Article

Key clinical point: The preadmission antidiabetic medications may influence mortality outcomes in patients with COVID-19 and type 2 diabetes (T2D).

Major finding: The risk for in-hospital mortality was significantly lower among patients taking metformin (odd ratio [OR] 0.54; 95% CI 0.47-0.62), glucagon-like peptide-1 receptor agonist (OR 0.51; 95% CI 0.37-0.69), and sodium-glucose transporter-2 inhibitor (OR 0.60; 95% CI 0.40-0.88), but higher among those taking dipeptidyl peptidase-4 inhibitor (OR 1.23; 95% CI 1.07-1.42) and insulin (OR 1.70; 95% CI 1.33-2.19), compared with patients taking none of these medications. Sulfonylurea, thiazolidinedione, and alpha-glucosidase inhibitors showed neutral effects on mortality.

Study details: The data come from a meta-analysis of 61 studies including 3,061,584 patients with COVID-19 and T2D.

Disclosures: This study received no specific grant from any funding agency.

Source: Nguyen NN et al. Preadmission use of antidiabetic medications and mortality among patients with COVID-19 having type 2 diabetes: A meta-analysis. Metabolism. 2022;131:155196 (Mar 31). Doi: 10.1016/j.metabol.2022.155196

Key clinical point: The preadmission antidiabetic medications may influence mortality outcomes in patients with COVID-19 and type 2 diabetes (T2D).

Major finding: The risk for in-hospital mortality was significantly lower among patients taking metformin (odd ratio [OR] 0.54; 95% CI 0.47-0.62), glucagon-like peptide-1 receptor agonist (OR 0.51; 95% CI 0.37-0.69), and sodium-glucose transporter-2 inhibitor (OR 0.60; 95% CI 0.40-0.88), but higher among those taking dipeptidyl peptidase-4 inhibitor (OR 1.23; 95% CI 1.07-1.42) and insulin (OR 1.70; 95% CI 1.33-2.19), compared with patients taking none of these medications. Sulfonylurea, thiazolidinedione, and alpha-glucosidase inhibitors showed neutral effects on mortality.

Study details: The data come from a meta-analysis of 61 studies including 3,061,584 patients with COVID-19 and T2D.

Disclosures: This study received no specific grant from any funding agency.

Source: Nguyen NN et al. Preadmission use of antidiabetic medications and mortality among patients with COVID-19 having type 2 diabetes: A meta-analysis. Metabolism. 2022;131:155196 (Mar 31). Doi: 10.1016/j.metabol.2022.155196

Key clinical point: The preadmission antidiabetic medications may influence mortality outcomes in patients with COVID-19 and type 2 diabetes (T2D).

Major finding: The risk for in-hospital mortality was significantly lower among patients taking metformin (odd ratio [OR] 0.54; 95% CI 0.47-0.62), glucagon-like peptide-1 receptor agonist (OR 0.51; 95% CI 0.37-0.69), and sodium-glucose transporter-2 inhibitor (OR 0.60; 95% CI 0.40-0.88), but higher among those taking dipeptidyl peptidase-4 inhibitor (OR 1.23; 95% CI 1.07-1.42) and insulin (OR 1.70; 95% CI 1.33-2.19), compared with patients taking none of these medications. Sulfonylurea, thiazolidinedione, and alpha-glucosidase inhibitors showed neutral effects on mortality.

Study details: The data come from a meta-analysis of 61 studies including 3,061,584 patients with COVID-19 and T2D.

Disclosures: This study received no specific grant from any funding agency.

Source: Nguyen NN et al. Preadmission use of antidiabetic medications and mortality among patients with COVID-19 having type 2 diabetes: A meta-analysis. Metabolism. 2022;131:155196 (Mar 31). Doi: 10.1016/j.metabol.2022.155196

Key clinical point: In patients with type 2 diabetes (T2D), the use of sodium-glucose cotransporter 2 inhibitors (SGLT2i) vs. dipeptidyl peptidase-4 inhibitors (DPP4i) was associated with a lower risk for end-stage renal disease (ESRD) and acute renal failure (ARF) and a slower decline in the estimated glomerular filtration rate (eGFR).

Major finding: Over a median follow-up of 3.8 years, the use of SGLT2i vs. DPP4i was associated with a significantly lower risk for ESRD (hazard ratio [HR] 0.51; P < .001) and ARF (HR 0.59; P < .001) and a significantly slower decline in eGFR (−0.060 vs. −0.625 mL/min/1.73m²  per year; P_interaction < .001).

Study details: This retrospective cohort study propensity score matched 6333 patients with T2D receiving an SGLT2i with 25,332 of those receiving a DPP4i.

Disclosures: This study did not receive any funding. The authors declared no conflicts of interest.

Source: Au PCM et al. Association between SGLT20iInhibitors vs DPP4 inhibitors and renal outcomes among patients with type 2 diabetes. J Clin Endocrinol Metab. 2022 (Mar 18). Doi:  10.1210/clinem/dgac164

Key clinical point: In patients with type 2 diabetes (T2D), the use of sodium-glucose cotransporter 2 inhibitors (SGLT2i) vs. dipeptidyl peptidase-4 inhibitors (DPP4i) was associated with a lower risk for end-stage renal disease (ESRD) and acute renal failure (ARF) and a slower decline in the estimated glomerular filtration rate (eGFR).

Major finding: Over a median follow-up of 3.8 years, the use of SGLT2i vs. DPP4i was associated with a significantly lower risk for ESRD (hazard ratio [HR] 0.51; P < .001) and ARF (HR 0.59; P < .001) and a significantly slower decline in eGFR (−0.060 vs. −0.625 mL/min/1.73m²  per year; P_interaction < .001).

Study details: This retrospective cohort study propensity score matched 6333 patients with T2D receiving an SGLT2i with 25,332 of those receiving a DPP4i.

Disclosures: This study did not receive any funding. The authors declared no conflicts of interest.

Source: Au PCM et al. Association between SGLT20iInhibitors vs DPP4 inhibitors and renal outcomes among patients with type 2 diabetes. J Clin Endocrinol Metab. 2022 (Mar 18). Doi:  10.1210/clinem/dgac164

Key clinical point: In patients with type 2 diabetes (T2D), the use of sodium-glucose cotransporter 2 inhibitors (SGLT2i) vs. dipeptidyl peptidase-4 inhibitors (DPP4i) was associated with a lower risk for end-stage renal disease (ESRD) and acute renal failure (ARF) and a slower decline in the estimated glomerular filtration rate (eGFR).

Major finding: Over a median follow-up of 3.8 years, the use of SGLT2i vs. DPP4i was associated with a significantly lower risk for ESRD (hazard ratio [HR] 0.51; P < .001) and ARF (HR 0.59; P < .001) and a significantly slower decline in eGFR (−0.060 vs. −0.625 mL/min/1.73m²  per year; P_interaction < .001).

Study details: This retrospective cohort study propensity score matched 6333 patients with T2D receiving an SGLT2i with 25,332 of those receiving a DPP4i.

Disclosures: This study did not receive any funding. The authors declared no conflicts of interest.

Source: Au PCM et al. Association between SGLT20iInhibitors vs DPP4 inhibitors and renal outcomes among patients with type 2 diabetes. J Clin Endocrinol Metab. 2022 (Mar 18). Doi:  10.1210/clinem/dgac164

Key clinical point: Resistance training (RT) effectively reduces glycosylated hemoglobin (HbA1c) in patients with type 2 diabetes mellitus (T2D), with RT interventions triggering a larger vs. medium or smaller improvement in muscular strength leading to a greater reduction in HbA1c.

Major finding: RT intervention vs. control treatment significantly decreased HbA1c (weighted mean difference −0.39; P < .001), with a larger vs. medium or small effect on muscular strength leading to a greater reduction in HbA1c (β −0.99; P = .0470).

Study details: Findings are from a meta-analysis of 20 trials including 1172 patients with T2DM.

Disclosures: The study received no specific funding. The authors declared no competing interests.

Source: Jansson AK et al. Effect of resistance training on HbA1c in adults with type 2 diabetes mellitus and the moderating effect of changes in muscular strength: a systematic review and meta-analysis. BMJ Open Diabetes Res Care. 2022;10:e002595 (Mar 10). Doi: 10.1136/bmjdrc-2021-002595

Key clinical point: Resistance training (RT) effectively reduces glycosylated hemoglobin (HbA1c) in patients with type 2 diabetes mellitus (T2D), with RT interventions triggering a larger vs. medium or smaller improvement in muscular strength leading to a greater reduction in HbA1c.

Major finding: RT intervention vs. control treatment significantly decreased HbA1c (weighted mean difference −0.39; P < .001), with a larger vs. medium or small effect on muscular strength leading to a greater reduction in HbA1c (β −0.99; P = .0470).

Study details: Findings are from a meta-analysis of 20 trials including 1172 patients with T2DM.

Disclosures: The study received no specific funding. The authors declared no competing interests.

