The Food and Drug Administration has cleared the expanded use of a procalcitonin test to help determine antibiotic use in patients with lower respiratory tract infections (LRTI) and sepsis.

The Vidas Brahms PCT Assay (bioMérieux) uses procalcitonin levels to determine whether a patient with a lower respiratory tract infection (LRTI) should begin or remain on antibiotics and when antibiotics should be withdrawn in a patient with sepsis.

The test will be used primarily in hospital settings and emergency departments, according to the FDA. Test levels that are high levels suggest bacterial infection and the need for antibiotics while low levels indicate viral or noninfectious processes. However, concerns exist regarding false-positive or false-negative test results, which can prompt clinicians to prematurely stop or unnecessarily continue an antibiotic regimen in certain patients.

“Health care providers should not rely solely on PCT test results when making treatment decisions but should interpret test results in the context of a patient’s clinical status and other laboratory results,” according to the FDA statement.

The expanded use of the test was approved based on promising data from clinical trials that was presented at an FDA advisory committee meeting in November 2016. The Vidas Brahms test was already approved by the FDA for use in determining a patient’s risk of dying from sepsis. The test was cleared via the FDA 510(k) regulatory pathway, which is meant for tests or devices for which there is already something similar on the market.

Support for the test’s expanded usage comes from published prospective, randomized clinical trials that compared PCT-guided therapy with standard therapy. In those studies, patients who had received PCT-guided therapy experienced significant decreases in antibiotic use without significant affects to their safety.
 

[email protected]

The Food and Drug Administration has cleared the expanded use of a procalcitonin test to help determine antibiotic use in patients with lower respiratory tract infections (LRTI) and sepsis.

The Vidas Brahms PCT Assay (bioMérieux) uses procalcitonin levels to determine whether a patient with a lower respiratory tract infection (LRTI) should begin or remain on antibiotics and when antibiotics should be withdrawn in a patient with sepsis.

The test will be used primarily in hospital settings and emergency departments, according to the FDA. Test levels that are high levels suggest bacterial infection and the need for antibiotics while low levels indicate viral or noninfectious processes. However, concerns exist regarding false-positive or false-negative test results, which can prompt clinicians to prematurely stop or unnecessarily continue an antibiotic regimen in certain patients.

“Health care providers should not rely solely on PCT test results when making treatment decisions but should interpret test results in the context of a patient’s clinical status and other laboratory results,” according to the FDA statement.

The expanded use of the test was approved based on promising data from clinical trials that was presented at an FDA advisory committee meeting in November 2016. The Vidas Brahms test was already approved by the FDA for use in determining a patient’s risk of dying from sepsis. The test was cleared via the FDA 510(k) regulatory pathway, which is meant for tests or devices for which there is already something similar on the market.

Support for the test’s expanded usage comes from published prospective, randomized clinical trials that compared PCT-guided therapy with standard therapy. In those studies, patients who had received PCT-guided therapy experienced significant decreases in antibiotic use without significant affects to their safety.
 

[email protected]

The Food and Drug Administration has cleared the expanded use of a procalcitonin test to help determine antibiotic use in patients with lower respiratory tract infections (LRTI) and sepsis.

The Vidas Brahms PCT Assay (bioMérieux) uses procalcitonin levels to determine whether a patient with a lower respiratory tract infection (LRTI) should begin or remain on antibiotics and when antibiotics should be withdrawn in a patient with sepsis.

The test will be used primarily in hospital settings and emergency departments, according to the FDA. Test levels that are high levels suggest bacterial infection and the need for antibiotics while low levels indicate viral or noninfectious processes. However, concerns exist regarding false-positive or false-negative test results, which can prompt clinicians to prematurely stop or unnecessarily continue an antibiotic regimen in certain patients.

“Health care providers should not rely solely on PCT test results when making treatment decisions but should interpret test results in the context of a patient’s clinical status and other laboratory results,” according to the FDA statement.

The expanded use of the test was approved based on promising data from clinical trials that was presented at an FDA advisory committee meeting in November 2016. The Vidas Brahms test was already approved by the FDA for use in determining a patient’s risk of dying from sepsis. The test was cleared via the FDA 510(k) regulatory pathway, which is meant for tests or devices for which there is already something similar on the market.

Support for the test’s expanded usage comes from published prospective, randomized clinical trials that compared PCT-guided therapy with standard therapy. In those studies, patients who had received PCT-guided therapy experienced significant decreases in antibiotic use without significant affects to their safety.
 

[email protected]

Infections, autoimmune disease, bone marrow failure, medications, and total-body irradiation may induce CD4 lymphopenia, defined as a CD4 T-cell count below 300 cells/mL or less than 20% of total lymphocytes.¹ Human immunodeficiency virus (HIV) is the most common cause of CD4 lymphopenia, with sepsis (bacterial and fungal) and postoperative states the most common causes in hospital settings.² No underlying factors are found in 0.02% of CD4 lymphopenia cases, which are considered to be idiopathic.^3,4 We report a patient with cutaneous T-cell lymphoma (CTCL) who developed profound CD4 lymphopenia in the setting of long-term bexarotene therapy.

