moderate-to-severe, persistent, allergic asthma that is not controlled by inhaled corticosteroids in patients aged ≥ 6 years, and for chronic idiopathic urticaria not controlled by H1 antihistamine therapy in patients aged ≥ 12 years.¹⁰ However, it stands to reason that this therapy also should be effective in the treatment of other poorly controlled atopic conditions, especially mastocytosis, the symptoms of which are driven by excessive mast cell degranulation and tissue infiltration.

As early as 2007, preliminary data showed that treatment with omalizumab could decrease the frequency of episodes of anaphylaxis.¹¹ A National Institutes of Health case report followed 2 patients, one for 5 months and the other for 24 months. Both patients experienced a decrease in frequency of anaphylaxis following initiation of omalizumab. In 2010, a second case report described the treatment of an Australian patient with recurrent idiopathic anaphylaxis also diagnosed with SM. After initiation of treatment with omalizumab, she, too, experienced decreased frequency of episodes of anaphylaxis over 14 months.¹² A review of patients treated at the Mastocytosis Centre Odense University Hospital in Denmark was published in 2017. Of 13 patients with SM treated with omalizumab, 5 experienced what was considered a complete response to the medication, with 3 each experiencing major and partial responses.⁵ The median treatment time in these patients was 27 months. Each of these cases showed significant promise in the use of omalizumab to treat SM, informing the decision to attempt this treatment in our patient.

The potential positive effects of omalizumab in reducing symptom severity in patients with SM was further supported by a 2017 meta-analysis. This review included several individual case reports noting that omalizumab could decrease frequency of pulmonary and gastrointestinal manifestations of SM.¹³ A small randomized control trial of omalizumab for treatment of mild symptoms of SM found improvement in disease severity, although neither primary nor secondary endpoints reached statistical significance.¹⁴

This case demonstrates a substantial, long-term, clinical benefit and quality of life improvement with omalizumab therapy in a patient with indolent SM that was not adequately controlled by conventional therapies. This is evidenced by an impressive decline in the frequency of mastocytic anaphylactic episodes as well as diminished patient-endorsed cutaneous symptoms.

This case provides further evidence of the efficacy of this therapy in diminishing disease burden for patients with SM who are otherwise limited to treatments aimed at transient symptomatic relief without significant alteration of the underlying cause of symptoms. At the time this article was written, our patient had now 52 months of continuous treatment without any adverse reactions noted, suggesting the treatment's long-term efficacy. It also adds to a small but growing body of literature that supports the use of anti-IgE therapy as a treatment option for improved management of this distressing, life-altering illness. Even in the time that our patient has been receiving omalizumab for SM, another small case series of 2 patients has been published showing sustained treatment effect at 12 years of therapy.¹⁵ This adds further insight that omalizumab can offer long-term, safe treatment for this limiting condition.

Omalizumab therapy is not without risk, but for patients afflicted by unrestrained mastocytic disease, the benefits may outweigh the risks. The most common significant risk with this medication is anaphylaxis, occurring in 1 to 2 per 1,000 patients, usually within 2 hours of an injection.¹⁶ This may correlate to the underlying degree of atopy in patients receiving omalizumab, and the risk of anaphylaxis is relatively low compared with that of many other biologic medications.¹⁷ Additionally, early data from initial phases of clinical trials indicated a potentially elevated malignancy risk with omalizumab. However, subsequent pooled analysis of larger numbers of patients has decreased suspicion that a causal relationship exists.¹⁸

Conclusions

Omalizumab has proven value in the treatment of atopic conditions, such as asthma and idiopathic urticaria, for which it has been approved for use by the FDA. Its effectiveness in significantly decreasing free serum IgE levels, and inhibiting IgE activation of mast cells makes it a possible treatment option for patients with SM who are not sufficiently controlled with conventional therapy. The findings in this case suggest that omalizumab may be effective in the prevention of anaphylaxis and in the reduction of disease burden associated with SM. Further studies and formal clinical trials are needed to confirm these findings. Patients should be counseled appropriately concerning the risks, benefits, and off-label status of this treatment option.

Mastocytosis is a rare disease that causes allergic and anaphylactic symptoms due to chronic or episodic, excessive mast cell degranulation as well as mast cell infiltration of the skin or other organs.¹ Mast cells aid in innate immunity by generation of a vasodilatory and inflammatory response and are significant contributors to allergic reactions. Cutaneous mastocytosis is defined by isolated skin involvement. Systemic mastocytosis (SM) is characterized by mast cell infiltration of extracutaneous organs, most often bone marrow.²

Background

SM is divided into distinct subtypes (Table 1). Nonadvanced SM subtypes include indolent SM and smoldering SM. These are the most common forms and tend to have more slowly progressing courses without evidence of organ tissue dysfunction, a myelodysplastic syndrome, or of a myeloproliferative disorder.³ Advanced SM is less common and is associated with organ tissue dysfunction. It also may be associated with myeloproliferative, myelodysplastic, or lymphoproliferative hematologic neoplasms, and subtypes include aggressive SM, SM with an associated hematologic neoplasm, and mast cell leukemia (Table 2).⁴

Treatment options approved by the US Food and Drug Administration (FDA) for advanced SM include disease-altering medications, such as tyrosine kinase inhibitors (eg, imatinib), but the approved treatment options for nonadvanced SM are generally aimed at managing only symptoms (Table 3). Although not approved by the FDA for the treatment of SM, omalizumab may aid in the prevention of anaphylaxis, the reduction of disease burden, and the improvement in quality of life for patients with SM.⁵ Omalizumab is a humanized monoclonal antibody against the Fc portion of immunoglobulin E (IgE). It is approved by the FDA for treatment of asthma as well as chronic idiopathic urticaria.⁶

Case Presentation

A 32-year-old female initially presented to Womack Army Medical Center at Fort Bragg, North Carolina, for evaluation due to recurrent episodes of anaphylaxis occurring 1 to 2 times per month as well as chronic skin rashes that progressed over the previous 5 years (Figure). She initially was diagnosed with idiopathic anaphylaxis and subsequently had multiple emergency department (ED) and clinic visits for vasovagal syncope, unexplained allergic reactions, dizziness, giddiness, and shortness of breath. More recently, she was diagnosed with idiopathic urticaria.

The patient reported at least 12 episodes in the previous year involving facial flushing that proceeded inferiorly, chest tightness, shortness of breath, labored breathing, crampy abdominal pain, and nausea without urticaria or significant pruritus. These bouts often were accompanied by mild facial angioedema, acute sinus pressure, vomiting, tachycardia, and lightheadedness. She reported experiencing brief losses of consciousness with at least 4 of these episodes. Home and ED blood pressure measurements revealed hypotension on several occasions with systolic readings in the 80s. She also developed nonpruritic freckles on her upper chest initially with subsequent increase in number and spread to involve her entire trunk, proximal extremities, and eventually distal extremities.

Discussion

Mast cell overactivation and degranulation in mastocytosis is largely driven by the IgE antibody, which plays a significant role in atopic conditions, immediate hypersensitivity reactions, and anaphylaxis, as well as in the immunologic response to parasitic infections. The severity of atopic disease seems to be associated with serum IgE levels in many patients.⁷ IgE binding to surface receptors on mast cells and eosinophils prompts the release of toxic mediators, incites inflammation, and induces allergic symptoms.⁸ Activation of mast cells is classically elicited by IgE binding to the high-affinity Fcε RI receptor, the expression of which correlates with IgE levels.⁹

The anti-IgE, recombinant, humanized immunoglobulin G monoclonal antibody, omalizumab, decreases mastocytic and eosinophilic symptoms by binding and inhibiting IgE. This diminishes free IgE levels, inhibits IgE binding to the Fcε RI receptor, and affects downregulation of this high-affinity receptor on mast cells and basophils.⁶ Omalizumab is currently FDA approved only for the treatment of moderate-to-severe, persistent, allergic asthma that is not controlled by inhaled corticosteroids in patients aged ≥ 6 years, and for chronic idiopathic urticaria not controlled by H1 antihistamine therapy in patients aged ≥ 12 years.¹⁰ However, it stands to reason that this therapy also should be effective in the treatment of other poorly controlled atopic conditions, especially mastocytosis, the symptoms of which are driven by excessive mast cell degranulation and tissue infiltration.

As early as 2007, preliminary data showed that treatment with omalizumab could decrease the frequency of episodes of anaphylaxis.¹¹ A National Institutes of Health case report followed 2 patients, one for 5 months and the other for 24 months. Both patients experienced a decrease in frequency of anaphylaxis following initiation of omalizumab. In 2010, a second case report described the treatment of an Australian patient with recurrent idiopathic anaphylaxis also diagnosed with SM. After initiation of treatment with omalizumab, she, too, experienced decreased frequency of episodes of anaphylaxis over 14 months.¹² A review of patients treated at the Mastocytosis Centre Odense University Hospital in Denmark was published in 2017. Of 13 patients with SM treated with omalizumab, 5 experienced what was considered a complete response to the medication, with 3 each experiencing major and partial responses.⁵ The median treatment time in these patients was 27 months. Each of these cases showed significant promise in the use of omalizumab to treat SM, informing the decision to attempt this treatment in our patient.

The potential positive effects of omalizumab in reducing symptom severity in patients with SM was further supported by a 2017 meta-analysis. This review included several individual case reports noting that omalizumab could decrease frequency of pulmonary and gastrointestinal manifestations of SM.¹³ A small randomized control trial of omalizumab for treatment of mild symptoms of SM found improvement in disease severity, although neither primary nor secondary endpoints reached statistical significance.¹⁴

This case demonstrates a substantial, long-term, clinical benefit and quality of life improvement with omalizumab therapy in a patient with indolent SM that was not adequately controlled by conventional therapies. This is evidenced by an impressive decline in the frequency of mastocytic anaphylactic episodes as well as diminished patient-endorsed cutaneous symptoms.

This case provides further evidence of the efficacy of this therapy in diminishing disease burden for patients with SM who are otherwise limited to treatments aimed at transient symptomatic relief without significant alteration of the underlying cause of symptoms. At the time this article was written, our patient had now 52 months of continuous treatment without any adverse reactions noted, suggesting the treatment's long-term efficacy. It also adds to a small but growing body of literature that supports the use of anti-IgE therapy as a treatment option for improved management of this distressing, life-altering illness. Even in the time that our patient has been receiving omalizumab for SM, another small case series of 2 patients has been published showing sustained treatment effect at 12 years of therapy.¹⁵ This adds further insight that omalizumab can offer long-term, safe treatment for this limiting condition.

Omalizumab therapy is not without risk, but for patients afflicted by unrestrained mastocytic disease, the benefits may outweigh the risks. The most common significant risk with this medication is anaphylaxis, occurring in 1 to 2 per 1,000 patients, usually within 2 hours of an injection.¹⁶ This may correlate to the underlying degree of atopy in patients receiving omalizumab, and the risk of anaphylaxis is relatively low compared with that of many other biologic medications.¹⁷ Additionally, early data from initial phases of clinical trials indicated a potentially elevated malignancy risk with omalizumab. However, subsequent pooled analysis of larger numbers of patients has decreased suspicion that a causal relationship exists.¹⁸

Conclusions

Omalizumab has proven value in the treatment of atopic conditions, such as asthma and idiopathic urticaria, for which it has been approved for use by the FDA. Its effectiveness in significantly decreasing free serum IgE levels, and inhibiting IgE activation of mast cells makes it a possible treatment option for patients with SM who are not sufficiently controlled with conventional therapy. The findings in this case suggest that omalizumab may be effective in the prevention of anaphylaxis and in the reduction of disease burden associated with SM. Further studies and formal clinical trials are needed to confirm these findings. Patients should be counseled appropriately concerning the risks, benefits, and off-label status of this treatment option.

Mastocytosis is a rare disease that causes allergic and anaphylactic symptoms due to chronic or episodic, excessive mast cell degranulation as well as mast cell infiltration of the skin or other organs.¹ Mast cells aid in innate immunity by generation of a vasodilatory and inflammatory response and are significant contributors to allergic reactions. Cutaneous mastocytosis is defined by isolated skin involvement. Systemic mastocytosis (SM) is characterized by mast cell infiltration of extracutaneous organs, most often bone marrow.²

Background

SM is divided into distinct subtypes (Table 1). Nonadvanced SM subtypes include indolent SM and smoldering SM. These are the most common forms and tend to have more slowly progressing courses without evidence of organ tissue dysfunction, a myelodysplastic syndrome, or of a myeloproliferative disorder.³ Advanced SM is less common and is associated with organ tissue dysfunction. It also may be associated with myeloproliferative, myelodysplastic, or lymphoproliferative hematologic neoplasms, and subtypes include aggressive SM, SM with an associated hematologic neoplasm, and mast cell leukemia (Table 2).⁴

Treatment options approved by the US Food and Drug Administration (FDA) for advanced SM include disease-altering medications, such as tyrosine kinase inhibitors (eg, imatinib), but the approved treatment options for nonadvanced SM are generally aimed at managing only symptoms (Table 3). Although not approved by the FDA for the treatment of SM, omalizumab may aid in the prevention of anaphylaxis, the reduction of disease burden, and the improvement in quality of life for patients with SM.⁵ Omalizumab is a humanized monoclonal antibody against the Fc portion of immunoglobulin E (IgE). It is approved by the FDA for treatment of asthma as well as chronic idiopathic urticaria.⁶

Case Presentation

A 32-year-old female initially presented to Womack Army Medical Center at Fort Bragg, North Carolina, for evaluation due to recurrent episodes of anaphylaxis occurring 1 to 2 times per month as well as chronic skin rashes that progressed over the previous 5 years (Figure). She initially was diagnosed with idiopathic anaphylaxis and subsequently had multiple emergency department (ED) and clinic visits for vasovagal syncope, unexplained allergic reactions, dizziness, giddiness, and shortness of breath. More recently, she was diagnosed with idiopathic urticaria.

The patient reported at least 12 episodes in the previous year involving facial flushing that proceeded inferiorly, chest tightness, shortness of breath, labored breathing, crampy abdominal pain, and nausea without urticaria or significant pruritus. These bouts often were accompanied by mild facial angioedema, acute sinus pressure, vomiting, tachycardia, and lightheadedness. She reported experiencing brief losses of consciousness with at least 4 of these episodes. Home and ED blood pressure measurements revealed hypotension on several occasions with systolic readings in the 80s. She also developed nonpruritic freckles on her upper chest initially with subsequent increase in number and spread to involve her entire trunk, proximal extremities, and eventually distal extremities.