Source: Jansson AK et al. Effect of resistance training on HbA1c in adults with type 2 diabetes mellitus and the moderating effect of changes in muscular strength: a systematic review and meta-analysis. BMJ Open Diabetes Res Care. 2022;10:e002595 (Mar 10). Doi: 10.1136/bmjdrc-2021-002595

Key clinical point: Resistance training (RT) effectively reduces glycosylated hemoglobin (HbA1c) in patients with type 2 diabetes mellitus (T2D), with RT interventions triggering a larger vs. medium or smaller improvement in muscular strength leading to a greater reduction in HbA1c.

Major finding: RT intervention vs. control treatment significantly decreased HbA1c (weighted mean difference −0.39; P < .001), with a larger vs. medium or small effect on muscular strength leading to a greater reduction in HbA1c (β −0.99; P = .0470).

Study details: Findings are from a meta-analysis of 20 trials including 1172 patients with T2DM.

Disclosures: The study received no specific funding. The authors declared no competing interests.

Source: Jansson AK et al. Effect of resistance training on HbA1c in adults with type 2 diabetes mellitus and the moderating effect of changes in muscular strength: a systematic review and meta-analysis. BMJ Open Diabetes Res Care. 2022;10:e002595 (Mar 10). Doi: 10.1136/bmjdrc-2021-002595

Key clinical point: Fenofibrate reduced the composite outcome of heart failure (HF) hospitalizations or cardiovascular death in patients with type 2 diabetes (T2D) treated with simvastatin, predominantly in those who received the standard background glucose-lowering therapy.

Major finding: The composite outcome of HF hospitalization or cardiovascular death was significantly lower with fenofibrate vs. placebo (hazard ratio [HR] 0.82; P = .048), with reduction primarily observed with the standard glucose-lowering strategy (HR 0.64; 95% CI 0.48-0.85), but not with the intensive glucose-lowering strategy (HR 1.02; 95% CI 0.79-1.33; P_interaction = .017).

Study details: Findings are from the ACCORD Lipid trial including 5518 patients with T2D who were randomly assigned to receive simvastatin plus fenofibrate (n = 2765) or simvastatin plus placebo (n = 2753).

Disclosures: The study was funded by national funds through FCT-Portuguese Foundation for

Science and Technology, under the scope of the Cardiovascular R&D Center-UnIC. Some authors declared being consultants and receiving research support or personal fees from various sources.

Source: Ferreira JP et al. Fenofibrate and heart failure outcomes in patients with type 2 diabetes: analysis from ACCORD. Diabetes Care. 2022 (Mar 23). Doi: 10.2337/dc21-1977

Key clinical point: Fenofibrate reduced the composite outcome of heart failure (HF) hospitalizations or cardiovascular death in patients with type 2 diabetes (T2D) treated with simvastatin, predominantly in those who received the standard background glucose-lowering therapy.

Major finding: The composite outcome of HF hospitalization or cardiovascular death was significantly lower with fenofibrate vs. placebo (hazard ratio [HR] 0.82; P = .048), with reduction primarily observed with the standard glucose-lowering strategy (HR 0.64; 95% CI 0.48-0.85), but not with the intensive glucose-lowering strategy (HR 1.02; 95% CI 0.79-1.33; P_interaction = .017).

Study details: Findings are from the ACCORD Lipid trial including 5518 patients with T2D who were randomly assigned to receive simvastatin plus fenofibrate (n = 2765) or simvastatin plus placebo (n = 2753).

Disclosures: The study was funded by national funds through FCT-Portuguese Foundation for

Science and Technology, under the scope of the Cardiovascular R&D Center-UnIC. Some authors declared being consultants and receiving research support or personal fees from various sources.

Source: Ferreira JP et al. Fenofibrate and heart failure outcomes in patients with type 2 diabetes: analysis from ACCORD. Diabetes Care. 2022 (Mar 23). Doi: 10.2337/dc21-1977

Key clinical point: Fenofibrate reduced the composite outcome of heart failure (HF) hospitalizations or cardiovascular death in patients with type 2 diabetes (T2D) treated with simvastatin, predominantly in those who received the standard background glucose-lowering therapy.

Major finding: The composite outcome of HF hospitalization or cardiovascular death was significantly lower with fenofibrate vs. placebo (hazard ratio [HR] 0.82; P = .048), with reduction primarily observed with the standard glucose-lowering strategy (HR 0.64; 95% CI 0.48-0.85), but not with the intensive glucose-lowering strategy (HR 1.02; 95% CI 0.79-1.33; P_interaction = .017).

Study details: Findings are from the ACCORD Lipid trial including 5518 patients with T2D who were randomly assigned to receive simvastatin plus fenofibrate (n = 2765) or simvastatin plus placebo (n = 2753).

Disclosures: The study was funded by national funds through FCT-Portuguese Foundation for

Science and Technology, under the scope of the Cardiovascular R&D Center-UnIC. Some authors declared being consultants and receiving research support or personal fees from various sources.

Source: Ferreira JP et al. Fenofibrate and heart failure outcomes in patients with type 2 diabetes: analysis from ACCORD. Diabetes Care. 2022 (Mar 23). Doi: 10.2337/dc21-1977

Key clinical point: Empagliflozin showed a beneficial effect on cognitive and physical impairment in frail older patients with type 2 diabetes (T2D) and heart failure with preserved ejection fraction (HFpEF).

Major finding: The mean Montreal Cognitive Assessment score significantly improved from baseline to 1 month in the empagliflozin group (19.80 vs. 22.25; P < .001) but not in the metformin (P = .26) and insulin (P = .81) groups, with empagliflozin showing a significant effect on amelioration of cognitive impairment (odds ratio 3.609; P = .03). The 5-meter gait speed improved significantly in the empagliflozin and metformin groups (both P < .05), but not in the insulin group.

Study details: This prospective observational study included 162 frail older patients aged >65 years who had T2D and HFpEF and were treated with empagliflozin (n = 52), metformin (n = 56), or insulin (n = 54).

Disclosures: The study was partly supported by the US National Institute of Diabetes and Digestive and Kidney Diseases, US National Heart, Lung, and Blood Institute, and US National Institute on Aging, among others. The authors declared no conflicts of interest.

Source: Mone P et al. Empagliflozin improves cognitive impairment in frail older adults with type 2 diabetes and heart failure with preserved ejection fraction. Diabetes Care. 2022 (Mar 21). Doi: 10.2337/dc21-2434

Key clinical point: Empagliflozin showed a beneficial effect on cognitive and physical impairment in frail older patients with type 2 diabetes (T2D) and heart failure with preserved ejection fraction (HFpEF).

Major finding: The mean Montreal Cognitive Assessment score significantly improved from baseline to 1 month in the empagliflozin group (19.80 vs. 22.25; P < .001) but not in the metformin (P = .26) and insulin (P = .81) groups, with empagliflozin showing a significant effect on amelioration of cognitive impairment (odds ratio 3.609; P = .03). The 5-meter gait speed improved significantly in the empagliflozin and metformin groups (both P < .05), but not in the insulin group.

Study details: This prospective observational study included 162 frail older patients aged >65 years who had T2D and HFpEF and were treated with empagliflozin (n = 52), metformin (n = 56), or insulin (n = 54).

Disclosures: The study was partly supported by the US National Institute of Diabetes and Digestive and Kidney Diseases, US National Heart, Lung, and Blood Institute, and US National Institute on Aging, among others. The authors declared no conflicts of interest.

Source: Mone P et al. Empagliflozin improves cognitive impairment in frail older adults with type 2 diabetes and heart failure with preserved ejection fraction. Diabetes Care. 2022 (Mar 21). Doi: 10.2337/dc21-2434

Key clinical point: Empagliflozin showed a beneficial effect on cognitive and physical impairment in frail older patients with type 2 diabetes (T2D) and heart failure with preserved ejection fraction (HFpEF).

Major finding: The mean Montreal Cognitive Assessment score significantly improved from baseline to 1 month in the empagliflozin group (19.80 vs. 22.25; P < .001) but not in the metformin (P = .26) and insulin (P = .81) groups, with empagliflozin showing a significant effect on amelioration of cognitive impairment (odds ratio 3.609; P = .03). The 5-meter gait speed improved significantly in the empagliflozin and metformin groups (both P < .05), but not in the insulin group.

Study details: This prospective observational study included 162 frail older patients aged >65 years who had T2D and HFpEF and were treated with empagliflozin (n = 52), metformin (n = 56), or insulin (n = 54).

Disclosures: The study was partly supported by the US National Institute of Diabetes and Digestive and Kidney Diseases, US National Heart, Lung, and Blood Institute, and US National Institute on Aging, among others. The authors declared no conflicts of interest.

Source: Mone P et al. Empagliflozin improves cognitive impairment in frail older adults with type 2 diabetes and heart failure with preserved ejection fraction. Diabetes Care. 2022 (Mar 21). Doi: 10.2337/dc21-2434

Key clinical point: Dapagliflozin in addition to standard-of-care treatment demonstrated a clinically relevant decrease in glycated hemoglobin (HbA1c) and an acceptable safety profile in young people with type 2 diabetes (T2D).

Major finding: At 24 weeks, the adjusted mean change in HbA1c was not significantly different between the dapagliflozin and placebo groups in the intention-to-treat analysis (between-group difference [Δ] −0.75%; P = .10), but was significantly different in the sensitivity analysis in the per-protocol population (Δ −1.13%; P = .012). No new safety signals or episodes of death or diabetic ketoacidosis were recorded.