Case Report

A 63-year-old man with hypertension presented to our dermatology clinic with pruritic scaly plaques on the scalp of 4 months’ duration that had progressed to full-body exfoliative erythroderma (Figure 1). He had diffuse palmoplantar keratoderma and lymphadenopathy. His only long-term medications were terazosin for benign prostatic hyperplasia and atenolol for hypertension; he reported no new medications. Laboratory evaluation revealed normal liver and kidney function. A complete blood cell count (CBC) revealed a white blood cell (WBC) count within reference range (8000/µL [reference range, 4500–11,000/µL]) but with increased eosinophils (12.9% [reference range, 2.7%]) and monocytes (11.8% [reference range, 4%]) and reduced lymphocytes (16.8% [reference range, 34%]). Flow cytometry showed a CD4:CD8 ratio of 1.18 to 1 (reference range, 0.8–4.2)(absolute CD4⁺ cells, 764/µL [reference range, 297–1551/µL]; absolute CD8⁺ cells, 654/µL [reference range, 100–1047/µL]). Skin biopsy revealed subacute spongiotic dermatitis with numerous eosinophils, exocytosis including folliculotropism, and rare atypical lymphocytes (Figure 2). Molecular studies showed T-cell receptor γ gene rearrangement. The patient did not have any other underlying conditions that would predispose him to lymphopenia. Based on these findings, a diagnosis of CTCL stage IIIA was made and agreed on by experts at the University of California, San Diego Dermatology Grand Rounds.

The patient was subsequently started on acitretin, topical corticosteroids, and hydroxyzine. However, the erythroderma progressed and he developed fever, chills, and malaise, and he was hospitalized 2 months later for intensive therapy and to rule out infection. He improved on daily wet wraps, topical steroids, oral antibiotics, and initiation of narrowband UVB therapy. He was discharged 1 week later. Acitretin was switched to bexarotene 3 months later due to peeling and cracking of the palmoplantar skin. The initial dose was 225 mg once daily, which was steadily increased over the next 4 months to a therapeutic dose of 600 mg once daily, which was much lower than the maximum dose of 400 mg/m² daily (calculated at 750 mg/d in our patient). The patient achieved clinical remission 1 year after initiation of bexarotene in conjunction with narrowband UVB therapy. Serum eosinophils also normalized. Because there were no intolerable side effects, this dose was continued for 2 more years before it was slowly tapered to 375 mg once daily over a 1-year period. The new dose was maintained thereafter. Secondary hypertriglyceridemia and hypothyroidism, known side effects of bexarotene, developed 1 and 5 months after initiating therapy, respectively, and were treated with levothyroxine and fenofibrate. Blood counts were checked every 3 months and remained within reference range. Within the first few months of therapy, lymphocytes did trend down to 16.8%, but segmented neutrophils were normal at 59.4%. For the next 5 years the total WBC count and differential remained within reference range. T-cell subsets and flow cytometry data were not measured. No new medications were started during this period, and none of his existing medications had lymphopenia as a known side effect.

Five years after the initial diagnosis, the patient was still on bexarotene and was suspected to have pneumonia that was treated by his primary care provider with cefuroxime and azithromycin for 2 weeks with no improvement. He was then admitted to the hospital with shortness of breath, productive cough, night sweats, and dyspnea of 1 month’s duration. There was no associated weight loss or fever. Notably, the skin was clear. He was further treated for community-acquired pneumonia, first with vancomycin and ceftazidime, then with ciprofloxacin and sulfamethoxazole-trimethoprim, with no improvement. A CBC with differential was obtained on the patient’s first admission and revealed a WBC count of 3600/µL with decreased lymphocytes (8.6%), no eosinophilia, and anemia (hemoglobin, 10.5 g/dL [reference range, 33–37 g/dL]). T-cell subset studies revealed a CD4:CD8 ratio of 0.06 to 1 (absolute CD4⁺ cells, 6/µL; absolute CD8⁺ cells, 107/µL). The patient also had an elevated lactate dehydrogenase level of 1015 U/L (reference range, 100–200 U/L) and a normal comprehensive metabolic panel. A comprehensive workup, including urine and blood cultures, serum Cryptococcus and coccidioidomycosis IgG/IgM, histoplasmosis urine antigen, legionella, HIV, purified protein derivative (tuberculin), and aspergillosis galactomannan antigen panel, was negative. Blood tests for HIV and human T-lymphotropic virus also were negative. Bronchoscopy with cytology and sputum cultures for fungi, acid-fast bacteria, and viruses identified Pneumocystis jiroveci in the bronchial wash. Pneumocystis pneumonia was treated with intravenous clindamycin, primaquine, and leucovorin. The patient’s WBC count continued to drop over the next 2 weeks to a nadir of 1.7% with few lymphocytes noted on the differential. At that point, the bexarotene was stopped and was considered causative in inducing CD4 lymphopenia, resulting in opportunistic infection. The patient steadily improved and was discharged on sulfamethoxazole-trimethoprim prophylaxis for pneumocystis after a 4-month hospitalization.