Discussion

Mast cell overactivation and degranulation in mastocytosis is largely driven by the IgE antibody, which plays a significant role in atopic conditions, immediate hypersensitivity reactions, and anaphylaxis, as well as in the immunologic response to parasitic infections. The severity of atopic disease seems to be associated with serum IgE levels in many patients.⁷ IgE binding to surface receptors on mast cells and eosinophils prompts the release of toxic mediators, incites inflammation, and induces allergic symptoms.⁸ Activation of mast cells is classically elicited by IgE binding to the high-affinity Fcε RI receptor, the expression of which correlates with IgE levels.⁹

The anti-IgE, recombinant, humanized immunoglobulin G monoclonal antibody, omalizumab, decreases mastocytic and eosinophilic symptoms by binding and inhibiting IgE. This diminishes free IgE levels, inhibits IgE binding to the Fcε RI receptor, and affects downregulation of this high-affinity receptor on mast cells and basophils.⁶ Omalizumab is currently FDA approved only for the treatment of moderate-to-severe, persistent, allergic asthma that is not controlled by inhaled corticosteroids in patients aged ≥ 6 years, and for chronic idiopathic urticaria not controlled by H1 antihistamine therapy in patients aged ≥ 12 years.¹⁰ However, it stands to reason that this therapy also should be effective in the treatment of other poorly controlled atopic conditions, especially mastocytosis, the symptoms of which are driven by excessive mast cell degranulation and tissue infiltration.

As early as 2007, preliminary data showed that treatment with omalizumab could decrease the frequency of episodes of anaphylaxis.¹¹ A National Institutes of Health case report followed 2 patients, one for 5 months and the other for 24 months. Both patients experienced a decrease in frequency of anaphylaxis following initiation of omalizumab. In 2010, a second case report described the treatment of an Australian patient with recurrent idiopathic anaphylaxis also diagnosed with SM. After initiation of treatment with omalizumab, she, too, experienced decreased frequency of episodes of anaphylaxis over 14 months.¹² A review of patients treated at the Mastocytosis Centre Odense University Hospital in Denmark was published in 2017. Of 13 patients with SM treated with omalizumab, 5 experienced what was considered a complete response to the medication, with 3 each experiencing major and partial responses.⁵ The median treatment time in these patients was 27 months. Each of these cases showed significant promise in the use of omalizumab to treat SM, informing the decision to attempt this treatment in our patient.

The potential positive effects of omalizumab in reducing symptom severity in patients with SM was further supported by a 2017 meta-analysis. This review included several individual case reports noting that omalizumab could decrease frequency of pulmonary and gastrointestinal manifestations of SM.¹³ A small randomized control trial of omalizumab for treatment of mild symptoms of SM found improvement in disease severity, although neither primary nor secondary endpoints reached statistical significance.¹⁴

This case demonstrates a substantial, long-term, clinical benefit and quality of life improvement with omalizumab therapy in a patient with indolent SM that was not adequately controlled by conventional therapies. This is evidenced by an impressive decline in the frequency of mastocytic anaphylactic episodes as well as diminished patient-endorsed cutaneous symptoms.

This case provides further evidence of the efficacy of this therapy in diminishing disease burden for patients with SM who are otherwise limited to treatments aimed at transient symptomatic relief without significant alteration of the underlying cause of symptoms. At the time this article was written, our patient had now 52 months of continuous treatment without any adverse reactions noted, suggesting the treatment's long-term efficacy. It also adds to a small but growing body of literature that supports the use of anti-IgE therapy as a treatment option for improved management of this distressing, life-altering illness. Even in the time that our patient has been receiving omalizumab for SM, another small case series of 2 patients has been published showing sustained treatment effect at 12 years of therapy.¹⁵ This adds further insight that omalizumab can offer long-term, safe treatment for this limiting condition.

Omalizumab therapy is not without risk, but for patients afflicted by unrestrained mastocytic disease, the benefits may outweigh the risks. The most common significant risk with this medication is anaphylaxis, occurring in 1 to 2 per 1,000 patients, usually within 2 hours of an injection.¹⁶ This may correlate to the underlying degree of atopy in patients receiving omalizumab, and the risk of anaphylaxis is relatively low compared with that of many other biologic medications.¹⁷ Additionally, early data from initial phases of clinical trials indicated a potentially elevated malignancy risk with omalizumab. However, subsequent pooled analysis of larger numbers of patients has decreased suspicion that a causal relationship exists.¹⁸

Conclusions

Omalizumab has proven value in the treatment of atopic conditions, such as asthma and idiopathic urticaria, for which it has been approved for use by the FDA. Its effectiveness in significantly decreasing free serum IgE levels, and inhibiting IgE activation of mast cells makes it a possible treatment option for patients with SM who are not sufficiently controlled with conventional therapy. The findings in this case suggest that omalizumab may be effective in the prevention of anaphylaxis and in the reduction of disease burden associated with SM. Further studies and formal clinical trials are needed to confirm these findings. Patients should be counseled appropriately concerning the risks, benefits, and off-label status of this treatment option.

Case Report

A 67-year-old Black woman presented with a long-standing history of pruritus and “scaly thick bumps” on the lower extremities. Upon further questioning, she reported a 30-year history of placing her feet by an electric space heater and daily baths in “very hot” water. A review of systems and medical history were unremarkable, and the patient was not on any medications. Initial physical examination of the lower extremities demonstrated lichenified plaques and scattered, firm, ulcerated nodules surrounded by mottled postinflammatory hyperpigmentation with sharp demarcation at the midcalf bilaterally (Figure 1).

Subsequently, the patient was shown to have multiple actinic keratoses and SCCs, both in situ and invasive, within the areas of EAI (Figure 2). The patient had no actinic keratoses or other cutaneous malignant neoplasms elsewhere on the skin. Management of actinic keratoses, SCC in situ, and invasive SCC on the lower extremities included numerous excisions, treatment with liquid nitrogen, and topical 5-fluorouracil under occlusion. The patient continues to be monitored frequently.

Comment

Presentation of EAI
Erythema ab igne is a cutaneous reaction resulting from prolonged exposure to an infrared heat source at temperatures insufficient to cause a burn (37 °F to 113 °F [2.78 °C to 45 °C]). Initially presenting as transient blanchable erythema, chronic heat exposure induces persistent areas of reticular erythema, often accompanied by hyperpigmentation, epidermal atrophy, and telangiectases.¹ Erythema ab igne is most commonly reported on the anterior shins, inner thighs, and back, and it is historically associated with open fires and coal stoves. More recently, other implicated causes include heating pads, laptop computers, heated furniture, and electric space heaters.^2,3 Erythema ab igne often is asymptomatic but can present with pruritus and a burning sensation. Treatment involves removal of the inciting heat source, which might allow resolution of early-stage lesions. Long-term exposure leads to permanent skin discoloration and on occasion predisposes patients to malignant transformation.³

Histopathology of EAI
Histologically, later stages of EAI can demonstrate focal hyperkeratosis with dyskeratosis and increased dermal elastosis, similar to actinic damage, with a predisposition to develop SCC.² Notably, early reports document various heat-induced carcinomas, including kangri-burn cancers among Kashmiris, kang thermal cancers in China, and kairo cancers in Japan.^2,4,5 More recent reports identify cutaneous carcinomas arising specifically in the setting of EAI, most commonly SCC³; Merkel cell carcinoma and cutaneous marginal zone lymphoma are less commonly reported malignancies.^6,7 Given the frequency of malignant transformation within sites of thermal exposure, chronic heat exposure may share a common pathophysiology with SCC and other neoplasms, including Merkel cell carcinoma and cutaneous marginal zone lymphoma.

SCC in Black Individuals
Squamous cell carcinoma is the most common skin cancer in Black individuals, with a notably higher incidence in high-risk subpopulations (immunosuppressed patients). Unlike White individuals, SCCs frequently occur in non–sun-exposed areas in Black individuals and are associated with unique risk factors, such as human papillomavirus, as demonstrated in Black transplant patients.⁸ A retrospective study examining the characteristics of SCC on the legs of Black individuals documented atypical hyperkeratotic neoplasms surrounded by abnormal pigmentation and mottling of surrounding skin.⁹ Morphologic skin changes could be the result of chronic thermal damage: Numerous patients reported a history of leg warming from an open heat source. Other patients had an actual diagnosis of EAI. The predilection for less-exposed skin suggests UV radiation (UVR) might be a less important predisposing risk factor for this racial group, and the increased mortality associated with SCC in Black individuals might represent a more aggressive nature to this subset of SCCs.⁹ Furthermore, infrared radiation (IRR), such as fires and coal stoves, might have the potential to stimulate skin changes similar to those associated with UVR and ultimately malignant changes.

Infrared Radiation
Compared to UVR, little is known about the biological effects of IRR (wavelength, 760 nm to 1 mm), to which human skin is constantly exposed from natural and artificial light sources. Early studies have demonstrated the carcinogenic potential of IRR, observing an augmentation of UVR-induced tumorigenesis in the presence of heat. More recently, IRR was observed to stimulate increased collagenase production from dermal fibroblasts and influence pathways (extracellular signal-related kinases 1/2 and p38 mitogen-activated protein kinases) in a similar fashion to UVB and UVA.^10,11 Therefore, IRR might be capable of eliciting molecular responses comparable to those caused by UVR.

Conclusion

Although SCC in association with EAI is uncommon, historical reports of thermal cancers and scientific observations of IRR-induced biological and molecular effects support EAI as a predisposing risk factor for SCC and the important need for close monitoring by physicians. Studies are needed to further elucidate the pathologic effects of IRR, with more promotion of caution relating to thermal exposure.

Case Report

A 67-year-old Black woman presented with a long-standing history of pruritus and “scaly thick bumps” on the lower extremities. Upon further questioning, she reported a 30-year history of placing her feet by an electric space heater and daily baths in “very hot” water. A review of systems and medical history were unremarkable, and the patient was not on any medications. Initial physical examination of the lower extremities demonstrated lichenified plaques and scattered, firm, ulcerated nodules surrounded by mottled postinflammatory hyperpigmentation with sharp demarcation at the midcalf bilaterally (Figure 1).

Subsequently, the patient was shown to have multiple actinic keratoses and SCCs, both in situ and invasive, within the areas of EAI (Figure 2). The patient had no actinic keratoses or other cutaneous malignant neoplasms elsewhere on the skin. Management of actinic keratoses, SCC in situ, and invasive SCC on the lower extremities included numerous excisions, treatment with liquid nitrogen, and topical 5-fluorouracil under occlusion. The patient continues to be monitored frequently.

Comment

Presentation of EAI
Erythema ab igne is a cutaneous reaction resulting from prolonged exposure to an infrared heat source at temperatures insufficient to cause a burn (37 °F to 113 °F [2.78 °C to 45 °C]). Initially presenting as transient blanchable erythema, chronic heat exposure induces persistent areas of reticular erythema, often accompanied by hyperpigmentation, epidermal atrophy, and telangiectases.¹ Erythema ab igne is most commonly reported on the anterior shins, inner thighs, and back, and it is historically associated with open fires and coal stoves. More recently, other implicated causes include heating pads, laptop computers, heated furniture, and electric space heaters.^2,3 Erythema ab igne often is asymptomatic but can present with pruritus and a burning sensation. Treatment involves removal of the inciting heat source, which might allow resolution of early-stage lesions. Long-term exposure leads to permanent skin discoloration and on occasion predisposes patients to malignant transformation.³

Histopathology of EAI
Histologically, later stages of EAI can demonstrate focal hyperkeratosis with dyskeratosis and increased dermal elastosis, similar to actinic damage, with a predisposition to develop SCC.² Notably, early reports document various heat-induced carcinomas, including kangri-burn cancers among Kashmiris, kang thermal cancers in China, and kairo cancers in Japan.^2,4,5 More recent reports identify cutaneous carcinomas arising specifically in the setting of EAI, most commonly SCC³; Merkel cell carcinoma and cutaneous marginal zone lymphoma are less commonly reported malignancies.^6,7 Given the frequency of malignant transformation within sites of thermal exposure, chronic heat exposure may share a common pathophysiology with SCC and other neoplasms, including Merkel cell carcinoma and cutaneous marginal zone lymphoma.

SCC in Black Individuals
Squamous cell carcinoma is the most common skin cancer in Black individuals, with a notably higher incidence in high-risk subpopulations (immunosuppressed patients). Unlike White individuals, SCCs frequently occur in non–sun-exposed areas in Black individuals and are associated with unique risk factors, such as human papillomavirus, as demonstrated in Black transplant patients.⁸ A retrospective study examining the characteristics of SCC on the legs of Black individuals documented atypical hyperkeratotic neoplasms surrounded by abnormal pigmentation and mottling of surrounding skin.⁹ Morphologic skin changes could be the result of chronic thermal damage: Numerous patients reported a history of leg warming from an open heat source. Other patients had an actual diagnosis of EAI. The predilection for less-exposed skin suggests UV radiation (UVR) might be a less important predisposing risk factor for this racial group, and the increased mortality associated with SCC in Black individuals might represent a more aggressive nature to this subset of SCCs.⁹ Furthermore, infrared radiation (IRR), such as fires and coal stoves, might have the potential to stimulate skin changes similar to those associated with UVR and ultimately malignant changes.

Infrared Radiation
Compared to UVR, little is known about the biological effects of IRR (wavelength, 760 nm to 1 mm), to which human skin is constantly exposed from natural and artificial light sources. Early studies have demonstrated the carcinogenic potential of IRR, observing an augmentation of UVR-induced tumorigenesis in the presence of heat. More recently, IRR was observed to stimulate increased collagenase production from dermal fibroblasts and influence pathways (extracellular signal-related kinases 1/2 and p38 mitogen-activated protein kinases) in a similar fashion to UVB and UVA.^10,11 Therefore, IRR might be capable of eliciting molecular responses comparable to those caused by UVR.

Conclusion

Although SCC in association with EAI is uncommon, historical reports of thermal cancers and scientific observations of IRR-induced biological and molecular effects support EAI as a predisposing risk factor for SCC and the important need for close monitoring by physicians. Studies are needed to further elucidate the pathologic effects of IRR, with more promotion of caution relating to thermal exposure.

Case Report

A 67-year-old Black woman presented with a long-standing history of pruritus and “scaly thick bumps” on the lower extremities. Upon further questioning, she reported a 30-year history of placing her feet by an electric space heater and daily baths in “very hot” water. A review of systems and medical history were unremarkable, and the patient was not on any medications. Initial physical examination of the lower extremities demonstrated lichenified plaques and scattered, firm, ulcerated nodules surrounded by mottled postinflammatory hyperpigmentation with sharp demarcation at the midcalf bilaterally (Figure 1).

Subsequently, the patient was shown to have multiple actinic keratoses and SCCs, both in situ and invasive, within the areas of EAI (Figure 2). The patient had no actinic keratoses or other cutaneous malignant neoplasms elsewhere on the skin. Management of actinic keratoses, SCC in situ, and invasive SCC on the lower extremities included numerous excisions, treatment with liquid nitrogen, and topical 5-fluorouracil under occlusion. The patient continues to be monitored frequently.