Study details: The data come from a phase 3 trial including 72 participants aged 10-24 years with T2D and HbA1c concentration of 6.5%-11% who were randomly assigned to receive oral dapagliflozin (10 mg) or placebo in addition to standard-of-care treatment for 24 weeks followed by dapagliflozin for 28 weeks

Disclosures: The study was funded by AstraZeneca. Some authors declared receiving consulting fees or research grants or serving on advisory boards for various sources, including AstraZeneca. Three authors declared being stockholders or employees of AstraZeneca.

Source: Tamborlane WV, Laffel LM et al. Efficacy and safety of dapagliflozin in children and young adults with type 2 diabetes: a prospective, multicentre, randomised, parallel group, phase 3 study. Lancet Diabetes Endocrinol. 2022 (Apr 1). Doi: 10.1016/S2213-8587(22)00052-3

Key clinical point: Dapagliflozin in addition to standard-of-care treatment demonstrated a clinically relevant decrease in glycated hemoglobin (HbA1c) and an acceptable safety profile in young people with type 2 diabetes (T2D).

Major finding: At 24 weeks, the adjusted mean change in HbA1c was not significantly different between the dapagliflozin and placebo groups in the intention-to-treat analysis (between-group difference [Δ] −0.75%; P = .10), but was significantly different in the sensitivity analysis in the per-protocol population (Δ −1.13%; P = .012). No new safety signals or episodes of death or diabetic ketoacidosis were recorded.

Study details: The data come from a phase 3 trial including 72 participants aged 10-24 years with T2D and HbA1c concentration of 6.5%-11% who were randomly assigned to receive oral dapagliflozin (10 mg) or placebo in addition to standard-of-care treatment for 24 weeks followed by dapagliflozin for 28 weeks

Disclosures: The study was funded by AstraZeneca. Some authors declared receiving consulting fees or research grants or serving on advisory boards for various sources, including AstraZeneca. Three authors declared being stockholders or employees of AstraZeneca.

Source: Tamborlane WV, Laffel LM et al. Efficacy and safety of dapagliflozin in children and young adults with type 2 diabetes: a prospective, multicentre, randomised, parallel group, phase 3 study. Lancet Diabetes Endocrinol. 2022 (Apr 1). Doi: 10.1016/S2213-8587(22)00052-3

Key clinical point: Dapagliflozin in addition to standard-of-care treatment demonstrated a clinically relevant decrease in glycated hemoglobin (HbA1c) and an acceptable safety profile in young people with type 2 diabetes (T2D).

Major finding: At 24 weeks, the adjusted mean change in HbA1c was not significantly different between the dapagliflozin and placebo groups in the intention-to-treat analysis (between-group difference [Δ] −0.75%; P = .10), but was significantly different in the sensitivity analysis in the per-protocol population (Δ −1.13%; P = .012). No new safety signals or episodes of death or diabetic ketoacidosis were recorded.

Study details: The data come from a phase 3 trial including 72 participants aged 10-24 years with T2D and HbA1c concentration of 6.5%-11% who were randomly assigned to receive oral dapagliflozin (10 mg) or placebo in addition to standard-of-care treatment for 24 weeks followed by dapagliflozin for 28 weeks

Disclosures: The study was funded by AstraZeneca. Some authors declared receiving consulting fees or research grants or serving on advisory boards for various sources, including AstraZeneca. Three authors declared being stockholders or employees of AstraZeneca.

Source: Tamborlane WV, Laffel LM et al. Efficacy and safety of dapagliflozin in children and young adults with type 2 diabetes: a prospective, multicentre, randomised, parallel group, phase 3 study. Lancet Diabetes Endocrinol. 2022 (Apr 1). Doi: 10.1016/S2213-8587(22)00052-3

The Diagnosis: Cutaneous B-cell Lymphoma

Shave biopsies of 3 lesions revealed a dense, diffuse, atypical lymphoid infiltrate occupying the entirety of the dermis and obscuring the dermoepidermal junction. The infiltrate consisted predominantly of largesized lymphoid cells with fine chromatin and conspicuous nucleoli (Figure). Immunohistochemistry was positive for CD45 and CD20, indicating B-cell lineage. Bcl-2, multiple myeloma oncogene 1, and forkhead box protein P1 also were expressed in the vast majority of lesional cells, distinguishing the lesion from other forms of cutaneous B-cell lymphomas.¹ These findings were consistent with large B-cell lymphoma with a high proliferation index, consistent with primary cutaneous diffuse large B-cell lymphoma, leg type, which often presents on the lower leg.² The patient had a negative systemic workup including bone marrow biopsy. He was started on the R-CEOP (rituximab, cyclophosphamide, etoposide, vincristine, prednisone) chemotherapy regimen.

Primary cutaneous diffuse large B-cell lymphoma, leg type, is an intermediately aggressive and rare form of B-cell lymphoma with a poor prognosis that primarily affects elderly female patients. Primary cutaneous diffuse large B-cell lymphoma, leg type, accounts for only 1% to 3% of cutaneous lymphomas and approximately 10% to 20% of primary cutaneous B-cell lymphomas.² It typically presents as multiple red-brown or bluish nodules on the lower extremities or trunk. Presentation as a solitary nodule also is possible.^1,2 Histologic analysis of primary cutaneous diffuse large B-cell lymphoma, leg type, reveals large cells with round nuclei (immunoblasts and centroblasts), and the immunohistochemical profile shows strong Bcl-2 expression often accompanied by the multiple myeloma oncogene 1 protein.³ The 5-year survival rate is approximately 50%, which is lower than other types of primary cutaneous B-cell lymphomas, and the progression of disease is characterized by frequent relapses and involvement of extracutaneous regions such as the lymph nodes, bone marrow, and central nervous system.^1,2,4 Patients with multiple tumors on the leg have a particularly poor prognosis; in particular, having 1 or more lesions on the leg results in a 43% 3-year survival rate while having multiple lesions has a 36% 3-year survival rate compared with a 77% 3-year survival rate for patients with the non–leg subtype or a single lesion.3 Treatment with rituximab has been shown to be effective in at least short-term control of the disease, and the R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) regimen is the standard of treatment.^3,4

Primary cutaneous diffuse large B-cell lymphoma, leg type, can mimic multiple other cutaneous presentations of disease. Myeloid sarcoma (leukemia cutis) is a rare condition that presents as an extramedullary tumor often simultaneously with the onset or relapse of acute myeloid leukemia.⁵ Our patient had no history of leukemia, but myeloid sarcoma may predate acute myeloid leukemia in about a quarter of cases.⁵ It most commonly presents histologically as a diffuse dermal infiltrate that splays between collagen bundles and often is associated with an overlying Grenz zone. A nodular, or perivascular and periadnexal, pattern also may be seen. Upon closer inspection, the infiltrate is composed of immature myeloid cells (blasts) with background inflammation occasionally containing eosinophils. The immunohistochemical profile varies depending on the type of differentiation and degree of maturity of the cells. The histologic findings in our patient were inconsistent with myeloid sarcoma.

Erythema elevatum diutinum (EED) usually presents as dark red, brown, or violaceous papules or plaques and often is found on the extensor surfaces. It often is associated with hematologic abnormalities as well as recurrent bacterial or viral infections.⁶ Histologically, EED initially manifests as leukocytoclastic vasculitis with a mixed inflammatory infiltrate typically featuring an abundance of neutrophils, making this condition unlikely in this case. As the lesion progresses, fibrosis and scarring ensue as inflammation wanes. The fibrosis often is described as having an onion skin–like pattern, which is characteristic of established EED lesions. Our patient had no history of vasculitis, and the histologic findings were inconsistent with EED.

Angiosarcoma can present as a central nodule surrounded by an erythematous plaque. Although potentially clinically similar to primary cutaneous diffuse large B-cell lymphoma, leg type, angiosarcoma was unlikely in this case because of an absence of lymphedema and no history of radiation to the leg, both of which are key historical features of angiosarcoma.⁷ Additionally, the histology of cutaneous angiosarcoma is marked by vascular proliferation, which was not seen in the lesion biopsied in our patient. The histology of angiosarcoma is that of an atypical vascular proliferation, and a hallmark feature is infiltration between collagen, often referred to as giving the appearance of dissection between collagen bundles. The degree of atypia can vary widely, and epithelioid variants exist, producing a potential diagnostic pitfall. Lesional cells are positive for vascular markers, which can be used for confirmation of the endothelial lineage.

Sarcoidosis is notorious for its mimicry, which can be the case both clinically and histologically. Characteristic pathology of sarcoidosis is that of well-formed epithelioid granulomas with minimal associated inflammation and lack of caseating necrosis. Our patient had no known history of systemic sarcoidosis, and the pathologic features of noncaseating granulomas were not present. As a diagnosis of exclusion, correlation with special stains and culture studies is necessary to exclude an infectious process. The differential diagnosis for sarcoidal granulomatous dermatitis also includes foreign body reaction, inflammatory bowel disease, and granulomatous cheilitis, among others.