His CD4 count slowly improved over the next 18 months; however, his skin disease recurred and progressed to exfoliative erythroderma with marked scarring alopecia (Figure 3), facial swelling, extreme pruritus, and notable eosinophilia. Repeat computed tomography was negative for extracutaneous involvement. A repeat skin biopsy showed recurrent mycosis fungoides similar to the original biopsy (Figure 4). Topical steroids and narrowband UVB therapy were restarted. A bone marrow biopsy revealed no definitive lymphoma, but the peripheral blood showed occasional CD8⁺ “flower cells” and no CD4⁺ Sézary cells. Two repeat molecular studies failed to show the T-cell receptor gene rearrangement. Localized electron beam radiation therapy, lenalidomide, and clobetasol were tried without benefit. The patient was hospitalized 3 months later and was started on wet wraps as well as weekly infusions of the histone deacetylase inhibitor romidepsin (14 mg/m² over a 4-hour period) on days 1, 8, and 15 of a 28-day cycle with rapid improvement. He experienced transient slight neutropenia with the first several treatments that quickly resolved. His skin was clear while on a regimen of triamcinolone, wet wraps, and intravenous romidepsin. He demonstrated visible improvement after 3 weekly infusions of romedepsin (Figure 5). His skin disease cleared after 9 infusions of romidepsin, and he currently remains in remission; however, he developed presumed bronchopneumonia after approximately 3 to 4 infusions. He then presented with severe headaches after his ninth infusion and was found to have cryptococcal meningitis. Romedepsin was stopped and he was treated with systemic antifungal therapy. His CTCL never recurred despite not restarting romidepsin.

Comment

The retinoids are chemically related to vitamin A. They regulate epithelial cell growth and are beneficial in inflammatory skin disorders and in patients with increased cell turnover as well as in skin cancer and precancer prevention/treatment.⁵ The first- and second-generation retinoids, isotretinoin and acitretin, respectively, cause anemia or leukopenia in less than 10% of patients; adverse effects are noted more commonly in doses greater than 1 mg/kg daily.^6-8

Bexarotene is a third-generation retinoid drug that is more selective for retinoid X receptors. It was approved in 1991 for treatment of advanced CTCL (stages IIB–IVB) in adult patients who have failed at least 1 prior systemic therapy. Bexarotene is noted to promote cell cycle arrest and apoptosis in CTCL cell lines.⁹ However, one study suggested that for bexarotene, inhibition of proliferation is more important than causing apoptosis in CTCL cells, and this effect is achieved through triggering the p53/p73-dependent cell cycle inhibition pathway.¹⁰ Studies in patients with Sézary syndrome have shown that bexarotene changes the chemokine receptor expression in circulating malignant T cells, making them less likely to traffic to the skin (lower chemokine receptor type 4 expression),¹¹ which may explain why some CTCL cases have shown improvement of skin disease on bexarotene despite progression of extradermal disease.¹²

Common side effects of bexarotene include hyperlipidemia and central hypothyroidism.¹³ In addition, dose-related myelosuppression with isolated leukopenia, particularly neutropenia, also has been reported (18% of patients at a dosage of 300 mg/m²/d and 43% of patients with a dosage greater than 300 mg/m²/d). Leukopenia generally occurs within the first 4 to 8 weeks of treatment, is relatively mild (WBC, 1000–2999/µL), and generally is reversible.^13-15 One review of 66 mycosis fungoides patients treated with bexarotene described a patient who developed leukopenia 15 months after initiating bexarotene therapy.¹⁴ The manufacturer recommends that treatment with bexarotene be continued as long as the patient is receiving benefit from the treatment. One trial of 70 mycosis fungoides patient treated with bexarotene reported response rates of 48% on bexarotene monotherapy (n=54) and 69% on bexarotene plus an additional agent (n=16).¹⁵ The authors noted higher response rates in patients on 2 lipid-lowering agents. They concluded that bexarotene was a safe and effective agent for treatment of cutaneous T-cell lymphoma and recommended continued treatment with a lowered dose of bexarotene in those achieving complete responses for a period of 2 years. Although the recommended initial dose is 300 mg/m²/d, bexarotene can be increased to 400 mg/m²/d after 8 weeks if no response to treatment is appreciated.¹⁶ Our patient was on a maximum bexarotene dose of 600 mg once daily (280 mg/m²/d) for the first 2 years, and a maintenance dose of 300 mg once daily for the next 3 years. He was not on any medicines known to induce leukopenia and he was not given any known cytochrome P450 3A4 inhibitors that could increase the toxicity of bexarotene.