Comment

Presentation of EAI
Erythema ab igne is a cutaneous reaction resulting from prolonged exposure to an infrared heat source at temperatures insufficient to cause a burn (37 °F to 113 °F [2.78 °C to 45 °C]). Initially presenting as transient blanchable erythema, chronic heat exposure induces persistent areas of reticular erythema, often accompanied by hyperpigmentation, epidermal atrophy, and telangiectases.¹ Erythema ab igne is most commonly reported on the anterior shins, inner thighs, and back, and it is historically associated with open fires and coal stoves. More recently, other implicated causes include heating pads, laptop computers, heated furniture, and electric space heaters.^2,3 Erythema ab igne often is asymptomatic but can present with pruritus and a burning sensation. Treatment involves removal of the inciting heat source, which might allow resolution of early-stage lesions. Long-term exposure leads to permanent skin discoloration and on occasion predisposes patients to malignant transformation.³

Histopathology of EAI
Histologically, later stages of EAI can demonstrate focal hyperkeratosis with dyskeratosis and increased dermal elastosis, similar to actinic damage, with a predisposition to develop SCC.² Notably, early reports document various heat-induced carcinomas, including kangri-burn cancers among Kashmiris, kang thermal cancers in China, and kairo cancers in Japan.^2,4,5 More recent reports identify cutaneous carcinomas arising specifically in the setting of EAI, most commonly SCC³; Merkel cell carcinoma and cutaneous marginal zone lymphoma are less commonly reported malignancies.^6,7 Given the frequency of malignant transformation within sites of thermal exposure, chronic heat exposure may share a common pathophysiology with SCC and other neoplasms, including Merkel cell carcinoma and cutaneous marginal zone lymphoma.

SCC in Black Individuals
Squamous cell carcinoma is the most common skin cancer in Black individuals, with a notably higher incidence in high-risk subpopulations (immunosuppressed patients). Unlike White individuals, SCCs frequently occur in non–sun-exposed areas in Black individuals and are associated with unique risk factors, such as human papillomavirus, as demonstrated in Black transplant patients.⁸ A retrospective study examining the characteristics of SCC on the legs of Black individuals documented atypical hyperkeratotic neoplasms surrounded by abnormal pigmentation and mottling of surrounding skin.⁹ Morphologic skin changes could be the result of chronic thermal damage: Numerous patients reported a history of leg warming from an open heat source. Other patients had an actual diagnosis of EAI. The predilection for less-exposed skin suggests UV radiation (UVR) might be a less important predisposing risk factor for this racial group, and the increased mortality associated with SCC in Black individuals might represent a more aggressive nature to this subset of SCCs.⁹ Furthermore, infrared radiation (IRR), such as fires and coal stoves, might have the potential to stimulate skin changes similar to those associated with UVR and ultimately malignant changes.

Infrared Radiation
Compared to UVR, little is known about the biological effects of IRR (wavelength, 760 nm to 1 mm), to which human skin is constantly exposed from natural and artificial light sources. Early studies have demonstrated the carcinogenic potential of IRR, observing an augmentation of UVR-induced tumorigenesis in the presence of heat. More recently, IRR was observed to stimulate increased collagenase production from dermal fibroblasts and influence pathways (extracellular signal-related kinases 1/2 and p38 mitogen-activated protein kinases) in a similar fashion to UVB and UVA.^10,11 Therefore, IRR might be capable of eliciting molecular responses comparable to those caused by UVR.

Conclusion

Although SCC in association with EAI is uncommon, historical reports of thermal cancers and scientific observations of IRR-induced biological and molecular effects support EAI as a predisposing risk factor for SCC and the important need for close monitoring by physicians. Studies are needed to further elucidate the pathologic effects of IRR, with more promotion of caution relating to thermal exposure.

THE CASE

A 17-year-old White girl with no known past medical history presented to the emergency department (ED) with complaints of abdominal pain and pruritus. The abdominal pain had started 9 days prior and lasted for 3 days. One day after resolution, she developed bilateral lower extremity itching, which was not relieved with loratadine.

Review of systems included dark urine and yellow eyes noted for several days. The patient denied nausea, vomiting, diarrhea, constipation, fevers, chills, arthralgias, recent illness, travel, or sick contacts. Immunizations were up to date. The patient had no history of surgery or liver disease and no pertinent family history. Her current medications included ethinyl estradiol/norethindrone acetate for birth control and minocycline for acne vulgaris. She had been taking the latter medication for 2 years. No additional medications were noted, including vitamins, over-the-counter medications, or supplements. She denied smoking and alcohol or recreational drug use.

In the ED, the patient had normal vital signs. Physical exam findings included bilateral scleral icterus and scattered skin excoriations on the hands, arms, back of the neck, and feet. At the time of hospital admission, the patient’s minocycline and birth control were held under the initial presumption that one or both might be contributing to her presentation.

Pertinent laboratory findings included aspartate transaminase (AST), 828 U/L (normal range, 2-40 U/L); alanine aminotransferase (ALT), 784 U/L (normal range, 3-30 U/L); lactic acid dehydrogenase, 520 U/L (normal range, 140-280 U/L); alkaline phosphatase, 119 U/L (normal range, 44-147 U/L); total bilirubin, 1.9 µmol/L (normal range, 2-18 µmol/L); and direct bilirubin, 1.3 µmol/L (normal range, 0-4 µmol/L). Baseline liver function test results (prior to admission) were unknown. Results of a coagulation panel, complete blood count, basic metabolic panel, amylase, lipase, urine toxicology, and urinalysis all were within normal limits.

Ultrasound of the abdomen revealed a normal abdomen, liver, pancreas, gallbladder, and common bile duct. This imaging study was negative for other obstructive pathologies.

THE DIAGNOSIS

During hospital admission, a noninvasive liver work-up was pursued by Gastroenterology. A hepatitis panel, Epstein-Barr virus testing, and levels of ceruloplasmin and acetaminophen were all found to be within normal limits, excluding additional causes of liver disease. Serum antinuclear antibody (ANA) testing was significantly positive, with a titer of 1:640 (range, < 1:20) and, as noted above, liver transaminases were severely elevated, leading to a presumptive diagnosis of drug-induced liver pathology.

Continue to: During outpatient follow-up...

During outpatient follow-up with Gastroenterology 2 days after discharge, the patient’s liver transaminases and bilirubin continued to trend upward (to a maximum ALT of 871 U/L; AST, 1097 U/L; alkaline phosphatase, 122 U/L; and bilirubin, 2.9 µmol/L). Immunoglobulin G was 1342 mg/mL (normal range, 694-1618 mg/mL).

An ultrasound-guided liver biopsy was performed; it demonstrated lobular, portal, and periportal hepatitis with focal bridging necrosis, consistent with a diagnosis of autoimmune hepatitis. Mild-to-moderate focal cholestasis was demonstrated, consistent with cholestatic hepatitis.

DISCUSSION

Autoimmune hepatitis is characterized by inflammation of the liver, secondary to the presence of circulating antibodies or hypergammaglobulinemia. The pathogenesis is thought to involve a T-cell–mediated immune attack on the liver. Based on case reports,the use of minocycline is associated with risk for liver injury, although the incidence is rare.^1-4 Use of this medication may be associated with autoimmune disease in patients who are predisposed to autoimmune tendencies or who have genetic predeterminants.

Diagnosis is typically made based on abnormalities in aminotransferases (AST, ALT), elevation in serum immunoglobulins, and positive auto-antibody titers including ANA, smooth muscle antibodies, and anti-liver kidney microsomal type 1 antibodies. Although clinical presentations tend to differ, the confirmatory diagnosis is typically made histologically, with the presence of lobular and perivenular necro-inflammatory changes and plasma cell infiltration.⁵

Other infectious and metabolic causes of hepatitis should be excluded. Many medications and herbal agents have been noted to cause autoimmune hepatitis or similar syndromes that mimic the condition.

Medication history. Review of the case patient’s medication list identified ethinyl estradiol/norethindrone acetate and minocycline as potential culprits. Ethinyl estradiol/norethindrone acetate is a low-dose combination oral contraceptive pill (OCP). Although earlier formulations of OCPs were associated with hepatobiliary complications, these adverse effects are noted to be rare in the absence of predisposing conditions.⁶ In some cases, OCPs have been linked to cholestasis, chronic hepatocellular carcinoma, or hepatic adenomas, but studies have shown that these medications do not affect the course of acute liver failure.⁷

Continue to: Minocycline...

Minocyclineassociated hepatotoxicity can be due to a systemic hypersensitivity reaction, occurring within a few weeks of therapy initiation, whereas autoimmune hepatitis manifests after a year or more of exposure to the medication.

In this case, given the patient’s 2-year history of minocycline use, it is possible that she developed an acute presentation of autoimmune hepatitis. With drug-induced autoimmune liver injury, complete resolution occurs after withdrawal of the offending medication, and a response to corticosteroid therapy supports the diagnosis. Recurrence of signs or symptoms following corticosteroid cessation may indicate idiopathic autoimmune hepatitis as opposed to a drug-induced form.²

Our patient was started on steroid and immunomodulator therapy, with prednisone 40 mg/d and mycophenolate 250 mg bid. At follow-up with Gastroenterology, the patient’s symptoms and liver function test results had improved significantly (AST, 27 U/L; ALT, 14 U/L; alkaline phosphatase, 51 U/L; and total bilirubin, 0.4 µmol/L). The patient was continued on a prednisone taper while simultaneously titrating mycophenolate. The ultimate plan of care included continuing mycophenolate for a total of 4 to 5 years.

THE TAKEAWAY

During evaluation of a patient with new-onset liver disease, it is important to inquire about prescription medications, drugs, vitamins, and herbal supplements as possible contributors to the disease process. This case highlights the importance of monitoring patients while on minocycline and of weighing the risks vs benefits of long-term therapy. It has been suggested that liver enzymes be tested before therapy initiation and about every 3 months during long-term antibiotic treatment.⁴ Careful consideration and caution should be taken prior to the initiation of medications that have been linked to rare, but important, adverse reactions.

ACKNOWLEDGEMENT

The authors would like to thank Frank Bauer, MD, and Eva Sotil, MD, for their contributions to this case presentation.

CORRESPONDENCE

Andrea Gillis, DO, Asylum Hill Family Medicine Center, 99 Woodland Street, Hartford, CT 06105; andrea.gillis@ trinityhealthofne.org

THE CASE

A 17-year-old White girl with no known past medical history presented to the emergency department (ED) with complaints of abdominal pain and pruritus. The abdominal pain had started 9 days prior and lasted for 3 days. One day after resolution, she developed bilateral lower extremity itching, which was not relieved with loratadine.

Review of systems included dark urine and yellow eyes noted for several days. The patient denied nausea, vomiting, diarrhea, constipation, fevers, chills, arthralgias, recent illness, travel, or sick contacts. Immunizations were up to date. The patient had no history of surgery or liver disease and no pertinent family history. Her current medications included ethinyl estradiol/norethindrone acetate for birth control and minocycline for acne vulgaris. She had been taking the latter medication for 2 years. No additional medications were noted, including vitamins, over-the-counter medications, or supplements. She denied smoking and alcohol or recreational drug use.

In the ED, the patient had normal vital signs. Physical exam findings included bilateral scleral icterus and scattered skin excoriations on the hands, arms, back of the neck, and feet. At the time of hospital admission, the patient’s minocycline and birth control were held under the initial presumption that one or both might be contributing to her presentation.

Pertinent laboratory findings included aspartate transaminase (AST), 828 U/L (normal range, 2-40 U/L); alanine aminotransferase (ALT), 784 U/L (normal range, 3-30 U/L); lactic acid dehydrogenase, 520 U/L (normal range, 140-280 U/L); alkaline phosphatase, 119 U/L (normal range, 44-147 U/L); total bilirubin, 1.9 µmol/L (normal range, 2-18 µmol/L); and direct bilirubin, 1.3 µmol/L (normal range, 0-4 µmol/L). Baseline liver function test results (prior to admission) were unknown. Results of a coagulation panel, complete blood count, basic metabolic panel, amylase, lipase, urine toxicology, and urinalysis all were within normal limits.

Ultrasound of the abdomen revealed a normal abdomen, liver, pancreas, gallbladder, and common bile duct. This imaging study was negative for other obstructive pathologies.

THE DIAGNOSIS

During hospital admission, a noninvasive liver work-up was pursued by Gastroenterology. A hepatitis panel, Epstein-Barr virus testing, and levels of ceruloplasmin and acetaminophen were all found to be within normal limits, excluding additional causes of liver disease. Serum antinuclear antibody (ANA) testing was significantly positive, with a titer of 1:640 (range, < 1:20) and, as noted above, liver transaminases were severely elevated, leading to a presumptive diagnosis of drug-induced liver pathology.

Continue to: During outpatient follow-up...

During outpatient follow-up with Gastroenterology 2 days after discharge, the patient’s liver transaminases and bilirubin continued to trend upward (to a maximum ALT of 871 U/L; AST, 1097 U/L; alkaline phosphatase, 122 U/L; and bilirubin, 2.9 µmol/L). Immunoglobulin G was 1342 mg/mL (normal range, 694-1618 mg/mL).

An ultrasound-guided liver biopsy was performed; it demonstrated lobular, portal, and periportal hepatitis with focal bridging necrosis, consistent with a diagnosis of autoimmune hepatitis. Mild-to-moderate focal cholestasis was demonstrated, consistent with cholestatic hepatitis.

DISCUSSION

Autoimmune hepatitis is characterized by inflammation of the liver, secondary to the presence of circulating antibodies or hypergammaglobulinemia. The pathogenesis is thought to involve a T-cell–mediated immune attack on the liver. Based on case reports,the use of minocycline is associated with risk for liver injury, although the incidence is rare.^1-4 Use of this medication may be associated with autoimmune disease in patients who are predisposed to autoimmune tendencies or who have genetic predeterminants.

Diagnosis is typically made based on abnormalities in aminotransferases (AST, ALT), elevation in serum immunoglobulins, and positive auto-antibody titers including ANA, smooth muscle antibodies, and anti-liver kidney microsomal type 1 antibodies. Although clinical presentations tend to differ, the confirmatory diagnosis is typically made histologically, with the presence of lobular and perivenular necro-inflammatory changes and plasma cell infiltration.⁵

Other infectious and metabolic causes of hepatitis should be excluded. Many medications and herbal agents have been noted to cause autoimmune hepatitis or similar syndromes that mimic the condition.

Medication history. Review of the case patient’s medication list identified ethinyl estradiol/norethindrone acetate and minocycline as potential culprits. Ethinyl estradiol/norethindrone acetate is a low-dose combination oral contraceptive pill (OCP). Although earlier formulations of OCPs were associated with hepatobiliary complications, these adverse effects are noted to be rare in the absence of predisposing conditions.⁶ In some cases, OCPs have been linked to cholestasis, chronic hepatocellular carcinoma, or hepatic adenomas, but studies have shown that these medications do not affect the course of acute liver failure.⁷

Continue to: Minocycline...

Minocyclineassociated hepatotoxicity can be due to a systemic hypersensitivity reaction, occurring within a few weeks of therapy initiation, whereas autoimmune hepatitis manifests after a year or more of exposure to the medication.

In this case, given the patient’s 2-year history of minocycline use, it is possible that she developed an acute presentation of autoimmune hepatitis. With drug-induced autoimmune liver injury, complete resolution occurs after withdrawal of the offending medication, and a response to corticosteroid therapy supports the diagnosis. Recurrence of signs or symptoms following corticosteroid cessation may indicate idiopathic autoimmune hepatitis as opposed to a drug-induced form.²

Our patient was started on steroid and immunomodulator therapy, with prednisone 40 mg/d and mycophenolate 250 mg bid. At follow-up with Gastroenterology, the patient’s symptoms and liver function test results had improved significantly (AST, 27 U/L; ALT, 14 U/L; alkaline phosphatase, 51 U/L; and total bilirubin, 0.4 µmol/L). The patient was continued on a prednisone taper while simultaneously titrating mycophenolate. The ultimate plan of care included continuing mycophenolate for a total of 4 to 5 years.