The Diagnosis: Cutaneous B-cell Lymphoma

Shave biopsies of 3 lesions revealed a dense, diffuse, atypical lymphoid infiltrate occupying the entirety of the dermis and obscuring the dermoepidermal junction. The infiltrate consisted predominantly of largesized lymphoid cells with fine chromatin and conspicuous nucleoli (Figure). Immunohistochemistry was positive for CD45 and CD20, indicating B-cell lineage. Bcl-2, multiple myeloma oncogene 1, and forkhead box protein P1 also were expressed in the vast majority of lesional cells, distinguishing the lesion from other forms of cutaneous B-cell lymphomas.¹ These findings were consistent with large B-cell lymphoma with a high proliferation index, consistent with primary cutaneous diffuse large B-cell lymphoma, leg type, which often presents on the lower leg.² The patient had a negative systemic workup including bone marrow biopsy. He was started on the R-CEOP (rituximab, cyclophosphamide, etoposide, vincristine, prednisone) chemotherapy regimen.

Primary cutaneous diffuse large B-cell lymphoma, leg type, is an intermediately aggressive and rare form of B-cell lymphoma with a poor prognosis that primarily affects elderly female patients. Primary cutaneous diffuse large B-cell lymphoma, leg type, accounts for only 1% to 3% of cutaneous lymphomas and approximately 10% to 20% of primary cutaneous B-cell lymphomas.² It typically presents as multiple red-brown or bluish nodules on the lower extremities or trunk. Presentation as a solitary nodule also is possible.^1,2 Histologic analysis of primary cutaneous diffuse large B-cell lymphoma, leg type, reveals large cells with round nuclei (immunoblasts and centroblasts), and the immunohistochemical profile shows strong Bcl-2 expression often accompanied by the multiple myeloma oncogene 1 protein.³ The 5-year survival rate is approximately 50%, which is lower than other types of primary cutaneous B-cell lymphomas, and the progression of disease is characterized by frequent relapses and involvement of extracutaneous regions such as the lymph nodes, bone marrow, and central nervous system.^1,2,4 Patients with multiple tumors on the leg have a particularly poor prognosis; in particular, having 1 or more lesions on the leg results in a 43% 3-year survival rate while having multiple lesions has a 36% 3-year survival rate compared with a 77% 3-year survival rate for patients with the non–leg subtype or a single lesion.3 Treatment with rituximab has been shown to be effective in at least short-term control of the disease, and the R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) regimen is the standard of treatment.^3,4

Primary cutaneous diffuse large B-cell lymphoma, leg type, can mimic multiple other cutaneous presentations of disease. Myeloid sarcoma (leukemia cutis) is a rare condition that presents as an extramedullary tumor often simultaneously with the onset or relapse of acute myeloid leukemia.⁵ Our patient had no history of leukemia, but myeloid sarcoma may predate acute myeloid leukemia in about a quarter of cases.⁵ It most commonly presents histologically as a diffuse dermal infiltrate that splays between collagen bundles and often is associated with an overlying Grenz zone. A nodular, or perivascular and periadnexal, pattern also may be seen. Upon closer inspection, the infiltrate is composed of immature myeloid cells (blasts) with background inflammation occasionally containing eosinophils. The immunohistochemical profile varies depending on the type of differentiation and degree of maturity of the cells. The histologic findings in our patient were inconsistent with myeloid sarcoma.

Erythema elevatum diutinum (EED) usually presents as dark red, brown, or violaceous papules or plaques and often is found on the extensor surfaces. It often is associated with hematologic abnormalities as well as recurrent bacterial or viral infections.⁶ Histologically, EED initially manifests as leukocytoclastic vasculitis with a mixed inflammatory infiltrate typically featuring an abundance of neutrophils, making this condition unlikely in this case. As the lesion progresses, fibrosis and scarring ensue as inflammation wanes. The fibrosis often is described as having an onion skin–like pattern, which is characteristic of established EED lesions. Our patient had no history of vasculitis, and the histologic findings were inconsistent with EED.

Angiosarcoma can present as a central nodule surrounded by an erythematous plaque. Although potentially clinically similar to primary cutaneous diffuse large B-cell lymphoma, leg type, angiosarcoma was unlikely in this case because of an absence of lymphedema and no history of radiation to the leg, both of which are key historical features of angiosarcoma.⁷ Additionally, the histology of cutaneous angiosarcoma is marked by vascular proliferation, which was not seen in the lesion biopsied in our patient. The histology of angiosarcoma is that of an atypical vascular proliferation, and a hallmark feature is infiltration between collagen, often referred to as giving the appearance of dissection between collagen bundles. The degree of atypia can vary widely, and epithelioid variants exist, producing a potential diagnostic pitfall. Lesional cells are positive for vascular markers, which can be used for confirmation of the endothelial lineage.

Sarcoidosis is notorious for its mimicry, which can be the case both clinically and histologically. Characteristic pathology of sarcoidosis is that of well-formed epithelioid granulomas with minimal associated inflammation and lack of caseating necrosis. Our patient had no known history of systemic sarcoidosis, and the pathologic features of noncaseating granulomas were not present. As a diagnosis of exclusion, correlation with special stains and culture studies is necessary to exclude an infectious process. The differential diagnosis for sarcoidal granulomatous dermatitis also includes foreign body reaction, inflammatory bowel disease, and granulomatous cheilitis, among others.

The Diagnosis: Cutaneous B-cell Lymphoma

Shave biopsies of 3 lesions revealed a dense, diffuse, atypical lymphoid infiltrate occupying the entirety of the dermis and obscuring the dermoepidermal junction. The infiltrate consisted predominantly of largesized lymphoid cells with fine chromatin and conspicuous nucleoli (Figure). Immunohistochemistry was positive for CD45 and CD20, indicating B-cell lineage. Bcl-2, multiple myeloma oncogene 1, and forkhead box protein P1 also were expressed in the vast majority of lesional cells, distinguishing the lesion from other forms of cutaneous B-cell lymphomas.¹ These findings were consistent with large B-cell lymphoma with a high proliferation index, consistent with primary cutaneous diffuse large B-cell lymphoma, leg type, which often presents on the lower leg.² The patient had a negative systemic workup including bone marrow biopsy. He was started on the R-CEOP (rituximab, cyclophosphamide, etoposide, vincristine, prednisone) chemotherapy regimen.

Primary cutaneous diffuse large B-cell lymphoma, leg type, is an intermediately aggressive and rare form of B-cell lymphoma with a poor prognosis that primarily affects elderly female patients. Primary cutaneous diffuse large B-cell lymphoma, leg type, accounts for only 1% to 3% of cutaneous lymphomas and approximately 10% to 20% of primary cutaneous B-cell lymphomas.² It typically presents as multiple red-brown or bluish nodules on the lower extremities or trunk. Presentation as a solitary nodule also is possible.^1,2 Histologic analysis of primary cutaneous diffuse large B-cell lymphoma, leg type, reveals large cells with round nuclei (immunoblasts and centroblasts), and the immunohistochemical profile shows strong Bcl-2 expression often accompanied by the multiple myeloma oncogene 1 protein.³ The 5-year survival rate is approximately 50%, which is lower than other types of primary cutaneous B-cell lymphomas, and the progression of disease is characterized by frequent relapses and involvement of extracutaneous regions such as the lymph nodes, bone marrow, and central nervous system.^1,2,4 Patients with multiple tumors on the leg have a particularly poor prognosis; in particular, having 1 or more lesions on the leg results in a 43% 3-year survival rate while having multiple lesions has a 36% 3-year survival rate compared with a 77% 3-year survival rate for patients with the non–leg subtype or a single lesion.3 Treatment with rituximab has been shown to be effective in at least short-term control of the disease, and the R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) regimen is the standard of treatment.^3,4

Primary cutaneous diffuse large B-cell lymphoma, leg type, can mimic multiple other cutaneous presentations of disease. Myeloid sarcoma (leukemia cutis) is a rare condition that presents as an extramedullary tumor often simultaneously with the onset or relapse of acute myeloid leukemia.⁵ Our patient had no history of leukemia, but myeloid sarcoma may predate acute myeloid leukemia in about a quarter of cases.⁵ It most commonly presents histologically as a diffuse dermal infiltrate that splays between collagen bundles and often is associated with an overlying Grenz zone. A nodular, or perivascular and periadnexal, pattern also may be seen. Upon closer inspection, the infiltrate is composed of immature myeloid cells (blasts) with background inflammation occasionally containing eosinophils. The immunohistochemical profile varies depending on the type of differentiation and degree of maturity of the cells. The histologic findings in our patient were inconsistent with myeloid sarcoma.

Erythema elevatum diutinum (EED) usually presents as dark red, brown, or violaceous papules or plaques and often is found on the extensor surfaces. It often is associated with hematologic abnormalities as well as recurrent bacterial or viral infections.⁶ Histologically, EED initially manifests as leukocytoclastic vasculitis with a mixed inflammatory infiltrate typically featuring an abundance of neutrophils, making this condition unlikely in this case. As the lesion progresses, fibrosis and scarring ensue as inflammation wanes. The fibrosis often is described as having an onion skin–like pattern, which is characteristic of established EED lesions. Our patient had no history of vasculitis, and the histologic findings were inconsistent with EED.