The patient’s CBC was checked routinely every 2 to 3 months after he was started on bexarotene. For 5 years, the CBC and differential remained within reference range; however, his CD4 counts were not followed during those 5 years. We attribute his CD4 lymphopenia and subsequent pneumocystis pneumonia to bexarotene. After our patient’s CD4 lymphopenia was discovered, he developed a precipitous drop in his WBC and lymphocyte counts while hospitalized that worsened over a 2-week period. At this point, the bexarotene was discontinued and his WBC count slowly recovered. We believe that one of the initial antibiotics prescribed by the patient’s primary care physician at initial onset of pneumonia symptoms as an outpatient could have acted synergistically with bexarotene to worsen lymphopenia. Specifically, ceftazidime, vancomycin, and ciprofloxacin have all been reported to cause leukopenia; however, it was neutropenia in these cases, not lymphopenia.^17,18 Notwithstanding, the opportunistic pneumonia and therefore CD4 lymphopenia was present prior to any antibiotic use.

The CD4 lymphopenia was unlikely due to underlying infection(s) because an extensive workup was negative, except for the pneumocystis, which likely resulted from the lymphopenia. The CD4 lymphopenia also could be idiopathic, as it has been reported in 3 patients with mycosis fungoides.¹⁹ All 3 patients were erythrodermic at presentation and were noted to have numerous CD4⁺ lymphocytes in the cutaneous lesions but few circulating CD4⁺ T lymphocytes in the blood. The authors attributed the CD4 lymphopenia to cutaneous sequestration of CD4⁺ T lymphocytes.¹⁹ These cases contrast with our patient who was in clinical remission at the time of CD4 lymphopenia, which improved and normalized following discontinuation of bexarotene.

Conclusion

This case emphasizes the importance of monitoring for leukopenia, specifically CD4 lymphopenia, in patients on long-term bexarotene therapy. Routine CBC as well as T-cell subset counts should be performed during treatment. Rotation off bexarotene after several years of therapy should be considered, even in patients with continuous benefit from this systemic therapy.

Infections, autoimmune disease, bone marrow failure, medications, and total-body irradiation may induce CD4 lymphopenia, defined as a CD4 T-cell count below 300 cells/mL or less than 20% of total lymphocytes.¹ Human immunodeficiency virus (HIV) is the most common cause of CD4 lymphopenia, with sepsis (bacterial and fungal) and postoperative states the most common causes in hospital settings.² No underlying factors are found in 0.02% of CD4 lymphopenia cases, which are considered to be idiopathic.^3,4 We report a patient with cutaneous T-cell lymphoma (CTCL) who developed profound CD4 lymphopenia in the setting of long-term bexarotene therapy.

Case Report

A 63-year-old man with hypertension presented to our dermatology clinic with pruritic scaly plaques on the scalp of 4 months’ duration that had progressed to full-body exfoliative erythroderma (Figure 1). He had diffuse palmoplantar keratoderma and lymphadenopathy. His only long-term medications were terazosin for benign prostatic hyperplasia and atenolol for hypertension; he reported no new medications. Laboratory evaluation revealed normal liver and kidney function. A complete blood cell count (CBC) revealed a white blood cell (WBC) count within reference range (8000/µL [reference range, 4500–11,000/µL]) but with increased eosinophils (12.9% [reference range, 2.7%]) and monocytes (11.8% [reference range, 4%]) and reduced lymphocytes (16.8% [reference range, 34%]). Flow cytometry showed a CD4:CD8 ratio of 1.18 to 1 (reference range, 0.8–4.2)(absolute CD4⁺ cells, 764/µL [reference range, 297–1551/µL]; absolute CD8⁺ cells, 654/µL [reference range, 100–1047/µL]). Skin biopsy revealed subacute spongiotic dermatitis with numerous eosinophils, exocytosis including folliculotropism, and rare atypical lymphocytes (Figure 2). Molecular studies showed T-cell receptor γ gene rearrangement. The patient did not have any other underlying conditions that would predispose him to lymphopenia. Based on these findings, a diagnosis of CTCL stage IIIA was made and agreed on by experts at the University of California, San Diego Dermatology Grand Rounds.

The patient was subsequently started on acitretin, topical corticosteroids, and hydroxyzine. However, the erythroderma progressed and he developed fever, chills, and malaise, and he was hospitalized 2 months later for intensive therapy and to rule out infection. He improved on daily wet wraps, topical steroids, oral antibiotics, and initiation of narrowband UVB therapy. He was discharged 1 week later. Acitretin was switched to bexarotene 3 months later due to peeling and cracking of the palmoplantar skin. The initial dose was 225 mg once daily, which was steadily increased over the next 4 months to a therapeutic dose of 600 mg once daily, which was much lower than the maximum dose of 400 mg/m² daily (calculated at 750 mg/d in our patient). The patient achieved clinical remission 1 year after initiation of bexarotene in conjunction with narrowband UVB therapy. Serum eosinophils also normalized. Because there were no intolerable side effects, this dose was continued for 2 more years before it was slowly tapered to 375 mg once daily over a 1-year period. The new dose was maintained thereafter. Secondary hypertriglyceridemia and hypothyroidism, known side effects of bexarotene, developed 1 and 5 months after initiating therapy, respectively, and were treated with levothyroxine and fenofibrate. Blood counts were checked every 3 months and remained within reference range. Within the first few months of therapy, lymphocytes did trend down to 16.8%, but segmented neutrophils were normal at 59.4%. For the next 5 years the total WBC count and differential remained within reference range. T-cell subsets and flow cytometry data were not measured. No new medications were started during this period, and none of his existing medications had lymphopenia as a known side effect.