THE TAKEAWAY

During evaluation of a patient with new-onset liver disease, it is important to inquire about prescription medications, drugs, vitamins, and herbal supplements as possible contributors to the disease process. This case highlights the importance of monitoring patients while on minocycline and of weighing the risks vs benefits of long-term therapy. It has been suggested that liver enzymes be tested before therapy initiation and about every 3 months during long-term antibiotic treatment.⁴ Careful consideration and caution should be taken prior to the initiation of medications that have been linked to rare, but important, adverse reactions.

ACKNOWLEDGEMENT

The authors would like to thank Frank Bauer, MD, and Eva Sotil, MD, for their contributions to this case presentation.

CORRESPONDENCE

Andrea Gillis, DO, Asylum Hill Family Medicine Center, 99 Woodland Street, Hartford, CT 06105; andrea.gillis@ trinityhealthofne.org

THE CASE

A 17-year-old White girl with no known past medical history presented to the emergency department (ED) with complaints of abdominal pain and pruritus. The abdominal pain had started 9 days prior and lasted for 3 days. One day after resolution, she developed bilateral lower extremity itching, which was not relieved with loratadine.

Review of systems included dark urine and yellow eyes noted for several days. The patient denied nausea, vomiting, diarrhea, constipation, fevers, chills, arthralgias, recent illness, travel, or sick contacts. Immunizations were up to date. The patient had no history of surgery or liver disease and no pertinent family history. Her current medications included ethinyl estradiol/norethindrone acetate for birth control and minocycline for acne vulgaris. She had been taking the latter medication for 2 years. No additional medications were noted, including vitamins, over-the-counter medications, or supplements. She denied smoking and alcohol or recreational drug use.

In the ED, the patient had normal vital signs. Physical exam findings included bilateral scleral icterus and scattered skin excoriations on the hands, arms, back of the neck, and feet. At the time of hospital admission, the patient’s minocycline and birth control were held under the initial presumption that one or both might be contributing to her presentation.

Pertinent laboratory findings included aspartate transaminase (AST), 828 U/L (normal range, 2-40 U/L); alanine aminotransferase (ALT), 784 U/L (normal range, 3-30 U/L); lactic acid dehydrogenase, 520 U/L (normal range, 140-280 U/L); alkaline phosphatase, 119 U/L (normal range, 44-147 U/L); total bilirubin, 1.9 µmol/L (normal range, 2-18 µmol/L); and direct bilirubin, 1.3 µmol/L (normal range, 0-4 µmol/L). Baseline liver function test results (prior to admission) were unknown. Results of a coagulation panel, complete blood count, basic metabolic panel, amylase, lipase, urine toxicology, and urinalysis all were within normal limits.

Ultrasound of the abdomen revealed a normal abdomen, liver, pancreas, gallbladder, and common bile duct. This imaging study was negative for other obstructive pathologies.

THE DIAGNOSIS

During hospital admission, a noninvasive liver work-up was pursued by Gastroenterology. A hepatitis panel, Epstein-Barr virus testing, and levels of ceruloplasmin and acetaminophen were all found to be within normal limits, excluding additional causes of liver disease. Serum antinuclear antibody (ANA) testing was significantly positive, with a titer of 1:640 (range, < 1:20) and, as noted above, liver transaminases were severely elevated, leading to a presumptive diagnosis of drug-induced liver pathology.

Continue to: During outpatient follow-up...

During outpatient follow-up with Gastroenterology 2 days after discharge, the patient’s liver transaminases and bilirubin continued to trend upward (to a maximum ALT of 871 U/L; AST, 1097 U/L; alkaline phosphatase, 122 U/L; and bilirubin, 2.9 µmol/L). Immunoglobulin G was 1342 mg/mL (normal range, 694-1618 mg/mL).

An ultrasound-guided liver biopsy was performed; it demonstrated lobular, portal, and periportal hepatitis with focal bridging necrosis, consistent with a diagnosis of autoimmune hepatitis. Mild-to-moderate focal cholestasis was demonstrated, consistent with cholestatic hepatitis.

DISCUSSION

Autoimmune hepatitis is characterized by inflammation of the liver, secondary to the presence of circulating antibodies or hypergammaglobulinemia. The pathogenesis is thought to involve a T-cell–mediated immune attack on the liver. Based on case reports,the use of minocycline is associated with risk for liver injury, although the incidence is rare.^1-4 Use of this medication may be associated with autoimmune disease in patients who are predisposed to autoimmune tendencies or who have genetic predeterminants.

Diagnosis is typically made based on abnormalities in aminotransferases (AST, ALT), elevation in serum immunoglobulins, and positive auto-antibody titers including ANA, smooth muscle antibodies, and anti-liver kidney microsomal type 1 antibodies. Although clinical presentations tend to differ, the confirmatory diagnosis is typically made histologically, with the presence of lobular and perivenular necro-inflammatory changes and plasma cell infiltration.⁵

Other infectious and metabolic causes of hepatitis should be excluded. Many medications and herbal agents have been noted to cause autoimmune hepatitis or similar syndromes that mimic the condition.

Medication history. Review of the case patient’s medication list identified ethinyl estradiol/norethindrone acetate and minocycline as potential culprits. Ethinyl estradiol/norethindrone acetate is a low-dose combination oral contraceptive pill (OCP). Although earlier formulations of OCPs were associated with hepatobiliary complications, these adverse effects are noted to be rare in the absence of predisposing conditions.⁶ In some cases, OCPs have been linked to cholestasis, chronic hepatocellular carcinoma, or hepatic adenomas, but studies have shown that these medications do not affect the course of acute liver failure.⁷

Continue to: Minocycline...

Minocyclineassociated hepatotoxicity can be due to a systemic hypersensitivity reaction, occurring within a few weeks of therapy initiation, whereas autoimmune hepatitis manifests after a year or more of exposure to the medication.

In this case, given the patient’s 2-year history of minocycline use, it is possible that she developed an acute presentation of autoimmune hepatitis. With drug-induced autoimmune liver injury, complete resolution occurs after withdrawal of the offending medication, and a response to corticosteroid therapy supports the diagnosis. Recurrence of signs or symptoms following corticosteroid cessation may indicate idiopathic autoimmune hepatitis as opposed to a drug-induced form.²

Our patient was started on steroid and immunomodulator therapy, with prednisone 40 mg/d and mycophenolate 250 mg bid. At follow-up with Gastroenterology, the patient’s symptoms and liver function test results had improved significantly (AST, 27 U/L; ALT, 14 U/L; alkaline phosphatase, 51 U/L; and total bilirubin, 0.4 µmol/L). The patient was continued on a prednisone taper while simultaneously titrating mycophenolate. The ultimate plan of care included continuing mycophenolate for a total of 4 to 5 years.

THE TAKEAWAY

During evaluation of a patient with new-onset liver disease, it is important to inquire about prescription medications, drugs, vitamins, and herbal supplements as possible contributors to the disease process. This case highlights the importance of monitoring patients while on minocycline and of weighing the risks vs benefits of long-term therapy. It has been suggested that liver enzymes be tested before therapy initiation and about every 3 months during long-term antibiotic treatment.⁴ Careful consideration and caution should be taken prior to the initiation of medications that have been linked to rare, but important, adverse reactions.

ACKNOWLEDGEMENT

The authors would like to thank Frank Bauer, MD, and Eva Sotil, MD, for their contributions to this case presentation.

CORRESPONDENCE

Andrea Gillis, DO, Asylum Hill Family Medicine Center, 99 Woodland Street, Hartford, CT 06105; andrea.gillis@ trinityhealthofne.org

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the most recently identified member of the zoonotic pathogens of coronaviruses. It caused an outbreak of pneumonia in December 2019 in Wuhan, China.¹ Among all related acute respiratory syndromes (SARS-CoV, Middle East respiratory syndrome coronavirus), SARS-CoV-2 remains to be the most infectious, has the highest potential for human transmission, and can eventually result in acute respiratory distress syndrome.^2,3

Only 15% of coronavirus disease 2019 (COVID-19) cases progress to pneumonia, and approximately 5% of these cases develop acute respiratory distress syndrome, septic shock, and/or multiple organ failure. The majority of cases only exhibit mild to moderate symptoms.^4,5 A wide array of skin manifestations in COVID-19 infection have been reported, including maculopapular eruptions, morbilliform rashes, urticaria, chickenpoxlike lesions, livedo reticularis, COVID toes, erythema multiforme, pityriasis rosea, and several other patterns.⁶ We report a case of herpes zoster (HZ) complication in a COVID-19–positive woman who was 27 weeks pregnant.

Case Report

A 36-year-old woman who was 27 weeks pregnant was referred by her obstetrician to the dermatology clinic. She presented with a low-grade fever and a vesicular painful rash. Physical examination revealed painful, itchy, dysesthetic papules and vesicles on the left side of the forehead along with mild edema of the left upper eyelid but no watering of the eye or photophobia. She reported episodes of fever (temperature, 38.9°C), fatigue, and myalgia over the last week. She had bouts of dyspnea and tachycardia that she thought were related to being in the late second trimester of pregnancy. The area surrounding the vesicular eruption was tender to touch. No dry cough or any gastrointestinal or urinary tract symptoms were noted. She reported a burning sensation when splashing water on the face or when exposed to air currents. One week following the initial symptoms, she experienced a painful vesicular rash along the upper left forehead (Figure) associated with eyelid edema. Oral and ocular mucosae were free of any presentations. She had no relevant history and had not experienced any complications during pregnancy. A diagnosis of HZ was made, and she was prescribed valacyclovir 1 g 3 times daily for 7 days, acetaminophen for the fever, and calamine lotion. We recommended COVID-19 testing based on her symptoms. A chest radiograph and a positive nasopharyngeal smear were consistent with COVID-19 infection. She reported via telephone follow-up 1 week after presentation that her skin condition had improved following the treatment course and that the vesicles eventually dried, leaving a crusting appearance after 5 to 7 days. Regarding her SARS-CoV-2 condition, her oxygen saturation was 95% at presentation; she self-quarantined at home; and she was treated with oseltamivir 75 mg orally every 12 hours for 5 days, azithromycin 500 mg orally daily, acetaminophen, and vitamin C. Electronic fetal heart rate monitoring and ultrasound examinations were performed to assess the condition of the fetus and were reported normal. At the time of writing this article, she was 32 weeks pregnant and tested negative to 2 consecutive nasopharyngeal swabs for COVID-19 and was in good general condition. She continued her pregnancy according to her obstetrician’s recommendations.

Comment

The incubation time of COVID-19 can be up to 14 days. Fever, dry cough, fatigue, and diarrhea have been speculated to be clinical symptoms; however, many cases may be asymptomatic. Aside from a medical or travel history at risk for COVID-19, diagnosis can be confirmed by detection of viral RNA by reverse transcriptase–polymerase chain reaction for nasopharyngeal swabs or bronchoalveolar fluid. Patients who are immunocompromised, older, or male or who have a history of cardiovascular conditions or debilitating chronic conditions are at an increased risk for severe disease and poor outcome compared to younger healthy individuals.⁷

The vesicular rash of COVID-19 has been reported to have different forms of presentation. A diffuse widespread pattern resembling hand-foot-and-mouth disease and a localized monomorphic pattern resembling chickenpox but with predilection to the trunk has been described.⁸

Physiologic changes in the immune and cardiopulmonary systems during pregnancy (eg, diaphragm elevation, increased oxygen consumption, edema of the respiratory tract mucosae) make pregnant women intolerant to hypoxia. The mortality rate of the 1918 influenza pandemic was 2.6% in the overall population but 37% among pregnant women.⁹ In 2009, pregnant women were reported to be at an increased risk for complications from the H1N1 influenza virus pandemic, with a higher estimated rate of hospital admission than the general population.¹⁰ In 2003, approximately 50% of pregnant women who received a diagnosis of SARS-CoV were admitted to the intensive care unit, approximately 33% of pregnant women with SARS-CoV required mechanical ventilation, and the mortality rate was as high as 25% for these women.¹¹ To date, data on the effects of COVID-19 in pregnancy are limited to small case series.^12-15

It was confirmed that COVID-19 infection is accompanied by a reduction in lymphocytes, monocytes, and eosinophils, along with a notable reduction of CD4/CD8 T cells, B cells, and natural killer cells. It was further revealed that nonsurvivor COVID-19 patients continued to show a decrease in lymphocyte counts along the course of their disease until death.^16-18

Different mechanisms for lymphocyte depletion and deficiency were speculated among COVID-19 patients and include direct lymphocyte death through coronavirus angiotensin-converting enzyme 2–lymphocyte-expressed receptors; direct damage to lymphatic organs, such as the thymus and spleen, but this theory needs to be further investigated; direct lymphocyte apoptosis mediated by tumor necrosis factor α, IL-6, and other proinflammatory cytokines; and direct inhibition of lymphocytes by metabolic upset, such as acidosis.^19,20

These causes may precipitate lymphopenia and impaired antiviral responses.²¹ It also has been postulated that the functional damage of CD4⁺ T cells may predispose patients with COVID-19 to severe disease.²² Such immune changes can render a patient more susceptible to developing shingles by reactivating varicella-zoster virus, which could be a sign of undiagnosed COVID-19 infection in younger age groups.

Two earlier reports discussed HZ among COVID-19–diagnosed patients. Shors²³ presented a case of a patient who developed varicella-zoster virus reactivation of the V2 dermatome during the course of COVID-19 infection. In addition, the patient developed severe acute herpetic neuralgia despite the early initiation of antiviral therapy.²³ Elsaie et al²⁴ described 2 cases of patients during the pandemic who first presented with HZ before later being diagnosed with COVID-19 infection.

New information and cutaneous manifestations possibly related to COVID-19 are emerging every day. We report a pregnant female presenting with HZ during the course of COVID-19 infection, which suggests that the clinical presentation of HZ at the time of the current pandemic, especially if associated with other signs of COVID-19 infection, should be carefully monitored and reported for further assessment.

Acknowledgment
The authors would like to thank all the health care workers who have been fighting COVID-19 in Egypt and worldwide.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the most recently identified member of the zoonotic pathogens of coronaviruses. It caused an outbreak of pneumonia in December 2019 in Wuhan, China.¹ Among all related acute respiratory syndromes (SARS-CoV, Middle East respiratory syndrome coronavirus), SARS-CoV-2 remains to be the most infectious, has the highest potential for human transmission, and can eventually result in acute respiratory distress syndrome.^2,3

Only 15% of coronavirus disease 2019 (COVID-19) cases progress to pneumonia, and approximately 5% of these cases develop acute respiratory distress syndrome, septic shock, and/or multiple organ failure. The majority of cases only exhibit mild to moderate symptoms.^4,5 A wide array of skin manifestations in COVID-19 infection have been reported, including maculopapular eruptions, morbilliform rashes, urticaria, chickenpoxlike lesions, livedo reticularis, COVID toes, erythema multiforme, pityriasis rosea, and several other patterns.⁶ We report a case of herpes zoster (HZ) complication in a COVID-19–positive woman who was 27 weeks pregnant.