Angiosarcoma can present as a central nodule surrounded by an erythematous plaque. Although potentially clinically similar to primary cutaneous diffuse large B-cell lymphoma, leg type, angiosarcoma was unlikely in this case because of an absence of lymphedema and no history of radiation to the leg, both of which are key historical features of angiosarcoma.⁷ Additionally, the histology of cutaneous angiosarcoma is marked by vascular proliferation, which was not seen in the lesion biopsied in our patient. The histology of angiosarcoma is that of an atypical vascular proliferation, and a hallmark feature is infiltration between collagen, often referred to as giving the appearance of dissection between collagen bundles. The degree of atypia can vary widely, and epithelioid variants exist, producing a potential diagnostic pitfall. Lesional cells are positive for vascular markers, which can be used for confirmation of the endothelial lineage.

Sarcoidosis is notorious for its mimicry, which can be the case both clinically and histologically. Characteristic pathology of sarcoidosis is that of well-formed epithelioid granulomas with minimal associated inflammation and lack of caseating necrosis. Our patient had no known history of systemic sarcoidosis, and the pathologic features of noncaseating granulomas were not present. As a diagnosis of exclusion, correlation with special stains and culture studies is necessary to exclude an infectious process. The differential diagnosis for sarcoidal granulomatous dermatitis also includes foreign body reaction, inflammatory bowel disease, and granulomatous cheilitis, among others.

None of us like being wrong, especially about a patient’s diagnosis. To help you avoid diagnostic errors for 4 difficult diagnoses, read and study the article in this issue of JFP by Rosen and colleagues.¹ They discuss misdiagnosis of polymyalgia rheumatica, fibromyalgia, ovarian cancer, and Lewy body dementia to illustrate how we can go astray if we do not take care to pause and think through things carefully. They point out that, for quick and mostly accurate diagnoses, pattern recognition or type 1 thinking serves us well in a busy office practice. However, we must frequently pause and reflect, using type 2 thinking—especially when the puzzle pieces don’t quite fit together.

I still recall vividly a diagnostic error I made many years ago. One of my patients, whom I had diagnosed and was treating for hyperlipidemia, returned for follow-up while I was on vacation. My partner conducted the follow-up visit. To my chagrin, he noticed her puffy face and weight gain and ordered thyroid studies. Sure enough, my patient was severely hypothyroid, and her lipid levels normalized with thyroid replacement therapy.

I recall vividly a diagnostic error I made years ago. I was treating a patient for hyperlipidemia but my partner recognized it as a case of severe hypothyroid.

A happier tale for me was making the correct diagnosis for a woman with chronic cough. She had been evaluated by multiple specialists during the prior year and treated with a nasal steroid for allergies, a proton pump inhibitor for reflux, and a steroid inhaler for possible asthma. None of these relieved her cough. After reviewing her medication list and noting that it included amitriptyline, which has anticholinergic adverse effects, I recommended she stop taking that medication and the cough resolved.

John Ely, MD, MPH, a family physician who has spent his academic career investigating causes of and solutions to diagnostic errors, has outlined important steps we can take. These include: (1) obtaining your own complete medical history, (2) performing a “focused and purposeful” physical exam, (3) generating initial hypotheses and differentiating them through additional history taking, exams, and diagnostic tests, (4) pausing to reflect [my emphasis], and (5) embarking on a plan (while acknowledging uncertainty) and ensuring there is a pathway for follow-up.²

To help avoid diagnostic errors, Dr. Ely developed and uses a set of checklists that cover the differential diagnosis for 72 presenting complaints/conditions, including syncope, back pain, insomnia, and headache.² When you are faced with diagnostic uncertainty, it takes just a few minutes to run through the checklist for the patient’s presenting complaint.

None of us like being wrong, especially about a patient’s diagnosis. To help you avoid diagnostic errors for 4 difficult diagnoses, read and study the article in this issue of JFP by Rosen and colleagues.¹ They discuss misdiagnosis of polymyalgia rheumatica, fibromyalgia, ovarian cancer, and Lewy body dementia to illustrate how we can go astray if we do not take care to pause and think through things carefully. They point out that, for quick and mostly accurate diagnoses, pattern recognition or type 1 thinking serves us well in a busy office practice. However, we must frequently pause and reflect, using type 2 thinking—especially when the puzzle pieces don’t quite fit together.

I still recall vividly a diagnostic error I made many years ago. One of my patients, whom I had diagnosed and was treating for hyperlipidemia, returned for follow-up while I was on vacation. My partner conducted the follow-up visit. To my chagrin, he noticed her puffy face and weight gain and ordered thyroid studies. Sure enough, my patient was severely hypothyroid, and her lipid levels normalized with thyroid replacement therapy.

I recall vividly a diagnostic error I made years ago. I was treating a patient for hyperlipidemia but my partner recognized it as a case of severe hypothyroid.

A happier tale for me was making the correct diagnosis for a woman with chronic cough. She had been evaluated by multiple specialists during the prior year and treated with a nasal steroid for allergies, a proton pump inhibitor for reflux, and a steroid inhaler for possible asthma. None of these relieved her cough. After reviewing her medication list and noting that it included amitriptyline, which has anticholinergic adverse effects, I recommended she stop taking that medication and the cough resolved.

John Ely, MD, MPH, a family physician who has spent his academic career investigating causes of and solutions to diagnostic errors, has outlined important steps we can take. These include: (1) obtaining your own complete medical history, (2) performing a “focused and purposeful” physical exam, (3) generating initial hypotheses and differentiating them through additional history taking, exams, and diagnostic tests, (4) pausing to reflect [my emphasis], and (5) embarking on a plan (while acknowledging uncertainty) and ensuring there is a pathway for follow-up.²

To help avoid diagnostic errors, Dr. Ely developed and uses a set of checklists that cover the differential diagnosis for 72 presenting complaints/conditions, including syncope, back pain, insomnia, and headache.² When you are faced with diagnostic uncertainty, it takes just a few minutes to run through the checklist for the patient’s presenting complaint.

None of us like being wrong, especially about a patient’s diagnosis. To help you avoid diagnostic errors for 4 difficult diagnoses, read and study the article in this issue of JFP by Rosen and colleagues.¹ They discuss misdiagnosis of polymyalgia rheumatica, fibromyalgia, ovarian cancer, and Lewy body dementia to illustrate how we can go astray if we do not take care to pause and think through things carefully. They point out that, for quick and mostly accurate diagnoses, pattern recognition or type 1 thinking serves us well in a busy office practice. However, we must frequently pause and reflect, using type 2 thinking—especially when the puzzle pieces don’t quite fit together.

I still recall vividly a diagnostic error I made many years ago. One of my patients, whom I had diagnosed and was treating for hyperlipidemia, returned for follow-up while I was on vacation. My partner conducted the follow-up visit. To my chagrin, he noticed her puffy face and weight gain and ordered thyroid studies. Sure enough, my patient was severely hypothyroid, and her lipid levels normalized with thyroid replacement therapy.

I recall vividly a diagnostic error I made years ago. I was treating a patient for hyperlipidemia but my partner recognized it as a case of severe hypothyroid.

A happier tale for me was making the correct diagnosis for a woman with chronic cough. She had been evaluated by multiple specialists during the prior year and treated with a nasal steroid for allergies, a proton pump inhibitor for reflux, and a steroid inhaler for possible asthma. None of these relieved her cough. After reviewing her medication list and noting that it included amitriptyline, which has anticholinergic adverse effects, I recommended she stop taking that medication and the cough resolved.

John Ely, MD, MPH, a family physician who has spent his academic career investigating causes of and solutions to diagnostic errors, has outlined important steps we can take. These include: (1) obtaining your own complete medical history, (2) performing a “focused and purposeful” physical exam, (3) generating initial hypotheses and differentiating them through additional history taking, exams, and diagnostic tests, (4) pausing to reflect [my emphasis], and (5) embarking on a plan (while acknowledging uncertainty) and ensuring there is a pathway for follow-up.²

To help avoid diagnostic errors, Dr. Ely developed and uses a set of checklists that cover the differential diagnosis for 72 presenting complaints/conditions, including syncope, back pain, insomnia, and headache.² When you are faced with diagnostic uncertainty, it takes just a few minutes to run through the checklist for the patient’s presenting complaint.

THE CASE 

An active 61-year-old woman (140 lbs) in good health became ill during a sailing holiday in the Virgin Islands. During the trip, she ate various fish in local restaurants; after one lunch, she developed nausea, diarrhea, dizziness, headache, and light-headedness. In the following days, she suffered “intense itching” in the ears, dizziness, malaise, a “fluttering feeling” throughout her body, genitourinary sensitivity, and a “rhythmic buzzing sensation near the rectum.”

She said that cold objects and beverages felt uncomfortably hot (cold allodynia). She noted heightened senses of smell and taste, as well as paresthesia down her spine, and described feeling “moody.” She reduced her workload, took many days off from work, and ceased consuming meat and alcohol because these items seemed to aggravate her symptoms.