Five years after the initial diagnosis, the patient was still on bexarotene and was suspected to have pneumonia that was treated by his primary care provider with cefuroxime and azithromycin for 2 weeks with no improvement. He was then admitted to the hospital with shortness of breath, productive cough, night sweats, and dyspnea of 1 month’s duration. There was no associated weight loss or fever. Notably, the skin was clear. He was further treated for community-acquired pneumonia, first with vancomycin and ceftazidime, then with ciprofloxacin and sulfamethoxazole-trimethoprim, with no improvement. A CBC with differential was obtained on the patient’s first admission and revealed a WBC count of 3600/µL with decreased lymphocytes (8.6%), no eosinophilia, and anemia (hemoglobin, 10.5 g/dL [reference range, 33–37 g/dL]). T-cell subset studies revealed a CD4:CD8 ratio of 0.06 to 1 (absolute CD4⁺ cells, 6/µL; absolute CD8⁺ cells, 107/µL). The patient also had an elevated lactate dehydrogenase level of 1015 U/L (reference range, 100–200 U/L) and a normal comprehensive metabolic panel. A comprehensive workup, including urine and blood cultures, serum Cryptococcus and coccidioidomycosis IgG/IgM, histoplasmosis urine antigen, legionella, HIV, purified protein derivative (tuberculin), and aspergillosis galactomannan antigen panel, was negative. Blood tests for HIV and human T-lymphotropic virus also were negative. Bronchoscopy with cytology and sputum cultures for fungi, acid-fast bacteria, and viruses identified Pneumocystis jiroveci in the bronchial wash. Pneumocystis pneumonia was treated with intravenous clindamycin, primaquine, and leucovorin. The patient’s WBC count continued to drop over the next 2 weeks to a nadir of 1.7% with few lymphocytes noted on the differential. At that point, the bexarotene was stopped and was considered causative in inducing CD4 lymphopenia, resulting in opportunistic infection. The patient steadily improved and was discharged on sulfamethoxazole-trimethoprim prophylaxis for pneumocystis after a 4-month hospitalization.

His CD4 count slowly improved over the next 18 months; however, his skin disease recurred and progressed to exfoliative erythroderma with marked scarring alopecia (Figure 3), facial swelling, extreme pruritus, and notable eosinophilia. Repeat computed tomography was negative for extracutaneous involvement. A repeat skin biopsy showed recurrent mycosis fungoides similar to the original biopsy (Figure 4). Topical steroids and narrowband UVB therapy were restarted. A bone marrow biopsy revealed no definitive lymphoma, but the peripheral blood showed occasional CD8⁺ “flower cells” and no CD4⁺ Sézary cells. Two repeat molecular studies failed to show the T-cell receptor gene rearrangement. Localized electron beam radiation therapy, lenalidomide, and clobetasol were tried without benefit. The patient was hospitalized 3 months later and was started on wet wraps as well as weekly infusions of the histone deacetylase inhibitor romidepsin (14 mg/m² over a 4-hour period) on days 1, 8, and 15 of a 28-day cycle with rapid improvement. He experienced transient slight neutropenia with the first several treatments that quickly resolved. His skin was clear while on a regimen of triamcinolone, wet wraps, and intravenous romidepsin. He demonstrated visible improvement after 3 weekly infusions of romedepsin (Figure 5). His skin disease cleared after 9 infusions of romidepsin, and he currently remains in remission; however, he developed presumed bronchopneumonia after approximately 3 to 4 infusions. He then presented with severe headaches after his ninth infusion and was found to have cryptococcal meningitis. Romedepsin was stopped and he was treated with systemic antifungal therapy. His CTCL never recurred despite not restarting romidepsin.

Comment

The retinoids are chemically related to vitamin A. They regulate epithelial cell growth and are beneficial in inflammatory skin disorders and in patients with increased cell turnover as well as in skin cancer and precancer prevention/treatment.⁵ The first- and second-generation retinoids, isotretinoin and acitretin, respectively, cause anemia or leukopenia in less than 10% of patients; adverse effects are noted more commonly in doses greater than 1 mg/kg daily.^6-8