Case Report

A 36-year-old woman who was 27 weeks pregnant was referred by her obstetrician to the dermatology clinic. She presented with a low-grade fever and a vesicular painful rash. Physical examination revealed painful, itchy, dysesthetic papules and vesicles on the left side of the forehead along with mild edema of the left upper eyelid but no watering of the eye or photophobia. She reported episodes of fever (temperature, 38.9°C), fatigue, and myalgia over the last week. She had bouts of dyspnea and tachycardia that she thought were related to being in the late second trimester of pregnancy. The area surrounding the vesicular eruption was tender to touch. No dry cough or any gastrointestinal or urinary tract symptoms were noted. She reported a burning sensation when splashing water on the face or when exposed to air currents. One week following the initial symptoms, she experienced a painful vesicular rash along the upper left forehead (Figure) associated with eyelid edema. Oral and ocular mucosae were free of any presentations. She had no relevant history and had not experienced any complications during pregnancy. A diagnosis of HZ was made, and she was prescribed valacyclovir 1 g 3 times daily for 7 days, acetaminophen for the fever, and calamine lotion. We recommended COVID-19 testing based on her symptoms. A chest radiograph and a positive nasopharyngeal smear were consistent with COVID-19 infection. She reported via telephone follow-up 1 week after presentation that her skin condition had improved following the treatment course and that the vesicles eventually dried, leaving a crusting appearance after 5 to 7 days. Regarding her SARS-CoV-2 condition, her oxygen saturation was 95% at presentation; she self-quarantined at home; and she was treated with oseltamivir 75 mg orally every 12 hours for 5 days, azithromycin 500 mg orally daily, acetaminophen, and vitamin C. Electronic fetal heart rate monitoring and ultrasound examinations were performed to assess the condition of the fetus and were reported normal. At the time of writing this article, she was 32 weeks pregnant and tested negative to 2 consecutive nasopharyngeal swabs for COVID-19 and was in good general condition. She continued her pregnancy according to her obstetrician’s recommendations.

Comment

The incubation time of COVID-19 can be up to 14 days. Fever, dry cough, fatigue, and diarrhea have been speculated to be clinical symptoms; however, many cases may be asymptomatic. Aside from a medical or travel history at risk for COVID-19, diagnosis can be confirmed by detection of viral RNA by reverse transcriptase–polymerase chain reaction for nasopharyngeal swabs or bronchoalveolar fluid. Patients who are immunocompromised, older, or male or who have a history of cardiovascular conditions or debilitating chronic conditions are at an increased risk for severe disease and poor outcome compared to younger healthy individuals.⁷

The vesicular rash of COVID-19 has been reported to have different forms of presentation. A diffuse widespread pattern resembling hand-foot-and-mouth disease and a localized monomorphic pattern resembling chickenpox but with predilection to the trunk has been described.⁸

Physiologic changes in the immune and cardiopulmonary systems during pregnancy (eg, diaphragm elevation, increased oxygen consumption, edema of the respiratory tract mucosae) make pregnant women intolerant to hypoxia. The mortality rate of the 1918 influenza pandemic was 2.6% in the overall population but 37% among pregnant women.⁹ In 2009, pregnant women were reported to be at an increased risk for complications from the H1N1 influenza virus pandemic, with a higher estimated rate of hospital admission than the general population.¹⁰ In 2003, approximately 50% of pregnant women who received a diagnosis of SARS-CoV were admitted to the intensive care unit, approximately 33% of pregnant women with SARS-CoV required mechanical ventilation, and the mortality rate was as high as 25% for these women.¹¹ To date, data on the effects of COVID-19 in pregnancy are limited to small case series.^12-15

It was confirmed that COVID-19 infection is accompanied by a reduction in lymphocytes, monocytes, and eosinophils, along with a notable reduction of CD4/CD8 T cells, B cells, and natural killer cells. It was further revealed that nonsurvivor COVID-19 patients continued to show a decrease in lymphocyte counts along the course of their disease until death.^16-18

Different mechanisms for lymphocyte depletion and deficiency were speculated among COVID-19 patients and include direct lymphocyte death through coronavirus angiotensin-converting enzyme 2–lymphocyte-expressed receptors; direct damage to lymphatic organs, such as the thymus and spleen, but this theory needs to be further investigated; direct lymphocyte apoptosis mediated by tumor necrosis factor α, IL-6, and other proinflammatory cytokines; and direct inhibition of lymphocytes by metabolic upset, such as acidosis.^19,20

These causes may precipitate lymphopenia and impaired antiviral responses.²¹ It also has been postulated that the functional damage of CD4⁺ T cells may predispose patients with COVID-19 to severe disease.²² Such immune changes can render a patient more susceptible to developing shingles by reactivating varicella-zoster virus, which could be a sign of undiagnosed COVID-19 infection in younger age groups.

Two earlier reports discussed HZ among COVID-19–diagnosed patients. Shors²³ presented a case of a patient who developed varicella-zoster virus reactivation of the V2 dermatome during the course of COVID-19 infection. In addition, the patient developed severe acute herpetic neuralgia despite the early initiation of antiviral therapy.²³ Elsaie et al²⁴ described 2 cases of patients during the pandemic who first presented with HZ before later being diagnosed with COVID-19 infection.

New information and cutaneous manifestations possibly related to COVID-19 are emerging every day. We report a pregnant female presenting with HZ during the course of COVID-19 infection, which suggests that the clinical presentation of HZ at the time of the current pandemic, especially if associated with other signs of COVID-19 infection, should be carefully monitored and reported for further assessment.

Acknowledgment
The authors would like to thank all the health care workers who have been fighting COVID-19 in Egypt and worldwide.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the most recently identified member of the zoonotic pathogens of coronaviruses. It caused an outbreak of pneumonia in December 2019 in Wuhan, China.¹ Among all related acute respiratory syndromes (SARS-CoV, Middle East respiratory syndrome coronavirus), SARS-CoV-2 remains to be the most infectious, has the highest potential for human transmission, and can eventually result in acute respiratory distress syndrome.^2,3

Only 15% of coronavirus disease 2019 (COVID-19) cases progress to pneumonia, and approximately 5% of these cases develop acute respiratory distress syndrome, septic shock, and/or multiple organ failure. The majority of cases only exhibit mild to moderate symptoms.^4,5 A wide array of skin manifestations in COVID-19 infection have been reported, including maculopapular eruptions, morbilliform rashes, urticaria, chickenpoxlike lesions, livedo reticularis, COVID toes, erythema multiforme, pityriasis rosea, and several other patterns.⁶ We report a case of herpes zoster (HZ) complication in a COVID-19–positive woman who was 27 weeks pregnant.

Case Report

A 36-year-old woman who was 27 weeks pregnant was referred by her obstetrician to the dermatology clinic. She presented with a low-grade fever and a vesicular painful rash. Physical examination revealed painful, itchy, dysesthetic papules and vesicles on the left side of the forehead along with mild edema of the left upper eyelid but no watering of the eye or photophobia. She reported episodes of fever (temperature, 38.9°C), fatigue, and myalgia over the last week. She had bouts of dyspnea and tachycardia that she thought were related to being in the late second trimester of pregnancy. The area surrounding the vesicular eruption was tender to touch. No dry cough or any gastrointestinal or urinary tract symptoms were noted. She reported a burning sensation when splashing water on the face or when exposed to air currents. One week following the initial symptoms, she experienced a painful vesicular rash along the upper left forehead (Figure) associated with eyelid edema. Oral and ocular mucosae were free of any presentations. She had no relevant history and had not experienced any complications during pregnancy. A diagnosis of HZ was made, and she was prescribed valacyclovir 1 g 3 times daily for 7 days, acetaminophen for the fever, and calamine lotion. We recommended COVID-19 testing based on her symptoms. A chest radiograph and a positive nasopharyngeal smear were consistent with COVID-19 infection. She reported via telephone follow-up 1 week after presentation that her skin condition had improved following the treatment course and that the vesicles eventually dried, leaving a crusting appearance after 5 to 7 days. Regarding her SARS-CoV-2 condition, her oxygen saturation was 95% at presentation; she self-quarantined at home; and she was treated with oseltamivir 75 mg orally every 12 hours for 5 days, azithromycin 500 mg orally daily, acetaminophen, and vitamin C. Electronic fetal heart rate monitoring and ultrasound examinations were performed to assess the condition of the fetus and were reported normal. At the time of writing this article, she was 32 weeks pregnant and tested negative to 2 consecutive nasopharyngeal swabs for COVID-19 and was in good general condition. She continued her pregnancy according to her obstetrician’s recommendations.

Comment

The incubation time of COVID-19 can be up to 14 days. Fever, dry cough, fatigue, and diarrhea have been speculated to be clinical symptoms; however, many cases may be asymptomatic. Aside from a medical or travel history at risk for COVID-19, diagnosis can be confirmed by detection of viral RNA by reverse transcriptase–polymerase chain reaction for nasopharyngeal swabs or bronchoalveolar fluid. Patients who are immunocompromised, older, or male or who have a history of cardiovascular conditions or debilitating chronic conditions are at an increased risk for severe disease and poor outcome compared to younger healthy individuals.⁷

The vesicular rash of COVID-19 has been reported to have different forms of presentation. A diffuse widespread pattern resembling hand-foot-and-mouth disease and a localized monomorphic pattern resembling chickenpox but with predilection to the trunk has been described.⁸

Physiologic changes in the immune and cardiopulmonary systems during pregnancy (eg, diaphragm elevation, increased oxygen consumption, edema of the respiratory tract mucosae) make pregnant women intolerant to hypoxia. The mortality rate of the 1918 influenza pandemic was 2.6% in the overall population but 37% among pregnant women.⁹ In 2009, pregnant women were reported to be at an increased risk for complications from the H1N1 influenza virus pandemic, with a higher estimated rate of hospital admission than the general population.¹⁰ In 2003, approximately 50% of pregnant women who received a diagnosis of SARS-CoV were admitted to the intensive care unit, approximately 33% of pregnant women with SARS-CoV required mechanical ventilation, and the mortality rate was as high as 25% for these women.¹¹ To date, data on the effects of COVID-19 in pregnancy are limited to small case series.^12-15

It was confirmed that COVID-19 infection is accompanied by a reduction in lymphocytes, monocytes, and eosinophils, along with a notable reduction of CD4/CD8 T cells, B cells, and natural killer cells. It was further revealed that nonsurvivor COVID-19 patients continued to show a decrease in lymphocyte counts along the course of their disease until death.^16-18

Different mechanisms for lymphocyte depletion and deficiency were speculated among COVID-19 patients and include direct lymphocyte death through coronavirus angiotensin-converting enzyme 2–lymphocyte-expressed receptors; direct damage to lymphatic organs, such as the thymus and spleen, but this theory needs to be further investigated; direct lymphocyte apoptosis mediated by tumor necrosis factor α, IL-6, and other proinflammatory cytokines; and direct inhibition of lymphocytes by metabolic upset, such as acidosis.^19,20

These causes may precipitate lymphopenia and impaired antiviral responses.²¹ It also has been postulated that the functional damage of CD4⁺ T cells may predispose patients with COVID-19 to severe disease.²² Such immune changes can render a patient more susceptible to developing shingles by reactivating varicella-zoster virus, which could be a sign of undiagnosed COVID-19 infection in younger age groups.

Two earlier reports discussed HZ among COVID-19–diagnosed patients. Shors²³ presented a case of a patient who developed varicella-zoster virus reactivation of the V2 dermatome during the course of COVID-19 infection. In addition, the patient developed severe acute herpetic neuralgia despite the early initiation of antiviral therapy.²³ Elsaie et al²⁴ described 2 cases of patients during the pandemic who first presented with HZ before later being diagnosed with COVID-19 infection.

New information and cutaneous manifestations possibly related to COVID-19 are emerging every day. We report a pregnant female presenting with HZ during the course of COVID-19 infection, which suggests that the clinical presentation of HZ at the time of the current pandemic, especially if associated with other signs of COVID-19 infection, should be carefully monitored and reported for further assessment.

Acknowledgment
The authors would like to thank all the health care workers who have been fighting COVID-19 in Egypt and worldwide.

In December 2019, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) started an outbreak of respiratory illnesses in Wuhan, China. The respiratory disease was termed coronavirus disease 2019 (COVID-19) and rapidly spread worldwide, resulting in a pandemic classification on March 11, 2020. ¹ Recently, several cutaneous manifestations of COVID-19 have been reported. Skin manifestations have been reported to be similar to other common viral infections. ² However, there is a paucity of published clinical images of more atypical presentations.

Case Report

A 52-year-old black man presented via urgent store-and-forward teledermatology consultation from his primary care provider with a self-described “vesicular,” highly pruritic rash of both arms and legs of 1 week’s duration without involvement of the trunk, axillae, groin, face, genitalia, or any mucous membranes. He noted nausea, loss of appetite, and nonbloody diarrhea 4 days later. He denied fever, chills, dry cough, shortness of breath, or dyspnea. He had a history of hypertension and type 2 diabetes mellitus. There were no changes in medications; no outdoor activities, gardening, or yard work; no exposure to plants or metals; and no use of new personal care products.

The digital images showed zones of flesh-colored to slightly erythematous, somewhat “juicy” papules with some coalescence into ill-defined plaques. There were scattered foci of scale and hemorrhagic crust that involved both palms, forearms (Figure, A), and legs (Figure, B). There were no intact vesicles, and a herald patch was not identified. Vital signs at the time of imaging were normal, with the exception of a low-grade fever (temperature, 37.3°C). Basic laboratory testing showed only mild leukocytosis with mild neutropenia and mild aspartate aminotransaminase elevation. A skin biopsy was not performed. Pulmonary imaging and workup were not performed because of the lack of respiratory symptoms.

Comment

Coronavirus disease 2019 is caused by SARS-CoV2, an enveloped, nonsegmented, positive-sense RNA virus of the coronavirus family. It is currently believed that SARS-CoV-2 uses the angiotensin-converting enzyme 2 receptor to gain entry into human cells, leading to infection primarily affecting the lower respiratory tract.³ Patients suspected of COVID-19 infection most often present with fever, dry cough, dyspnea, and fatigue, while GI symptoms such as nausea, vomiting, and diarrhea are uncommon.⁴ More recently, several reports describe a variety of skin findings associated with COVID-19. A current theory suggests that the virus does not directly target keratinocytes but triggers a systemic immune response, leading to a diversity of skin morphologies.⁵ The main types of described cutaneous findings include pseudochilblains, overtly vesicular, urticarial, maculopapular, and livedo/necrosis.⁶ Others have described petechial⁷ and papulosquamous eruptions.⁸ Most of these patients initially presented with typical COVID-19 symptoms and frequently represented more severe cases of the disease. Additionally, the vesicular and papulosquamous eruptions reportedly occurred on the trunk and not the limbs, as in our case.

This confirmed COVID-19–positive patient presented with an ill-defined vesicular and papulosquamous-type eruption on the arms and legs and later developed only mild GI symptoms. By sharing this case, we report yet another skin manifestation of COVID-19 and propose the possible expansion of testing for SARS-CoV-2 in patients presenting with rash and GI symptoms, which holds the potential to increase the identification of COVID-19 in the population, thereby increasing strict contact tracing and slowing the spread of this pandemic.