The paresthesia persisted, and she consulted her family physician one month later. Laboratory tests—including a complete blood count, hematocrit, thyroid-stimulating hormone, antinuclear antibodies, and titers for Ehrlichia chaffeensis, Lyme disease, and Anaplasma phagocytophila—all yielded normal results. Her symptoms continued for 3 more months before referral to Medical Toxicology.

THE DIAGNOSIS

The patient’s symptoms and history were consistent with ciguatera poisoning. Features supporting this diagnosis included an acute gastrointestinal illness after eating fish caught in tropical waters and subsequent persistent paresthesia, including cold allodynia.¹ Laboratory testing excluded acute infection, anemia, thyroid dysfunction, vitamin B12 deficiency, lupus, rheumatoid arthritis, Lyme disease, ehrlichiosis, and anaplasmosis.

DISCUSSION

Ciguatera results from ciguatoxin, a class of heat-stable polycyclic toxins produced in warm tropical waters by microscopic dinoflagellates (most often Gambierdiscus toxicus).^2,3 Small variations exist in the Caribbean, Pacific, and Indian Ocean forms. Ciguatoxin bio-­accumulates in the food chain, and humans most often ingest it by eating larger fish (typically barracuda, snapper, grouper, or amberjack).⁴ Because ciguatoxin confers no characteristic taste or smell to the fish, people who prepare or eat contaminated seafood have no reliable means to detect and avoid it.

Ciguatoxin opens neuronal voltage-gated sodium channels and blocks delayed-­rectifier potassium channels.⁵ These cause repetitive, spontaneous action potentials that explain the paresthesia. Sodium influx triggers an increase in intracellular calcium concentrations. Increased intracellular sodium and calcium concentrations draw water into the intracellular space and cause neuronal edema.

Death is rarely associated with ciguatera (< 0.1% in the largest observational study).¹ Even without treatment (discussed shortly), symptoms of ciguatera will gradually resolve over several weeks to several months in most cases.^1,4,5 However, after recovery, patients often briefly experience milder symptoms after consuming fish, alcohol, or nuts.⁶

Continue to: Treatment of ciguatera

Treatment of ciguatera may include intravenous (IV) mannitol infusion. Other treatments, such as amitriptyline, gabapentin, pregabalin, and tocainide, have been used, but there is limited supporting evidence and they appear variably effective.⁷

Mannitol reverses the effects of ciguatoxin, with suppression of spontaneous action potentials and reversal of neuronal edema.^8,9 It is reasonable to offer mannitol for acute or persistent symptoms of ciguatera fish poisoning even after a delay of several weeks.

Ciguatoxin confers no characteristic taste or smell to the fish. Thus, people who prepare or eat contaminated seafood have no reliable means to detect and avoid it.

A recent systematic review found that mannitol has the largest body of evidence supporting its use, although that evidence is generally of low quality (case reports and large case series).⁷ While these reports^10-13 describe beneficial effects of mannitol, a single randomized trial suggested that mannitol is no more effective than normal saline.¹⁴ However, this study was underpowered and had inadequate treatment concealment; twice as many saline control patients as mannitol-treated patients requested a rescue dose of mannitol.¹⁴

Mannitol may be most effective when given early in the course of ciguatera but has shown some success when given later.^5,12,13 In 1 large case series, the longest interval from symptom onset to successful treatment was 70 days, although most patients with satisfactory results received mannitol in the first few days.⁵

Our patient was administered an IV infusion of 100 g of 20% mannitol over 1 hour. She received the infusion 140 days after the onset of her symptoms and experienced rapid symptom relief.

Continue to: At a follow-up visit...

At a follow-up visit 2 weeks later, she described increased energy and further improvement in her paresthesia. She returned to a full work schedule and resumed all of her daily activities. However, she continued to avoid alcohol and proteins, as she had experienced a mild recurrence that she temporally related to eating meat and drinking alcohol.

At the 2-month follow-up, the patient reported continued improvement in her paresthesia but continued to experience occasional gastrointestinal symptoms and fatigue associated with meat and alcohol consumption.

The Takeaway 

Ciguatera fish poisoning is largely a clinical diagnosis. It is based on early gastrointestinal symptoms followed by persistent paresthesia and cold allodynia after consumption of fish caught in tropical waters. Family physicians may see ciguatera in returning travelers or people who have consumed certain fish imported from endemic areas. Untreated symptoms may last for many weeks or months. IV mannitol may relieve symptoms of ciguatera poisoning even when administered several months after symptom onset.

Acknowledgement
We are grateful to our patient, who allowed us to share her story in the hope of helping other travelers.

CORRESPONDENCE
Michael E. Mullins, MD, Division of Medical Toxicology, Department of Emergency Medicine, Washington University School of Medicine, Campus Box 8072, 660 South Euclid Avenue, Saint Louis, MO 63110; [email protected]

THE CASE 

An active 61-year-old woman (140 lbs) in good health became ill during a sailing holiday in the Virgin Islands. During the trip, she ate various fish in local restaurants; after one lunch, she developed nausea, diarrhea, dizziness, headache, and light-headedness. In the following days, she suffered “intense itching” in the ears, dizziness, malaise, a “fluttering feeling” throughout her body, genitourinary sensitivity, and a “rhythmic buzzing sensation near the rectum.”

She said that cold objects and beverages felt uncomfortably hot (cold allodynia). She noted heightened senses of smell and taste, as well as paresthesia down her spine, and described feeling “moody.” She reduced her workload, took many days off from work, and ceased consuming meat and alcohol because these items seemed to aggravate her symptoms.

The paresthesia persisted, and she consulted her family physician one month later. Laboratory tests—including a complete blood count, hematocrit, thyroid-stimulating hormone, antinuclear antibodies, and titers for Ehrlichia chaffeensis, Lyme disease, and Anaplasma phagocytophila—all yielded normal results. Her symptoms continued for 3 more months before referral to Medical Toxicology.

THE DIAGNOSIS

The patient’s symptoms and history were consistent with ciguatera poisoning. Features supporting this diagnosis included an acute gastrointestinal illness after eating fish caught in tropical waters and subsequent persistent paresthesia, including cold allodynia.¹ Laboratory testing excluded acute infection, anemia, thyroid dysfunction, vitamin B12 deficiency, lupus, rheumatoid arthritis, Lyme disease, ehrlichiosis, and anaplasmosis.

DISCUSSION

Ciguatera results from ciguatoxin, a class of heat-stable polycyclic toxins produced in warm tropical waters by microscopic dinoflagellates (most often Gambierdiscus toxicus).^2,3 Small variations exist in the Caribbean, Pacific, and Indian Ocean forms. Ciguatoxin bio-­accumulates in the food chain, and humans most often ingest it by eating larger fish (typically barracuda, snapper, grouper, or amberjack).⁴ Because ciguatoxin confers no characteristic taste or smell to the fish, people who prepare or eat contaminated seafood have no reliable means to detect and avoid it.

Ciguatoxin opens neuronal voltage-gated sodium channels and blocks delayed-­rectifier potassium channels.⁵ These cause repetitive, spontaneous action potentials that explain the paresthesia. Sodium influx triggers an increase in intracellular calcium concentrations. Increased intracellular sodium and calcium concentrations draw water into the intracellular space and cause neuronal edema.

Death is rarely associated with ciguatera (< 0.1% in the largest observational study).¹ Even without treatment (discussed shortly), symptoms of ciguatera will gradually resolve over several weeks to several months in most cases.^1,4,5 However, after recovery, patients often briefly experience milder symptoms after consuming fish, alcohol, or nuts.⁶

Continue to: Treatment of ciguatera

Treatment of ciguatera may include intravenous (IV) mannitol infusion. Other treatments, such as amitriptyline, gabapentin, pregabalin, and tocainide, have been used, but there is limited supporting evidence and they appear variably effective.⁷

Mannitol reverses the effects of ciguatoxin, with suppression of spontaneous action potentials and reversal of neuronal edema.^8,9 It is reasonable to offer mannitol for acute or persistent symptoms of ciguatera fish poisoning even after a delay of several weeks.

Ciguatoxin confers no characteristic taste or smell to the fish. Thus, people who prepare or eat contaminated seafood have no reliable means to detect and avoid it.

A recent systematic review found that mannitol has the largest body of evidence supporting its use, although that evidence is generally of low quality (case reports and large case series).⁷ While these reports^10-13 describe beneficial effects of mannitol, a single randomized trial suggested that mannitol is no more effective than normal saline.¹⁴ However, this study was underpowered and had inadequate treatment concealment; twice as many saline control patients as mannitol-treated patients requested a rescue dose of mannitol.¹⁴

Mannitol may be most effective when given early in the course of ciguatera but has shown some success when given later.^5,12,13 In 1 large case series, the longest interval from symptom onset to successful treatment was 70 days, although most patients with satisfactory results received mannitol in the first few days.⁵

Our patient was administered an IV infusion of 100 g of 20% mannitol over 1 hour. She received the infusion 140 days after the onset of her symptoms and experienced rapid symptom relief.

Continue to: At a follow-up visit...

At a follow-up visit 2 weeks later, she described increased energy and further improvement in her paresthesia. She returned to a full work schedule and resumed all of her daily activities. However, she continued to avoid alcohol and proteins, as she had experienced a mild recurrence that she temporally related to eating meat and drinking alcohol.