Bexarotene is a third-generation retinoid drug that is more selective for retinoid X receptors. It was approved in 1991 for treatment of advanced CTCL (stages IIB–IVB) in adult patients who have failed at least 1 prior systemic therapy. Bexarotene is noted to promote cell cycle arrest and apoptosis in CTCL cell lines.⁹ However, one study suggested that for bexarotene, inhibition of proliferation is more important than causing apoptosis in CTCL cells, and this effect is achieved through triggering the p53/p73-dependent cell cycle inhibition pathway.¹⁰ Studies in patients with Sézary syndrome have shown that bexarotene changes the chemokine receptor expression in circulating malignant T cells, making them less likely to traffic to the skin (lower chemokine receptor type 4 expression),¹¹ which may explain why some CTCL cases have shown improvement of skin disease on bexarotene despite progression of extradermal disease.¹²

Common side effects of bexarotene include hyperlipidemia and central hypothyroidism.¹³ In addition, dose-related myelosuppression with isolated leukopenia, particularly neutropenia, also has been reported (18% of patients at a dosage of 300 mg/m²/d and 43% of patients with a dosage greater than 300 mg/m²/d). Leukopenia generally occurs within the first 4 to 8 weeks of treatment, is relatively mild (WBC, 1000–2999/µL), and generally is reversible.^13-15 One review of 66 mycosis fungoides patients treated with bexarotene described a patient who developed leukopenia 15 months after initiating bexarotene therapy.¹⁴ The manufacturer recommends that treatment with bexarotene be continued as long as the patient is receiving benefit from the treatment. One trial of 70 mycosis fungoides patient treated with bexarotene reported response rates of 48% on bexarotene monotherapy (n=54) and 69% on bexarotene plus an additional agent (n=16).¹⁵ The authors noted higher response rates in patients on 2 lipid-lowering agents. They concluded that bexarotene was a safe and effective agent for treatment of cutaneous T-cell lymphoma and recommended continued treatment with a lowered dose of bexarotene in those achieving complete responses for a period of 2 years. Although the recommended initial dose is 300 mg/m²/d, bexarotene can be increased to 400 mg/m²/d after 8 weeks if no response to treatment is appreciated.¹⁶ Our patient was on a maximum bexarotene dose of 600 mg once daily (280 mg/m²/d) for the first 2 years, and a maintenance dose of 300 mg once daily for the next 3 years. He was not on any medicines known to induce leukopenia and he was not given any known cytochrome P450 3A4 inhibitors that could increase the toxicity of bexarotene.

The patient’s CBC was checked routinely every 2 to 3 months after he was started on bexarotene. For 5 years, the CBC and differential remained within reference range; however, his CD4 counts were not followed during those 5 years. We attribute his CD4 lymphopenia and subsequent pneumocystis pneumonia to bexarotene. After our patient’s CD4 lymphopenia was discovered, he developed a precipitous drop in his WBC and lymphocyte counts while hospitalized that worsened over a 2-week period. At this point, the bexarotene was discontinued and his WBC count slowly recovered. We believe that one of the initial antibiotics prescribed by the patient’s primary care physician at initial onset of pneumonia symptoms as an outpatient could have acted synergistically with bexarotene to worsen lymphopenia. Specifically, ceftazidime, vancomycin, and ciprofloxacin have all been reported to cause leukopenia; however, it was neutropenia in these cases, not lymphopenia.^17,18 Notwithstanding, the opportunistic pneumonia and therefore CD4 lymphopenia was present prior to any antibiotic use.

The CD4 lymphopenia was unlikely due to underlying infection(s) because an extensive workup was negative, except for the pneumocystis, which likely resulted from the lymphopenia. The CD4 lymphopenia also could be idiopathic, as it has been reported in 3 patients with mycosis fungoides.¹⁹ All 3 patients were erythrodermic at presentation and were noted to have numerous CD4⁺ lymphocytes in the cutaneous lesions but few circulating CD4⁺ T lymphocytes in the blood. The authors attributed the CD4 lymphopenia to cutaneous sequestration of CD4⁺ T lymphocytes.¹⁹ These cases contrast with our patient who was in clinical remission at the time of CD4 lymphopenia, which improved and normalized following discontinuation of bexarotene.

Conclusion

This case emphasizes the importance of monitoring for leukopenia, specifically CD4 lymphopenia, in patients on long-term bexarotene therapy. Routine CBC as well as T-cell subset counts should be performed during treatment. Rotation off bexarotene after several years of therapy should be considered, even in patients with continuous benefit from this systemic therapy.

Infections, autoimmune disease, bone marrow failure, medications, and total-body irradiation may induce CD4 lymphopenia, defined as a CD4 T-cell count below 300 cells/mL or less than 20% of total lymphocytes.¹ Human immunodeficiency virus (HIV) is the most common cause of CD4 lymphopenia, with sepsis (bacterial and fungal) and postoperative states the most common causes in hospital settings.² No underlying factors are found in 0.02% of CD4 lymphopenia cases, which are considered to be idiopathic.^3,4 We report a patient with cutaneous T-cell lymphoma (CTCL) who developed profound CD4 lymphopenia in the setting of long-term bexarotene therapy.