In December 2019, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) started an outbreak of respiratory illnesses in Wuhan, China. The respiratory disease was termed coronavirus disease 2019 (COVID-19) and rapidly spread worldwide, resulting in a pandemic classification on March 11, 2020. ¹ Recently, several cutaneous manifestations of COVID-19 have been reported. Skin manifestations have been reported to be similar to other common viral infections. ² However, there is a paucity of published clinical images of more atypical presentations.

Case Report

A 52-year-old black man presented via urgent store-and-forward teledermatology consultation from his primary care provider with a self-described “vesicular,” highly pruritic rash of both arms and legs of 1 week’s duration without involvement of the trunk, axillae, groin, face, genitalia, or any mucous membranes. He noted nausea, loss of appetite, and nonbloody diarrhea 4 days later. He denied fever, chills, dry cough, shortness of breath, or dyspnea. He had a history of hypertension and type 2 diabetes mellitus. There were no changes in medications; no outdoor activities, gardening, or yard work; no exposure to plants or metals; and no use of new personal care products.

The digital images showed zones of flesh-colored to slightly erythematous, somewhat “juicy” papules with some coalescence into ill-defined plaques. There were scattered foci of scale and hemorrhagic crust that involved both palms, forearms (Figure, A), and legs (Figure, B). There were no intact vesicles, and a herald patch was not identified. Vital signs at the time of imaging were normal, with the exception of a low-grade fever (temperature, 37.3°C). Basic laboratory testing showed only mild leukocytosis with mild neutropenia and mild aspartate aminotransaminase elevation. A skin biopsy was not performed. Pulmonary imaging and workup were not performed because of the lack of respiratory symptoms.

Comment

Coronavirus disease 2019 is caused by SARS-CoV2, an enveloped, nonsegmented, positive-sense RNA virus of the coronavirus family. It is currently believed that SARS-CoV-2 uses the angiotensin-converting enzyme 2 receptor to gain entry into human cells, leading to infection primarily affecting the lower respiratory tract.³ Patients suspected of COVID-19 infection most often present with fever, dry cough, dyspnea, and fatigue, while GI symptoms such as nausea, vomiting, and diarrhea are uncommon.⁴ More recently, several reports describe a variety of skin findings associated with COVID-19. A current theory suggests that the virus does not directly target keratinocytes but triggers a systemic immune response, leading to a diversity of skin morphologies.⁵ The main types of described cutaneous findings include pseudochilblains, overtly vesicular, urticarial, maculopapular, and livedo/necrosis.⁶ Others have described petechial⁷ and papulosquamous eruptions.⁸ Most of these patients initially presented with typical COVID-19 symptoms and frequently represented more severe cases of the disease. Additionally, the vesicular and papulosquamous eruptions reportedly occurred on the trunk and not the limbs, as in our case.

This confirmed COVID-19–positive patient presented with an ill-defined vesicular and papulosquamous-type eruption on the arms and legs and later developed only mild GI symptoms. By sharing this case, we report yet another skin manifestation of COVID-19 and propose the possible expansion of testing for SARS-CoV-2 in patients presenting with rash and GI symptoms, which holds the potential to increase the identification of COVID-19 in the population, thereby increasing strict contact tracing and slowing the spread of this pandemic.

In December 2019, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) started an outbreak of respiratory illnesses in Wuhan, China. The respiratory disease was termed coronavirus disease 2019 (COVID-19) and rapidly spread worldwide, resulting in a pandemic classification on March 11, 2020. ¹ Recently, several cutaneous manifestations of COVID-19 have been reported. Skin manifestations have been reported to be similar to other common viral infections. ² However, there is a paucity of published clinical images of more atypical presentations.

Case Report

A 52-year-old black man presented via urgent store-and-forward teledermatology consultation from his primary care provider with a self-described “vesicular,” highly pruritic rash of both arms and legs of 1 week’s duration without involvement of the trunk, axillae, groin, face, genitalia, or any mucous membranes. He noted nausea, loss of appetite, and nonbloody diarrhea 4 days later. He denied fever, chills, dry cough, shortness of breath, or dyspnea. He had a history of hypertension and type 2 diabetes mellitus. There were no changes in medications; no outdoor activities, gardening, or yard work; no exposure to plants or metals; and no use of new personal care products.

The digital images showed zones of flesh-colored to slightly erythematous, somewhat “juicy” papules with some coalescence into ill-defined plaques. There were scattered foci of scale and hemorrhagic crust that involved both palms, forearms (Figure, A), and legs (Figure, B). There were no intact vesicles, and a herald patch was not identified. Vital signs at the time of imaging were normal, with the exception of a low-grade fever (temperature, 37.3°C). Basic laboratory testing showed only mild leukocytosis with mild neutropenia and mild aspartate aminotransaminase elevation. A skin biopsy was not performed. Pulmonary imaging and workup were not performed because of the lack of respiratory symptoms.

Comment

Coronavirus disease 2019 is caused by SARS-CoV2, an enveloped, nonsegmented, positive-sense RNA virus of the coronavirus family. It is currently believed that SARS-CoV-2 uses the angiotensin-converting enzyme 2 receptor to gain entry into human cells, leading to infection primarily affecting the lower respiratory tract.³ Patients suspected of COVID-19 infection most often present with fever, dry cough, dyspnea, and fatigue, while GI symptoms such as nausea, vomiting, and diarrhea are uncommon.⁴ More recently, several reports describe a variety of skin findings associated with COVID-19. A current theory suggests that the virus does not directly target keratinocytes but triggers a systemic immune response, leading to a diversity of skin morphologies.⁵ The main types of described cutaneous findings include pseudochilblains, overtly vesicular, urticarial, maculopapular, and livedo/necrosis.⁶ Others have described petechial⁷ and papulosquamous eruptions.⁸ Most of these patients initially presented with typical COVID-19 symptoms and frequently represented more severe cases of the disease. Additionally, the vesicular and papulosquamous eruptions reportedly occurred on the trunk and not the limbs, as in our case.

This confirmed COVID-19–positive patient presented with an ill-defined vesicular and papulosquamous-type eruption on the arms and legs and later developed only mild GI symptoms. By sharing this case, we report yet another skin manifestation of COVID-19 and propose the possible expansion of testing for SARS-CoV-2 in patients presenting with rash and GI symptoms, which holds the potential to increase the identification of COVID-19 in the population, thereby increasing strict contact tracing and slowing the spread of this pandemic.

A cute colonic pseudo-obstruction, or Ogilvie syndrome, is dilatation of the colon without mechanical obstruction. It is often seen postoperatively after cesarean section , pelvic , spinal, or other orthopedic surgery, such as knee arthroplasty. ¹ One study demonstrated an incidence of acute colonic pseudo-obstruction of 1.3% following hip replacement surgery. ²

The most common symptoms are abdominal distension, pain, nausea, vomiting, constipation, or diarrhea. Bowel sounds are present in the majority of cases.³ It is important to recognize the varied presentations of ileus in the postoperative setting. The most serious complications of acute colonic pseudo-obstruction are colonic ischemia and bowel perforation.

Case Presentation

An 84-year-old man underwent a total left hip arthroplasty revision. The evening after his surgery, his blood pressure (BP) decreased from 93/54 to 71/47 mm Hg, and his heart rate was 73 beats per minute. He was awake, in no acute distress, but reported loose stools. Results of cardiac and pulmonary examinations were normal, showing a regular rate and rhythm with no murmurs and clear lungs. There was normal jugular venous pressure and chronic pitting edema of the lower extremities bilaterally.

An abdominal examination revealed positive bowel sounds, a large ventral hernia, which was easily reducible, and a distended abdomen. His BP remained unchanged after IV normal saline 4 L, and urine output was 200 cc over 4 hours, which the care team determined represented adequate resuscitation. An infection workup, including chest X-ray, urinalysis, and blood and urine cultures, was unrevealing. Hemoglobin was stable at 8.5 g/dL (normal range 14-18), and creatinine level 0.66 mg/dL (normal range 0.7-1.2) at baseline. A transthoracic echocardiogram showed impaired diastolic filling suggestive of extrinsic compression of the left ventricle by mediastinal contents (Figure 1). An abdominal X-ray revealed diffuse dilatation of large bowel loops up to 10 cm, causing elevation and rightward shift of the heart (Figure 2A). A computed tomography scan of the abdomen showed total colonic dilatation without obstruction (Figure 2B).

Discussion

We present an unusual case of left ventricular compression leading to hypotension due to acute colonic pseudo-obstruction. Our patient presented with the rare complication of hypotension due to cardiac compression, which we have not previously seen reported in the literature. Analogous instance of cardiac compression may arise from hiatal hernias and diaphragmatic paralysis. ^4-6

Management of acute colonic pseudo-obstruction is through nothing by mouth status and abdominal decompression. For more severe cases, neostigmine, colonoscopic decompression, and surgery can be considered.

This surgical complication was diagnosed by internal medicine hospitalist consultants on a surgical comanagement service. In the comanagement model, the surgical specialties of orthopedic surgery, neurosurgery, and podiatry at San Francisco Veterans Affairs Medical Center in California have hospitalists who work with the team as active consultants for the medical care of the patients. Hospitalists develop a unique skill set in which they can anticipate new diagnoses, prevent or identify early complications, and individualize a patient’s postoperative care.⁷ One study found that a surgical comanagement service was associated with a decrease in the number of patients with at least 1 surgical complication, decrease in length of stay and 30-day readmissions for a medical cause, decreased consultant use, and an average cost savings per patient of about $2,600 to $4,300.⁸

Conclusions

With the increasing prevalence of hospitalist comanagement services, it is important for surgeons and nonsurgeons alike to recognize acute colonic pseudo-obstruction as a possible surgical complication.

A cute colonic pseudo-obstruction, or Ogilvie syndrome, is dilatation of the colon without mechanical obstruction. It is often seen postoperatively after cesarean section , pelvic , spinal, or other orthopedic surgery, such as knee arthroplasty. ¹ One study demonstrated an incidence of acute colonic pseudo-obstruction of 1.3% following hip replacement surgery. ²

The most common symptoms are abdominal distension, pain, nausea, vomiting, constipation, or diarrhea. Bowel sounds are present in the majority of cases.³ It is important to recognize the varied presentations of ileus in the postoperative setting. The most serious complications of acute colonic pseudo-obstruction are colonic ischemia and bowel perforation.

Case Presentation

An 84-year-old man underwent a total left hip arthroplasty revision. The evening after his surgery, his blood pressure (BP) decreased from 93/54 to 71/47 mm Hg, and his heart rate was 73 beats per minute. He was awake, in no acute distress, but reported loose stools. Results of cardiac and pulmonary examinations were normal, showing a regular rate and rhythm with no murmurs and clear lungs. There was normal jugular venous pressure and chronic pitting edema of the lower extremities bilaterally.

An abdominal examination revealed positive bowel sounds, a large ventral hernia, which was easily reducible, and a distended abdomen. His BP remained unchanged after IV normal saline 4 L, and urine output was 200 cc over 4 hours, which the care team determined represented adequate resuscitation. An infection workup, including chest X-ray, urinalysis, and blood and urine cultures, was unrevealing. Hemoglobin was stable at 8.5 g/dL (normal range 14-18), and creatinine level 0.66 mg/dL (normal range 0.7-1.2) at baseline. A transthoracic echocardiogram showed impaired diastolic filling suggestive of extrinsic compression of the left ventricle by mediastinal contents (Figure 1). An abdominal X-ray revealed diffuse dilatation of large bowel loops up to 10 cm, causing elevation and rightward shift of the heart (Figure 2A). A computed tomography scan of the abdomen showed total colonic dilatation without obstruction (Figure 2B).

Discussion

We present an unusual case of left ventricular compression leading to hypotension due to acute colonic pseudo-obstruction. Our patient presented with the rare complication of hypotension due to cardiac compression, which we have not previously seen reported in the literature. Analogous instance of cardiac compression may arise from hiatal hernias and diaphragmatic paralysis. ^4-6

Management of acute colonic pseudo-obstruction is through nothing by mouth status and abdominal decompression. For more severe cases, neostigmine, colonoscopic decompression, and surgery can be considered.

This surgical complication was diagnosed by internal medicine hospitalist consultants on a surgical comanagement service. In the comanagement model, the surgical specialties of orthopedic surgery, neurosurgery, and podiatry at San Francisco Veterans Affairs Medical Center in California have hospitalists who work with the team as active consultants for the medical care of the patients. Hospitalists develop a unique skill set in which they can anticipate new diagnoses, prevent or identify early complications, and individualize a patient’s postoperative care.⁷ One study found that a surgical comanagement service was associated with a decrease in the number of patients with at least 1 surgical complication, decrease in length of stay and 30-day readmissions for a medical cause, decreased consultant use, and an average cost savings per patient of about $2,600 to $4,300.⁸

Conclusions

With the increasing prevalence of hospitalist comanagement services, it is important for surgeons and nonsurgeons alike to recognize acute colonic pseudo-obstruction as a possible surgical complication.

A cute colonic pseudo-obstruction, or Ogilvie syndrome, is dilatation of the colon without mechanical obstruction. It is often seen postoperatively after cesarean section , pelvic , spinal, or other orthopedic surgery, such as knee arthroplasty. ¹ One study demonstrated an incidence of acute colonic pseudo-obstruction of 1.3% following hip replacement surgery. ²

The most common symptoms are abdominal distension, pain, nausea, vomiting, constipation, or diarrhea. Bowel sounds are present in the majority of cases.³ It is important to recognize the varied presentations of ileus in the postoperative setting. The most serious complications of acute colonic pseudo-obstruction are colonic ischemia and bowel perforation.

Case Presentation

An 84-year-old man underwent a total left hip arthroplasty revision. The evening after his surgery, his blood pressure (BP) decreased from 93/54 to 71/47 mm Hg, and his heart rate was 73 beats per minute. He was awake, in no acute distress, but reported loose stools. Results of cardiac and pulmonary examinations were normal, showing a regular rate and rhythm with no murmurs and clear lungs. There was normal jugular venous pressure and chronic pitting edema of the lower extremities bilaterally.

An abdominal examination revealed positive bowel sounds, a large ventral hernia, which was easily reducible, and a distended abdomen. His BP remained unchanged after IV normal saline 4 L, and urine output was 200 cc over 4 hours, which the care team determined represented adequate resuscitation. An infection workup, including chest X-ray, urinalysis, and blood and urine cultures, was unrevealing. Hemoglobin was stable at 8.5 g/dL (normal range 14-18), and creatinine level 0.66 mg/dL (normal range 0.7-1.2) at baseline. A transthoracic echocardiogram showed impaired diastolic filling suggestive of extrinsic compression of the left ventricle by mediastinal contents (Figure 1). An abdominal X-ray revealed diffuse dilatation of large bowel loops up to 10 cm, causing elevation and rightward shift of the heart (Figure 2A). A computed tomography scan of the abdomen showed total colonic dilatation without obstruction (Figure 2B).