At the 2-month follow-up, the patient reported continued improvement in her paresthesia but continued to experience occasional gastrointestinal symptoms and fatigue associated with meat and alcohol consumption.

The Takeaway 

Ciguatera fish poisoning is largely a clinical diagnosis. It is based on early gastrointestinal symptoms followed by persistent paresthesia and cold allodynia after consumption of fish caught in tropical waters. Family physicians may see ciguatera in returning travelers or people who have consumed certain fish imported from endemic areas. Untreated symptoms may last for many weeks or months. IV mannitol may relieve symptoms of ciguatera poisoning even when administered several months after symptom onset.

Acknowledgement
We are grateful to our patient, who allowed us to share her story in the hope of helping other travelers.

CORRESPONDENCE
Michael E. Mullins, MD, Division of Medical Toxicology, Department of Emergency Medicine, Washington University School of Medicine, Campus Box 8072, 660 South Euclid Avenue, Saint Louis, MO 63110; [email protected]

THE CASE 

An active 61-year-old woman (140 lbs) in good health became ill during a sailing holiday in the Virgin Islands. During the trip, she ate various fish in local restaurants; after one lunch, she developed nausea, diarrhea, dizziness, headache, and light-headedness. In the following days, she suffered “intense itching” in the ears, dizziness, malaise, a “fluttering feeling” throughout her body, genitourinary sensitivity, and a “rhythmic buzzing sensation near the rectum.”

She said that cold objects and beverages felt uncomfortably hot (cold allodynia). She noted heightened senses of smell and taste, as well as paresthesia down her spine, and described feeling “moody.” She reduced her workload, took many days off from work, and ceased consuming meat and alcohol because these items seemed to aggravate her symptoms.

The paresthesia persisted, and she consulted her family physician one month later. Laboratory tests—including a complete blood count, hematocrit, thyroid-stimulating hormone, antinuclear antibodies, and titers for Ehrlichia chaffeensis, Lyme disease, and Anaplasma phagocytophila—all yielded normal results. Her symptoms continued for 3 more months before referral to Medical Toxicology.

THE DIAGNOSIS

The patient’s symptoms and history were consistent with ciguatera poisoning. Features supporting this diagnosis included an acute gastrointestinal illness after eating fish caught in tropical waters and subsequent persistent paresthesia, including cold allodynia.¹ Laboratory testing excluded acute infection, anemia, thyroid dysfunction, vitamin B12 deficiency, lupus, rheumatoid arthritis, Lyme disease, ehrlichiosis, and anaplasmosis.

DISCUSSION

Ciguatera results from ciguatoxin, a class of heat-stable polycyclic toxins produced in warm tropical waters by microscopic dinoflagellates (most often Gambierdiscus toxicus).^2,3 Small variations exist in the Caribbean, Pacific, and Indian Ocean forms. Ciguatoxin bio-­accumulates in the food chain, and humans most often ingest it by eating larger fish (typically barracuda, snapper, grouper, or amberjack).⁴ Because ciguatoxin confers no characteristic taste or smell to the fish, people who prepare or eat contaminated seafood have no reliable means to detect and avoid it.

Ciguatoxin opens neuronal voltage-gated sodium channels and blocks delayed-­rectifier potassium channels.⁵ These cause repetitive, spontaneous action potentials that explain the paresthesia. Sodium influx triggers an increase in intracellular calcium concentrations. Increased intracellular sodium and calcium concentrations draw water into the intracellular space and cause neuronal edema.

Death is rarely associated with ciguatera (< 0.1% in the largest observational study).¹ Even without treatment (discussed shortly), symptoms of ciguatera will gradually resolve over several weeks to several months in most cases.^1,4,5 However, after recovery, patients often briefly experience milder symptoms after consuming fish, alcohol, or nuts.⁶

Continue to: Treatment of ciguatera

Treatment of ciguatera may include intravenous (IV) mannitol infusion. Other treatments, such as amitriptyline, gabapentin, pregabalin, and tocainide, have been used, but there is limited supporting evidence and they appear variably effective.⁷

Mannitol reverses the effects of ciguatoxin, with suppression of spontaneous action potentials and reversal of neuronal edema.^8,9 It is reasonable to offer mannitol for acute or persistent symptoms of ciguatera fish poisoning even after a delay of several weeks.

Ciguatoxin confers no characteristic taste or smell to the fish. Thus, people who prepare or eat contaminated seafood have no reliable means to detect and avoid it.

A recent systematic review found that mannitol has the largest body of evidence supporting its use, although that evidence is generally of low quality (case reports and large case series).⁷ While these reports^10-13 describe beneficial effects of mannitol, a single randomized trial suggested that mannitol is no more effective than normal saline.¹⁴ However, this study was underpowered and had inadequate treatment concealment; twice as many saline control patients as mannitol-treated patients requested a rescue dose of mannitol.¹⁴

Mannitol may be most effective when given early in the course of ciguatera but has shown some success when given later.^5,12,13 In 1 large case series, the longest interval from symptom onset to successful treatment was 70 days, although most patients with satisfactory results received mannitol in the first few days.⁵

Our patient was administered an IV infusion of 100 g of 20% mannitol over 1 hour. She received the infusion 140 days after the onset of her symptoms and experienced rapid symptom relief.

Continue to: At a follow-up visit...

At a follow-up visit 2 weeks later, she described increased energy and further improvement in her paresthesia. She returned to a full work schedule and resumed all of her daily activities. However, she continued to avoid alcohol and proteins, as she had experienced a mild recurrence that she temporally related to eating meat and drinking alcohol.

At the 2-month follow-up, the patient reported continued improvement in her paresthesia but continued to experience occasional gastrointestinal symptoms and fatigue associated with meat and alcohol consumption.

The Takeaway 

Ciguatera fish poisoning is largely a clinical diagnosis. It is based on early gastrointestinal symptoms followed by persistent paresthesia and cold allodynia after consumption of fish caught in tropical waters. Family physicians may see ciguatera in returning travelers or people who have consumed certain fish imported from endemic areas. Untreated symptoms may last for many weeks or months. IV mannitol may relieve symptoms of ciguatera poisoning even when administered several months after symptom onset.

Acknowledgement
We are grateful to our patient, who allowed us to share her story in the hope of helping other travelers.

CORRESPONDENCE
Michael E. Mullins, MD, Division of Medical Toxicology, Department of Emergency Medicine, Washington University School of Medicine, Campus Box 8072, 660 South Euclid Avenue, Saint Louis, MO 63110; [email protected]

A healthy woman in her 60s presented to the clinic with a 1-month history of red, itchy, and slightly painful nodules on the scalp and back. The patient had travelled to Belize for a vacation in the weeks prior to the onset of the lesions. She was initially given a course of cephalexin for presumed furunculosis at another clinic, without improvement.

Examination revealed inflamed nodules with a central open pore on the left upper back (FIGURE 1) and the occipital scalp. Notably, when the lesions were observed with a dermatoscope, intermittent air bubbles were seen through the skin opening.

WHAT IS YOUR DIAGNOSIS?
HOW WOULD YOU TREAT THIS PATIENT?

 

 

Diagnosis: Furuncular myiasis

Given the patient’s clinical presentation and travel history, furuncular myiasis infestation was suspected and confirmed by punch biopsy. Pathologic exam revealed botfly larvae in both wounds, consistent with the human botfly, Dermatobia hominis (FIGURE 2). Myiasis is not common in the United States but should be suspected in patients who have recently traveled to tropical or subtropical areas. Furuncular myiasis describes the condition in which fly larvae penetrate healthy skin in a localized fashion, leading to the development of a ­furuncle-like nodule with 1 or more larvae within it.

Dermatobia hominis is the most common causative organism for furuncular myiasis in the regions of the Americas. Patients typically present with 1 lesion on an exposed part of the body (eg, scalp, face, extremities). The lesions typically contain a central pore with purulent or serosanguinous exudate.¹ Upon dermatoscopic inspection, one can often see the posterior part of the larva or the respiratory spiracles, which look like tiny black dots on the surface of the wound. The organism may also be indirectly viewed through respiratory bubble formation within the exudate.^1,2 Diagnosis is confirmed by extracting the larvae from the wound and having the species identified by an experienced pathologist or parasitologist.

Mode of transmission

Phoresis is the name of the process by which Dermatobia hominis invades the skin.³ The female fly lays her eggs onto captured mosquitos using a quick-drying adhesive. The eggs are then transferred to the host by a mosquito bite. The host’s body heat induces egg hatching, and the larvae burrow into follicular openings or skin perforations. This leads to the development of a small erythematous papule, which can further lead to a furuncle-like nodule with a central pore that allows the organism to respirate. When ready to pupate, the larvae work their way to the skin surface and drop to the soil, where they can further develop. After pupation, the fly hatches and develops into an adult, and the cycle repeats.

Common infectious and inflammatory lesions are in the differential Dx

The differential diagnosis includes bacterial abscess, exaggerated arthropod reaction, and ruptured epidermal cyst. With our patient, the travel history and unique exam findings led to the suspicion of myiasis.

Bacterial abscess is likely to have more notable purulence with response to appropriate oral antibiotics and no bubbling phenomenon on exam. It is also unlikely to be present for 1 month without progressive worsening.