Case Report

A 63-year-old man with hypertension presented to our dermatology clinic with pruritic scaly plaques on the scalp of 4 months’ duration that had progressed to full-body exfoliative erythroderma (Figure 1). He had diffuse palmoplantar keratoderma and lymphadenopathy. His only long-term medications were terazosin for benign prostatic hyperplasia and atenolol for hypertension; he reported no new medications. Laboratory evaluation revealed normal liver and kidney function. A complete blood cell count (CBC) revealed a white blood cell (WBC) count within reference range (8000/µL [reference range, 4500–11,000/µL]) but with increased eosinophils (12.9% [reference range, 2.7%]) and monocytes (11.8% [reference range, 4%]) and reduced lymphocytes (16.8% [reference range, 34%]). Flow cytometry showed a CD4:CD8 ratio of 1.18 to 1 (reference range, 0.8–4.2)(absolute CD4⁺ cells, 764/µL [reference range, 297–1551/µL]; absolute CD8⁺ cells, 654/µL [reference range, 100–1047/µL]). Skin biopsy revealed subacute spongiotic dermatitis with numerous eosinophils, exocytosis including folliculotropism, and rare atypical lymphocytes (Figure 2). Molecular studies showed T-cell receptor γ gene rearrangement. The patient did not have any other underlying conditions that would predispose him to lymphopenia. Based on these findings, a diagnosis of CTCL stage IIIA was made and agreed on by experts at the University of California, San Diego Dermatology Grand Rounds.

The patient was subsequently started on acitretin, topical corticosteroids, and hydroxyzine. However, the erythroderma progressed and he developed fever, chills, and malaise, and he was hospitalized 2 months later for intensive therapy and to rule out infection. He improved on daily wet wraps, topical steroids, oral antibiotics, and initiation of narrowband UVB therapy. He was discharged 1 week later. Acitretin was switched to bexarotene 3 months later due to peeling and cracking of the palmoplantar skin. The initial dose was 225 mg once daily, which was steadily increased over the next 4 months to a therapeutic dose of 600 mg once daily, which was much lower than the maximum dose of 400 mg/m² daily (calculated at 750 mg/d in our patient). The patient achieved clinical remission 1 year after initiation of bexarotene in conjunction with narrowband UVB therapy. Serum eosinophils also normalized. Because there were no intolerable side effects, this dose was continued for 2 more years before it was slowly tapered to 375 mg once daily over a 1-year period. The new dose was maintained thereafter. Secondary hypertriglyceridemia and hypothyroidism, known side effects of bexarotene, developed 1 and 5 months after initiating therapy, respectively, and were treated with levothyroxine and fenofibrate. Blood counts were checked every 3 months and remained within reference range. Within the first few months of therapy, lymphocytes did trend down to 16.8%, but segmented neutrophils were normal at 59.4%. For the next 5 years the total WBC count and differential remained within reference range. T-cell subsets and flow cytometry data were not measured. No new medications were started during this period, and none of his existing medications had lymphopenia as a known side effect.

Five years after the initial diagnosis, the patient was still on bexarotene and was suspected to have pneumonia that was treated by his primary care provider with cefuroxime and azithromycin for 2 weeks with no improvement. He was then admitted to the hospital with shortness of breath, productive cough, night sweats, and dyspnea of 1 month’s duration. There was no associated weight loss or fever. Notably, the skin was clear. He was further treated for community-acquired pneumonia, first with vancomycin and ceftazidime, then with ciprofloxacin and sulfamethoxazole-trimethoprim, with no improvement. A CBC with differential was obtained on the patient’s first admission and revealed a WBC count of 3600/µL with decreased lymphocytes (8.6%), no eosinophilia, and anemia (hemoglobin, 10.5 g/dL [reference range, 33–37 g/dL]). T-cell subset studies revealed a CD4:CD8 ratio of 0.06 to 1 (absolute CD4⁺ cells, 6/µL; absolute CD8⁺ cells, 107/µL). The patient also had an elevated lactate dehydrogenase level of 1015 U/L (reference range, 100–200 U/L) and a normal comprehensive metabolic panel. A comprehensive workup, including urine and blood cultures, serum Cryptococcus and coccidioidomycosis IgG/IgM, histoplasmosis urine antigen, legionella, HIV, purified protein derivative (tuberculin), and aspergillosis galactomannan antigen panel, was negative. Blood tests for HIV and human T-lymphotropic virus also were negative. Bronchoscopy with cytology and sputum cultures for fungi, acid-fast bacteria, and viruses identified Pneumocystis jiroveci in the bronchial wash. Pneumocystis pneumonia was treated with intravenous clindamycin, primaquine, and leucovorin. The patient’s WBC count continued to drop over the next 2 weeks to a nadir of 1.7% with few lymphocytes noted on the differential. At that point, the bexarotene was stopped and was considered causative in inducing CD4 lymphopenia, resulting in opportunistic infection. The patient steadily improved and was discharged on sulfamethoxazole-trimethoprim prophylaxis for pneumocystis after a 4-month hospitalization.