Discussion

We present an unusual case of left ventricular compression leading to hypotension due to acute colonic pseudo-obstruction. Our patient presented with the rare complication of hypotension due to cardiac compression, which we have not previously seen reported in the literature. Analogous instance of cardiac compression may arise from hiatal hernias and diaphragmatic paralysis. ^4-6

Management of acute colonic pseudo-obstruction is through nothing by mouth status and abdominal decompression. For more severe cases, neostigmine, colonoscopic decompression, and surgery can be considered.

This surgical complication was diagnosed by internal medicine hospitalist consultants on a surgical comanagement service. In the comanagement model, the surgical specialties of orthopedic surgery, neurosurgery, and podiatry at San Francisco Veterans Affairs Medical Center in California have hospitalists who work with the team as active consultants for the medical care of the patients. Hospitalists develop a unique skill set in which they can anticipate new diagnoses, prevent or identify early complications, and individualize a patient’s postoperative care.⁷ One study found that a surgical comanagement service was associated with a decrease in the number of patients with at least 1 surgical complication, decrease in length of stay and 30-day readmissions for a medical cause, decreased consultant use, and an average cost savings per patient of about $2,600 to $4,300.⁸

Conclusions

With the increasing prevalence of hospitalist comanagement services, it is important for surgeons and nonsurgeons alike to recognize acute colonic pseudo-obstruction as a possible surgical complication.

Leptospirosis (LS) is considered the most common and widespread zoonotic disease in the world. Numerous outbreaks have occurred in the past 10 years. Due to its technically difficult diagnosis, LS is severely underrecognized, underdiagnosed, and therefore, underreported.^1,2 The Centers for Disease Control and Prevention (CDC) estimate 100 to 150 cases of LS are identified annually in the US, with about 50% of those cases occurring in Puerto Rico (PR).³ Specifically in PR, about 15 to 100 cases of suspected LS were reported annually between 2000 and 2009, with 59 cases and 1 death reported in 2010. The data are thought to be severely underreported due to a lack of widespread diagnostic testing availability in PR and no formal veterinary and environmental surveillance programs to monitor the incidence of animal cases and actual circulating serovars.⁴

A recent systematic review of 80 studies from 34 countries on morbidity and mortality of LS revealed that the global incidence and mortality is about 1.03 million cases and 58,900 deaths every year. Almost half of the reported deaths were adult males aged 20 to 49 years.⁵ Although mild cases of LS are not associated with an elevated mortality, icteric LS with renal failure (Weil disease) carries a mortality rate of 10%.⁶ In patients who develop hemorrhagic pneumonitis, mortality may be as high as 50 to 70%.⁷ Therefore, it is pivotal that clinicians recognize the disease early, that novel modalities of treatment continue to be developed, and that their impact on patient morbidity and mortality are studied and documented.

Case Presentation

A 43-year-old man with a medical history of schizophrenia presented to the emergency department at the US Department of Veterans Affairs (VA) Caribbean Healthcare System in San Juan, PR, after experiencing 1 week of intermittent fever, myalgia, and general weakness. Emergency medical services had found him disheveled and in a rodent-infested swamp area several days before admission. Initial vital signs were within normal limits.

On physical examination, the patient was afebrile, without acute distress, but he had diffuse jaundice and mild epigastric tenderness without evidence of peritoneal irritation. His complete blood count was remarkable for leukocytosis with left shifting, adequate hemoglobin levels but with 9 × 10³ U/L platelets. The complete metabolic panel demonstrated an aspartate aminotransferase level of 564 U/L, alanine transaminase level of 462 U/L, total bilirubin of 12 mg/dL, which 10.2 mg/dL were direct bilirubin, and an alkaline phosphate of 345 U/L. Lipase levels were measured at 626 U/L. Marked coagulopathy also was present. The toxicology panel, including acetaminophen and salicylate acid levels, did not reveal the presence of any of the tested substances, and chest imaging did not demonstrate any infiltrates.

An abdominal ultrasound was negative for acute cholestatic pathologies, such as cholelithiasis, cholecystitis, or choledocholithiasis. Nonetheless, a noncontrast abdominopelvic computed tomography was remarkable for peripancreatic fat stranding, which raised suspicion for a diagnosis of pancreatitis.

Once the patient was transferred to the intensive care unit, he developed several episodes of hematemesis, leading to hemodynamical instability and severe respiratory distress. Due to anticipated respiratory failure and need for airway securement, endotracheal intubation was performed. Multiple packed red blood cells were transfused, and the patient was started in vasopressor support.

Diagnosis

A presumptive diagnosis of LS was made due to a considerable history of rodent exposure. The patient was started on broad-spectrum parenteral antibiotics, vancomycin 750 mg every 24 hours, metronidazole 500 mg every 8 hours, and ceftriaxone 2 g IV daily for adequate coverage against Leptospira spp. Despite 72 hours of antibiotic treatment, the patient’s clinical state deteriorated. He required high dosages of norepinephrine (1.5 mcg/kg/min) and vasopressin (0.03 U/min) to maintain adequate organ perfusion. Despite lung protective settings with low tidal volume and a high positive end-expiratory pressure, there was difficulty maintaining adequate oxygenation. Chest imaging was remarkable for bilateral infiltrates concerning for acute respiratory distress syndrome (ARDS).

The coagulopathy and cholestasis continued to worsen, and the renal failure progressed from nonoliguric to anuric. Because of this progression, the patient was started on continuous renal replacement therapy (CRRT) by hemodialysis. Within 24 hours of initiating CRRT, the patient’s clinical status improved dramatically. Vasopressor support was weaned, the coagulopathy resolved, and the cholestasis was improving. The patient’s respiratory status improved in such a manner that he was extubated by the seventh day after being placed on mechanical ventilation. The urine and blood samples sent for identification of Leptospira spp. through polymerase chain reaction (PCR) returned positive by the ninth day of admission. While on CRRT, the patient’s renal function eventually returned to baseline, and he was discharged 12 days after admission.

Discussion

The spirochetes of the genus Leptospira include both saprophytic and pathogenic species. These pathogenic Leptospira spp. have adapted to a grand variety of zoonotic hosts, the most important being rodents. They serve as vectors for the contraction of the disease by humans. Initial infection in rodents by Leptospira spp. causes a systemic illness followed by a persistent colonization of renal tubules from which they are excreted in the urine and into the environment. Humans, in turn, are an incidental host unable to induce a carrier state for the transmission of the pathogenic organism.¹ The time from exposure to onset of symptoms, or incubation phase, averages 7 to 12 days but may range from 3 to 30 days.⁸

LS has been described as having 2 discernable but often coexisting phases. The first, an acute febrile bacteremic phase, has been noted to last about 9 days in about 85% of patients, although a minority have persistent fever from 2 weeks to > 30 days. A second phase, the immune or inflammatory phase, is characterized by a second fever spike preceded by 1 to 5 afebrile days in which there is presence of IgM antibodies and resolution of leptospiremia but positive urine cultures.⁹ Weil disease may present as the second phase of the disease or as a single, progressive illness from its first manifestation. It is characterized by a triad of jaundice, renal failure, and hemorrhage or coagulopathy.¹⁰ Weil disease is of great concern and importance due to its associated higher mortality than that found with the mildest form of the disease.

There are studies that advocate for RRT as an intricate part of the treatment regimen in LS to remove the inflammatory cytokines produced as a reaction to the spirochete.¹¹ In tropical countries with a higher incidence of the disease, leptospirosis is an important cause of acute kidney injury (AKI), depending on multiple factors, including the AKI definition that is used.¹² Renal invasion by Leptospira spp. produces acute tubular necrosis (ATN) and cell edema during the first week and then could progress to acute interstitial nephritis (AIN) in 2 to 3 weeks. It is believed that the mechanism for the Leptospira spp. invasion of the tubules that results in damage is associated with the antigenic components in its outer membrane; the most important outer membrane protein expressed during infection is LipL32. This protein increases the production of proinflammatory proteins, such as inducible nitric oxide synthase, monocyte chemotactic protein-1 (CCL2/MCP-1), T cells, and tumor necrosis factor.¹³

Although doxycycline has been recommended for the prophylaxis and treatment of mild LS, the preferred agent and the conferred benefits of antibiotic treatment overall for the severe form of the disease has been controversial. Traditionally, penicillin G sodium has been recommended as the first-line antibiotic treatment for moderate-to-severe LS.¹⁴ Nonetheless, there has been an increasing pattern of penicillin resistance among Leptospira spp. that has prompted the study and use of alternative agents.

An open-label, randomized comparison of parenteral cefotaxime, penicillin G sodium, and doxycycline for the treatment of suspected severe leptospirosis conducted by Suputtamongkol and colleagues showed no difference in mortality, defervescence, or time to resolution of abnormal laboratory findings.¹⁵ Current CDC recommendations include the use of parenteral penicillin 1.5 MU every 6 hours as the drug of choice, with ceftriaxone 1 g administered IV every 24 hours equally as effective.³

In addition to antimicrobial therapy, supportive care has shifted to include hemodialysis in those patients who develop AKI as part of the disease. Andrade and colleagues conducted a study of 33 patients with LS in Brazil that was set to compare the impact of door-to-dialysis time and dosage of hemodialysis on mortality. In patients with a quicker door-to-dialysis time and daily hemodialysis sessions, there was a 50% (16.7% vs 66.7%) absolute mortality reduction when compared with those with delayed initiation and alternate-day hemodialysis sessions.¹¹ A follow-up prospective study compared the use of traditional sustained low-efficiency dialysis (SLED) with the use of extended SLED via hemodiafiltration in patients with LS presenting with ARDS and AKI. Although hemodiafiltration resulted in a relative decrease in serum levels of interleukin (IL)-17, IL-7, and CCL2/MCP-1, there was no significant difference in mortality.¹⁶ The most important prognostic factor in severe LS presenting with AKI and relating to RRT is a shorter door-to-dialysis time and increased dose, not the mode of dialysis clearance. Nonetheless, both RRT methods resulted in a progressive decrease in inflammatory mediators that have been associated with ATN and AIN in the context of LS.¹⁶ The authors argue that using CRRT instead of SLED via hemodiafiltration could have accentuated the effects of the reduction that inflammatory mediators may have on mortality in patients with severe LS.

Conclusions

LS continues to be of interest due to its current status as the most common zoonotic disease and its widespread prevalence throughout the globe. Novel treatment modalities for LS, specifically for Weil disease, continue to be developed with the goal of reducing the current mortality rate associated with the disease.

In endemic areas, prompt recognition is essential to initiate the recommended therapy. Parenteral antibiotics, such as penicillin G sodium and ceftriaxone, continue to be the mainstay of treatment and constitute the current CDC recommendations. Nonetheless, early initiation of CRRT has been shown to greatly reduce the mortality associated with Weil disease and, when available, should be considered in these patients.

Our patient failed to improve while receiving parenteral antibiotics alone but showed marked improvement after being placed on CRRT. Furthermore, initiation of CRRT resulted in near-complete resolution of his organ dysfunction and eventual discharge from the hospital. This case serves to further support the use of early CRRT as part of the standard of care in severe LS.

Leptospirosis (LS) is considered the most common and widespread zoonotic disease in the world. Numerous outbreaks have occurred in the past 10 years. Due to its technically difficult diagnosis, LS is severely underrecognized, underdiagnosed, and therefore, underreported.^1,2 The Centers for Disease Control and Prevention (CDC) estimate 100 to 150 cases of LS are identified annually in the US, with about 50% of those cases occurring in Puerto Rico (PR).³ Specifically in PR, about 15 to 100 cases of suspected LS were reported annually between 2000 and 2009, with 59 cases and 1 death reported in 2010. The data are thought to be severely underreported due to a lack of widespread diagnostic testing availability in PR and no formal veterinary and environmental surveillance programs to monitor the incidence of animal cases and actual circulating serovars.⁴

A recent systematic review of 80 studies from 34 countries on morbidity and mortality of LS revealed that the global incidence and mortality is about 1.03 million cases and 58,900 deaths every year. Almost half of the reported deaths were adult males aged 20 to 49 years.⁵ Although mild cases of LS are not associated with an elevated mortality, icteric LS with renal failure (Weil disease) carries a mortality rate of 10%.⁶ In patients who develop hemorrhagic pneumonitis, mortality may be as high as 50 to 70%.⁷ Therefore, it is pivotal that clinicians recognize the disease early, that novel modalities of treatment continue to be developed, and that their impact on patient morbidity and mortality are studied and documented.

Case Presentation

A 43-year-old man with a medical history of schizophrenia presented to the emergency department at the US Department of Veterans Affairs (VA) Caribbean Healthcare System in San Juan, PR, after experiencing 1 week of intermittent fever, myalgia, and general weakness. Emergency medical services had found him disheveled and in a rodent-infested swamp area several days before admission. Initial vital signs were within normal limits.

On physical examination, the patient was afebrile, without acute distress, but he had diffuse jaundice and mild epigastric tenderness without evidence of peritoneal irritation. His complete blood count was remarkable for leukocytosis with left shifting, adequate hemoglobin levels but with 9 × 10³ U/L platelets. The complete metabolic panel demonstrated an aspartate aminotransferase level of 564 U/L, alanine transaminase level of 462 U/L, total bilirubin of 12 mg/dL, which 10.2 mg/dL were direct bilirubin, and an alkaline phosphate of 345 U/L. Lipase levels were measured at 626 U/L. Marked coagulopathy also was present. The toxicology panel, including acetaminophen and salicylate acid levels, did not reveal the presence of any of the tested substances, and chest imaging did not demonstrate any infiltrates.

An abdominal ultrasound was negative for acute cholestatic pathologies, such as cholelithiasis, cholecystitis, or choledocholithiasis. Nonetheless, a noncontrast abdominopelvic computed tomography was remarkable for peripancreatic fat stranding, which raised suspicion for a diagnosis of pancreatitis.

Once the patient was transferred to the intensive care unit, he developed several episodes of hematemesis, leading to hemodynamical instability and severe respiratory distress. Due to anticipated respiratory failure and need for airway securement, endotracheal intubation was performed. Multiple packed red blood cells were transfused, and the patient was started in vasopressor support.

Diagnosis

A presumptive diagnosis of LS was made due to a considerable history of rodent exposure. The patient was started on broad-spectrum parenteral antibiotics, vancomycin 750 mg every 24 hours, metronidazole 500 mg every 8 hours, and ceftriaxone 2 g IV daily for adequate coverage against Leptospira spp. Despite 72 hours of antibiotic treatment, the patient’s clinical state deteriorated. He required high dosages of norepinephrine (1.5 mcg/kg/min) and vasopressin (0.03 U/min) to maintain adequate organ perfusion. Despite lung protective settings with low tidal volume and a high positive end-expiratory pressure, there was difficulty maintaining adequate oxygenation. Chest imaging was remarkable for bilateral infiltrates concerning for acute respiratory distress syndrome (ARDS).

The coagulopathy and cholestasis continued to worsen, and the renal failure progressed from nonoliguric to anuric. Because of this progression, the patient was started on continuous renal replacement therapy (CRRT) by hemodialysis. Within 24 hours of initiating CRRT, the patient’s clinical status improved dramatically. Vasopressor support was weaned, the coagulopathy resolved, and the cholestasis was improving. The patient’s respiratory status improved in such a manner that he was extubated by the seventh day after being placed on mechanical ventilation. The urine and blood samples sent for identification of Leptospira spp. through polymerase chain reaction (PCR) returned positive by the ninth day of admission. While on CRRT, the patient’s renal function eventually returned to baseline, and he was discharged 12 days after admission.