Continue to: Exaggerated arthropod reaction

Exaggerated arthropod reaction usually manifests as a smooth, red, papular lesion without bubble formation from a central pore.

Ruptured epidermal cyst would be considered if there was a known preexisting cyst that recently changed. No bubble formation would be observed from the central pore.

Extraction is the treatment of choice

Treatment of furuncular myiasis involves removing the larvae or forcing them out of the lesion. Wounds can be covered with a substance, such as petrolatum, nail polish, beeswax, paraffin, or mineral oil, to block respiration.³ Occlusion may be needed for 24 hours to create adequate localized hypoxia to force the larvae to migrate from the wound and allow for easier manual extraction. Surgical removal of the larvae is also effective. A cruciate incision can be made adjacent to the central pore to avoid damaging the organisms.³ A topical, broad-based antiparasitic, such as a 10% ivermectin solution, has also been successfully used to treat furuncular myiasis. This approach works by either inducing larval migration outward or simply killing the larvae.³

Our patient recovered well after we performed a punch biopsy to make a larger wound opening and remove the intact larvae.

ACKNOWLEDGMENT
We thank Richard Pollack, PhD, at IdentifyUS, LLC, for providing the botfly larvae photo.

A healthy woman in her 60s presented to the clinic with a 1-month history of red, itchy, and slightly painful nodules on the scalp and back. The patient had travelled to Belize for a vacation in the weeks prior to the onset of the lesions. She was initially given a course of cephalexin for presumed furunculosis at another clinic, without improvement.

Examination revealed inflamed nodules with a central open pore on the left upper back (FIGURE 1) and the occipital scalp. Notably, when the lesions were observed with a dermatoscope, intermittent air bubbles were seen through the skin opening.

WHAT IS YOUR DIAGNOSIS?
HOW WOULD YOU TREAT THIS PATIENT?

 

 

Diagnosis: Furuncular myiasis

Given the patient’s clinical presentation and travel history, furuncular myiasis infestation was suspected and confirmed by punch biopsy. Pathologic exam revealed botfly larvae in both wounds, consistent with the human botfly, Dermatobia hominis (FIGURE 2). Myiasis is not common in the United States but should be suspected in patients who have recently traveled to tropical or subtropical areas. Furuncular myiasis describes the condition in which fly larvae penetrate healthy skin in a localized fashion, leading to the development of a ­furuncle-like nodule with 1 or more larvae within it.

Dermatobia hominis is the most common causative organism for furuncular myiasis in the regions of the Americas. Patients typically present with 1 lesion on an exposed part of the body (eg, scalp, face, extremities). The lesions typically contain a central pore with purulent or serosanguinous exudate.¹ Upon dermatoscopic inspection, one can often see the posterior part of the larva or the respiratory spiracles, which look like tiny black dots on the surface of the wound. The organism may also be indirectly viewed through respiratory bubble formation within the exudate.^1,2 Diagnosis is confirmed by extracting the larvae from the wound and having the species identified by an experienced pathologist or parasitologist.

Mode of transmission

Phoresis is the name of the process by which Dermatobia hominis invades the skin.³ The female fly lays her eggs onto captured mosquitos using a quick-drying adhesive. The eggs are then transferred to the host by a mosquito bite. The host’s body heat induces egg hatching, and the larvae burrow into follicular openings or skin perforations. This leads to the development of a small erythematous papule, which can further lead to a furuncle-like nodule with a central pore that allows the organism to respirate. When ready to pupate, the larvae work their way to the skin surface and drop to the soil, where they can further develop. After pupation, the fly hatches and develops into an adult, and the cycle repeats.

Common infectious and inflammatory lesions are in the differential Dx

The differential diagnosis includes bacterial abscess, exaggerated arthropod reaction, and ruptured epidermal cyst. With our patient, the travel history and unique exam findings led to the suspicion of myiasis.

Bacterial abscess is likely to have more notable purulence with response to appropriate oral antibiotics and no bubbling phenomenon on exam. It is also unlikely to be present for 1 month without progressive worsening.

Continue to: Exaggerated arthropod reaction

Exaggerated arthropod reaction usually manifests as a smooth, red, papular lesion without bubble formation from a central pore.

Ruptured epidermal cyst would be considered if there was a known preexisting cyst that recently changed. No bubble formation would be observed from the central pore.

Extraction is the treatment of choice

Treatment of furuncular myiasis involves removing the larvae or forcing them out of the lesion. Wounds can be covered with a substance, such as petrolatum, nail polish, beeswax, paraffin, or mineral oil, to block respiration.³ Occlusion may be needed for 24 hours to create adequate localized hypoxia to force the larvae to migrate from the wound and allow for easier manual extraction. Surgical removal of the larvae is also effective. A cruciate incision can be made adjacent to the central pore to avoid damaging the organisms.³ A topical, broad-based antiparasitic, such as a 10% ivermectin solution, has also been successfully used to treat furuncular myiasis. This approach works by either inducing larval migration outward or simply killing the larvae.³

Our patient recovered well after we performed a punch biopsy to make a larger wound opening and remove the intact larvae.

ACKNOWLEDGMENT
We thank Richard Pollack, PhD, at IdentifyUS, LLC, for providing the botfly larvae photo.

A healthy woman in her 60s presented to the clinic with a 1-month history of red, itchy, and slightly painful nodules on the scalp and back. The patient had travelled to Belize for a vacation in the weeks prior to the onset of the lesions. She was initially given a course of cephalexin for presumed furunculosis at another clinic, without improvement.

Examination revealed inflamed nodules with a central open pore on the left upper back (FIGURE 1) and the occipital scalp. Notably, when the lesions were observed with a dermatoscope, intermittent air bubbles were seen through the skin opening.

WHAT IS YOUR DIAGNOSIS?
HOW WOULD YOU TREAT THIS PATIENT?

 

 

Diagnosis: Furuncular myiasis

Given the patient’s clinical presentation and travel history, furuncular myiasis infestation was suspected and confirmed by punch biopsy. Pathologic exam revealed botfly larvae in both wounds, consistent with the human botfly, Dermatobia hominis (FIGURE 2). Myiasis is not common in the United States but should be suspected in patients who have recently traveled to tropical or subtropical areas. Furuncular myiasis describes the condition in which fly larvae penetrate healthy skin in a localized fashion, leading to the development of a ­furuncle-like nodule with 1 or more larvae within it.

Dermatobia hominis is the most common causative organism for furuncular myiasis in the regions of the Americas. Patients typically present with 1 lesion on an exposed part of the body (eg, scalp, face, extremities). The lesions typically contain a central pore with purulent or serosanguinous exudate.¹ Upon dermatoscopic inspection, one can often see the posterior part of the larva or the respiratory spiracles, which look like tiny black dots on the surface of the wound. The organism may also be indirectly viewed through respiratory bubble formation within the exudate.^1,2 Diagnosis is confirmed by extracting the larvae from the wound and having the species identified by an experienced pathologist or parasitologist.

Mode of transmission

Phoresis is the name of the process by which Dermatobia hominis invades the skin.³ The female fly lays her eggs onto captured mosquitos using a quick-drying adhesive. The eggs are then transferred to the host by a mosquito bite. The host’s body heat induces egg hatching, and the larvae burrow into follicular openings or skin perforations. This leads to the development of a small erythematous papule, which can further lead to a furuncle-like nodule with a central pore that allows the organism to respirate. When ready to pupate, the larvae work their way to the skin surface and drop to the soil, where they can further develop. After pupation, the fly hatches and develops into an adult, and the cycle repeats.

Common infectious and inflammatory lesions are in the differential Dx

The differential diagnosis includes bacterial abscess, exaggerated arthropod reaction, and ruptured epidermal cyst. With our patient, the travel history and unique exam findings led to the suspicion of myiasis.

Bacterial abscess is likely to have more notable purulence with response to appropriate oral antibiotics and no bubbling phenomenon on exam. It is also unlikely to be present for 1 month without progressive worsening.

Continue to: Exaggerated arthropod reaction

Exaggerated arthropod reaction usually manifests as a smooth, red, papular lesion without bubble formation from a central pore.

Ruptured epidermal cyst would be considered if there was a known preexisting cyst that recently changed. No bubble formation would be observed from the central pore.

Extraction is the treatment of choice

Treatment of furuncular myiasis involves removing the larvae or forcing them out of the lesion. Wounds can be covered with a substance, such as petrolatum, nail polish, beeswax, paraffin, or mineral oil, to block respiration.³ Occlusion may be needed for 24 hours to create adequate localized hypoxia to force the larvae to migrate from the wound and allow for easier manual extraction. Surgical removal of the larvae is also effective. A cruciate incision can be made adjacent to the central pore to avoid damaging the organisms.³ A topical, broad-based antiparasitic, such as a 10% ivermectin solution, has also been successfully used to treat furuncular myiasis. This approach works by either inducing larval migration outward or simply killing the larvae.³

Our patient recovered well after we performed a punch biopsy to make a larger wound opening and remove the intact larvae.

ACKNOWLEDGMENT
We thank Richard Pollack, PhD, at IdentifyUS, LLC, for providing the botfly larvae photo.