Discussion

The spirochetes of the genus Leptospira include both saprophytic and pathogenic species. These pathogenic Leptospira spp. have adapted to a grand variety of zoonotic hosts, the most important being rodents. They serve as vectors for the contraction of the disease by humans. Initial infection in rodents by Leptospira spp. causes a systemic illness followed by a persistent colonization of renal tubules from which they are excreted in the urine and into the environment. Humans, in turn, are an incidental host unable to induce a carrier state for the transmission of the pathogenic organism.¹ The time from exposure to onset of symptoms, or incubation phase, averages 7 to 12 days but may range from 3 to 30 days.⁸

LS has been described as having 2 discernable but often coexisting phases. The first, an acute febrile bacteremic phase, has been noted to last about 9 days in about 85% of patients, although a minority have persistent fever from 2 weeks to > 30 days. A second phase, the immune or inflammatory phase, is characterized by a second fever spike preceded by 1 to 5 afebrile days in which there is presence of IgM antibodies and resolution of leptospiremia but positive urine cultures.⁹ Weil disease may present as the second phase of the disease or as a single, progressive illness from its first manifestation. It is characterized by a triad of jaundice, renal failure, and hemorrhage or coagulopathy.¹⁰ Weil disease is of great concern and importance due to its associated higher mortality than that found with the mildest form of the disease.

There are studies that advocate for RRT as an intricate part of the treatment regimen in LS to remove the inflammatory cytokines produced as a reaction to the spirochete.¹¹ In tropical countries with a higher incidence of the disease, leptospirosis is an important cause of acute kidney injury (AKI), depending on multiple factors, including the AKI definition that is used.¹² Renal invasion by Leptospira spp. produces acute tubular necrosis (ATN) and cell edema during the first week and then could progress to acute interstitial nephritis (AIN) in 2 to 3 weeks. It is believed that the mechanism for the Leptospira spp. invasion of the tubules that results in damage is associated with the antigenic components in its outer membrane; the most important outer membrane protein expressed during infection is LipL32. This protein increases the production of proinflammatory proteins, such as inducible nitric oxide synthase, monocyte chemotactic protein-1 (CCL2/MCP-1), T cells, and tumor necrosis factor.¹³

Although doxycycline has been recommended for the prophylaxis and treatment of mild LS, the preferred agent and the conferred benefits of antibiotic treatment overall for the severe form of the disease has been controversial. Traditionally, penicillin G sodium has been recommended as the first-line antibiotic treatment for moderate-to-severe LS.¹⁴ Nonetheless, there has been an increasing pattern of penicillin resistance among Leptospira spp. that has prompted the study and use of alternative agents.

An open-label, randomized comparison of parenteral cefotaxime, penicillin G sodium, and doxycycline for the treatment of suspected severe leptospirosis conducted by Suputtamongkol and colleagues showed no difference in mortality, defervescence, or time to resolution of abnormal laboratory findings.¹⁵ Current CDC recommendations include the use of parenteral penicillin 1.5 MU every 6 hours as the drug of choice, with ceftriaxone 1 g administered IV every 24 hours equally as effective.³

In addition to antimicrobial therapy, supportive care has shifted to include hemodialysis in those patients who develop AKI as part of the disease. Andrade and colleagues conducted a study of 33 patients with LS in Brazil that was set to compare the impact of door-to-dialysis time and dosage of hemodialysis on mortality. In patients with a quicker door-to-dialysis time and daily hemodialysis sessions, there was a 50% (16.7% vs 66.7%) absolute mortality reduction when compared with those with delayed initiation and alternate-day hemodialysis sessions.¹¹ A follow-up prospective study compared the use of traditional sustained low-efficiency dialysis (SLED) with the use of extended SLED via hemodiafiltration in patients with LS presenting with ARDS and AKI. Although hemodiafiltration resulted in a relative decrease in serum levels of interleukin (IL)-17, IL-7, and CCL2/MCP-1, there was no significant difference in mortality.¹⁶ The most important prognostic factor in severe LS presenting with AKI and relating to RRT is a shorter door-to-dialysis time and increased dose, not the mode of dialysis clearance. Nonetheless, both RRT methods resulted in a progressive decrease in inflammatory mediators that have been associated with ATN and AIN in the context of LS.¹⁶ The authors argue that using CRRT instead of SLED via hemodiafiltration could have accentuated the effects of the reduction that inflammatory mediators may have on mortality in patients with severe LS.

Conclusions

LS continues to be of interest due to its current status as the most common zoonotic disease and its widespread prevalence throughout the globe. Novel treatment modalities for LS, specifically for Weil disease, continue to be developed with the goal of reducing the current mortality rate associated with the disease.

In endemic areas, prompt recognition is essential to initiate the recommended therapy. Parenteral antibiotics, such as penicillin G sodium and ceftriaxone, continue to be the mainstay of treatment and constitute the current CDC recommendations. Nonetheless, early initiation of CRRT has been shown to greatly reduce the mortality associated with Weil disease and, when available, should be considered in these patients.

Our patient failed to improve while receiving parenteral antibiotics alone but showed marked improvement after being placed on CRRT. Furthermore, initiation of CRRT resulted in near-complete resolution of his organ dysfunction and eventual discharge from the hospital. This case serves to further support the use of early CRRT as part of the standard of care in severe LS.

Leptospirosis (LS) is considered the most common and widespread zoonotic disease in the world. Numerous outbreaks have occurred in the past 10 years. Due to its technically difficult diagnosis, LS is severely underrecognized, underdiagnosed, and therefore, underreported.^1,2 The Centers for Disease Control and Prevention (CDC) estimate 100 to 150 cases of LS are identified annually in the US, with about 50% of those cases occurring in Puerto Rico (PR).³ Specifically in PR, about 15 to 100 cases of suspected LS were reported annually between 2000 and 2009, with 59 cases and 1 death reported in 2010. The data are thought to be severely underreported due to a lack of widespread diagnostic testing availability in PR and no formal veterinary and environmental surveillance programs to monitor the incidence of animal cases and actual circulating serovars.⁴

A recent systematic review of 80 studies from 34 countries on morbidity and mortality of LS revealed that the global incidence and mortality is about 1.03 million cases and 58,900 deaths every year. Almost half of the reported deaths were adult males aged 20 to 49 years.⁵ Although mild cases of LS are not associated with an elevated mortality, icteric LS with renal failure (Weil disease) carries a mortality rate of 10%.⁶ In patients who develop hemorrhagic pneumonitis, mortality may be as high as 50 to 70%.⁷ Therefore, it is pivotal that clinicians recognize the disease early, that novel modalities of treatment continue to be developed, and that their impact on patient morbidity and mortality are studied and documented.

Case Presentation

A 43-year-old man with a medical history of schizophrenia presented to the emergency department at the US Department of Veterans Affairs (VA) Caribbean Healthcare System in San Juan, PR, after experiencing 1 week of intermittent fever, myalgia, and general weakness. Emergency medical services had found him disheveled and in a rodent-infested swamp area several days before admission. Initial vital signs were within normal limits.

On physical examination, the patient was afebrile, without acute distress, but he had diffuse jaundice and mild epigastric tenderness without evidence of peritoneal irritation. His complete blood count was remarkable for leukocytosis with left shifting, adequate hemoglobin levels but with 9 × 10³ U/L platelets. The complete metabolic panel demonstrated an aspartate aminotransferase level of 564 U/L, alanine transaminase level of 462 U/L, total bilirubin of 12 mg/dL, which 10.2 mg/dL were direct bilirubin, and an alkaline phosphate of 345 U/L. Lipase levels were measured at 626 U/L. Marked coagulopathy also was present. The toxicology panel, including acetaminophen and salicylate acid levels, did not reveal the presence of any of the tested substances, and chest imaging did not demonstrate any infiltrates.

An abdominal ultrasound was negative for acute cholestatic pathologies, such as cholelithiasis, cholecystitis, or choledocholithiasis. Nonetheless, a noncontrast abdominopelvic computed tomography was remarkable for peripancreatic fat stranding, which raised suspicion for a diagnosis of pancreatitis.

Once the patient was transferred to the intensive care unit, he developed several episodes of hematemesis, leading to hemodynamical instability and severe respiratory distress. Due to anticipated respiratory failure and need for airway securement, endotracheal intubation was performed. Multiple packed red blood cells were transfused, and the patient was started in vasopressor support.

Diagnosis

A presumptive diagnosis of LS was made due to a considerable history of rodent exposure. The patient was started on broad-spectrum parenteral antibiotics, vancomycin 750 mg every 24 hours, metronidazole 500 mg every 8 hours, and ceftriaxone 2 g IV daily for adequate coverage against Leptospira spp. Despite 72 hours of antibiotic treatment, the patient’s clinical state deteriorated. He required high dosages of norepinephrine (1.5 mcg/kg/min) and vasopressin (0.03 U/min) to maintain adequate organ perfusion. Despite lung protective settings with low tidal volume and a high positive end-expiratory pressure, there was difficulty maintaining adequate oxygenation. Chest imaging was remarkable for bilateral infiltrates concerning for acute respiratory distress syndrome (ARDS).

The coagulopathy and cholestasis continued to worsen, and the renal failure progressed from nonoliguric to anuric. Because of this progression, the patient was started on continuous renal replacement therapy (CRRT) by hemodialysis. Within 24 hours of initiating CRRT, the patient’s clinical status improved dramatically. Vasopressor support was weaned, the coagulopathy resolved, and the cholestasis was improving. The patient’s respiratory status improved in such a manner that he was extubated by the seventh day after being placed on mechanical ventilation. The urine and blood samples sent for identification of Leptospira spp. through polymerase chain reaction (PCR) returned positive by the ninth day of admission. While on CRRT, the patient’s renal function eventually returned to baseline, and he was discharged 12 days after admission.

Discussion

The spirochetes of the genus Leptospira include both saprophytic and pathogenic species. These pathogenic Leptospira spp. have adapted to a grand variety of zoonotic hosts, the most important being rodents. They serve as vectors for the contraction of the disease by humans. Initial infection in rodents by Leptospira spp. causes a systemic illness followed by a persistent colonization of renal tubules from which they are excreted in the urine and into the environment. Humans, in turn, are an incidental host unable to induce a carrier state for the transmission of the pathogenic organism.¹ The time from exposure to onset of symptoms, or incubation phase, averages 7 to 12 days but may range from 3 to 30 days.⁸

LS has been described as having 2 discernable but often coexisting phases. The first, an acute febrile bacteremic phase, has been noted to last about 9 days in about 85% of patients, although a minority have persistent fever from 2 weeks to > 30 days. A second phase, the immune or inflammatory phase, is characterized by a second fever spike preceded by 1 to 5 afebrile days in which there is presence of IgM antibodies and resolution of leptospiremia but positive urine cultures.⁹ Weil disease may present as the second phase of the disease or as a single, progressive illness from its first manifestation. It is characterized by a triad of jaundice, renal failure, and hemorrhage or coagulopathy.¹⁰ Weil disease is of great concern and importance due to its associated higher mortality than that found with the mildest form of the disease.

There are studies that advocate for RRT as an intricate part of the treatment regimen in LS to remove the inflammatory cytokines produced as a reaction to the spirochete.¹¹ In tropical countries with a higher incidence of the disease, leptospirosis is an important cause of acute kidney injury (AKI), depending on multiple factors, including the AKI definition that is used.¹² Renal invasion by Leptospira spp. produces acute tubular necrosis (ATN) and cell edema during the first week and then could progress to acute interstitial nephritis (AIN) in 2 to 3 weeks. It is believed that the mechanism for the Leptospira spp. invasion of the tubules that results in damage is associated with the antigenic components in its outer membrane; the most important outer membrane protein expressed during infection is LipL32. This protein increases the production of proinflammatory proteins, such as inducible nitric oxide synthase, monocyte chemotactic protein-1 (CCL2/MCP-1), T cells, and tumor necrosis factor.¹³

Although doxycycline has been recommended for the prophylaxis and treatment of mild LS, the preferred agent and the conferred benefits of antibiotic treatment overall for the severe form of the disease has been controversial. Traditionally, penicillin G sodium has been recommended as the first-line antibiotic treatment for moderate-to-severe LS.¹⁴ Nonetheless, there has been an increasing pattern of penicillin resistance among Leptospira spp. that has prompted the study and use of alternative agents.

An open-label, randomized comparison of parenteral cefotaxime, penicillin G sodium, and doxycycline for the treatment of suspected severe leptospirosis conducted by Suputtamongkol and colleagues showed no difference in mortality, defervescence, or time to resolution of abnormal laboratory findings.¹⁵ Current CDC recommendations include the use of parenteral penicillin 1.5 MU every 6 hours as the drug of choice, with ceftriaxone 1 g administered IV every 24 hours equally as effective.³

In addition to antimicrobial therapy, supportive care has shifted to include hemodialysis in those patients who develop AKI as part of the disease. Andrade and colleagues conducted a study of 33 patients with LS in Brazil that was set to compare the impact of door-to-dialysis time and dosage of hemodialysis on mortality. In patients with a quicker door-to-dialysis time and daily hemodialysis sessions, there was a 50% (16.7% vs 66.7%) absolute mortality reduction when compared with those with delayed initiation and alternate-day hemodialysis sessions.¹¹ A follow-up prospective study compared the use of traditional sustained low-efficiency dialysis (SLED) with the use of extended SLED via hemodiafiltration in patients with LS presenting with ARDS and AKI. Although hemodiafiltration resulted in a relative decrease in serum levels of interleukin (IL)-17, IL-7, and CCL2/MCP-1, there was no significant difference in mortality.¹⁶ The most important prognostic factor in severe LS presenting with AKI and relating to RRT is a shorter door-to-dialysis time and increased dose, not the mode of dialysis clearance. Nonetheless, both RRT methods resulted in a progressive decrease in inflammatory mediators that have been associated with ATN and AIN in the context of LS.¹⁶ The authors argue that using CRRT instead of SLED via hemodiafiltration could have accentuated the effects of the reduction that inflammatory mediators may have on mortality in patients with severe LS.

Conclusions

LS continues to be of interest due to its current status as the most common zoonotic disease and its widespread prevalence throughout the globe. Novel treatment modalities for LS, specifically for Weil disease, continue to be developed with the goal of reducing the current mortality rate associated with the disease.

In endemic areas, prompt recognition is essential to initiate the recommended therapy. Parenteral antibiotics, such as penicillin G sodium and ceftriaxone, continue to be the mainstay of treatment and constitute the current CDC recommendations. Nonetheless, early initiation of CRRT has been shown to greatly reduce the mortality associated with Weil disease and, when available, should be considered in these patients.

Our patient failed to improve while receiving parenteral antibiotics alone but showed marked improvement after being placed on CRRT. Furthermore, initiation of CRRT resulted in near-complete resolution of his organ dysfunction and eventual discharge from the hospital. This case serves to further support the use of early CRRT as part of the standard of care in severe LS.