His CD4 count slowly improved over the next 18 months; however, his skin disease recurred and progressed to exfoliative erythroderma with marked scarring alopecia (Figure 3), facial swelling, extreme pruritus, and notable eosinophilia. Repeat computed tomography was negative for extracutaneous involvement. A repeat skin biopsy showed recurrent mycosis fungoides similar to the original biopsy (Figure 4). Topical steroids and narrowband UVB therapy were restarted. A bone marrow biopsy revealed no definitive lymphoma, but the peripheral blood showed occasional CD8⁺ “flower cells” and no CD4⁺ Sézary cells. Two repeat molecular studies failed to show the T-cell receptor gene rearrangement. Localized electron beam radiation therapy, lenalidomide, and clobetasol were tried without benefit. The patient was hospitalized 3 months later and was started on wet wraps as well as weekly infusions of the histone deacetylase inhibitor romidepsin (14 mg/m² over a 4-hour period) on days 1, 8, and 15 of a 28-day cycle with rapid improvement. He experienced transient slight neutropenia with the first several treatments that quickly resolved. His skin was clear while on a regimen of triamcinolone, wet wraps, and intravenous romidepsin. He demonstrated visible improvement after 3 weekly infusions of romedepsin (Figure 5). His skin disease cleared after 9 infusions of romidepsin, and he currently remains in remission; however, he developed presumed bronchopneumonia after approximately 3 to 4 infusions. He then presented with severe headaches after his ninth infusion and was found to have cryptococcal meningitis. Romedepsin was stopped and he was treated with systemic antifungal therapy. His CTCL never recurred despite not restarting romidepsin.

Comment

The retinoids are chemically related to vitamin A. They regulate epithelial cell growth and are beneficial in inflammatory skin disorders and in patients with increased cell turnover as well as in skin cancer and precancer prevention/treatment.⁵ The first- and second-generation retinoids, isotretinoin and acitretin, respectively, cause anemia or leukopenia in less than 10% of patients; adverse effects are noted more commonly in doses greater than 1 mg/kg daily.^6-8

Bexarotene is a third-generation retinoid drug that is more selective for retinoid X receptors. It was approved in 1991 for treatment of advanced CTCL (stages IIB–IVB) in adult patients who have failed at least 1 prior systemic therapy. Bexarotene is noted to promote cell cycle arrest and apoptosis in CTCL cell lines.⁹ However, one study suggested that for bexarotene, inhibition of proliferation is more important than causing apoptosis in CTCL cells, and this effect is achieved through triggering the p53/p73-dependent cell cycle inhibition pathway.¹⁰ Studies in patients with Sézary syndrome have shown that bexarotene changes the chemokine receptor expression in circulating malignant T cells, making them less likely to traffic to the skin (lower chemokine receptor type 4 expression),¹¹ which may explain why some CTCL cases have shown improvement of skin disease on bexarotene despite progression of extradermal disease.¹²

Common side effects of bexarotene include hyperlipidemia and central hypothyroidism.¹³ In addition, dose-related myelosuppression with isolated leukopenia, particularly neutropenia, also has been reported (18% of patients at a dosage of 300 mg/m²/d and 43% of patients with a dosage greater than 300 mg/m²/d). Leukopenia generally occurs within the first 4 to 8 weeks of treatment, is relatively mild (WBC, 1000–2999/µL), and generally is reversible.^13-15 One review of 66 mycosis fungoides patients treated with bexarotene described a patient who developed leukopenia 15 months after initiating bexarotene therapy.¹⁴ The manufacturer recommends that treatment with bexarotene be continued as long as the patient is receiving benefit from the treatment. One trial of 70 mycosis fungoides patient treated with bexarotene reported response rates of 48% on bexarotene monotherapy (n=54) and 69% on bexarotene plus an additional agent (n=16).¹⁵ The authors noted higher response rates in patients on 2 lipid-lowering agents. They concluded that bexarotene was a safe and effective agent for treatment of cutaneous T-cell lymphoma and recommended continued treatment with a lowered dose of bexarotene in those achieving complete responses for a period of 2 years. Although the recommended initial dose is 300 mg/m²/d, bexarotene can be increased to 400 mg/m²/d after 8 weeks if no response to treatment is appreciated.¹⁶ Our patient was on a maximum bexarotene dose of 600 mg once daily (280 mg/m²/d) for the first 2 years, and a maintenance dose of 300 mg once daily for the next 3 years. He was not on any medicines known to induce leukopenia and he was not given any known cytochrome P450 3A4 inhibitors that could increase the toxicity of bexarotene.

The patient’s CBC was checked routinely every 2 to 3 months after he was started on bexarotene. For 5 years, the CBC and differential remained within reference range; however, his CD4 counts were not followed during those 5 years. We attribute his CD4 lymphopenia and subsequent pneumocystis pneumonia to bexarotene. After our patient’s CD4 lymphopenia was discovered, he developed a precipitous drop in his WBC and lymphocyte counts while hospitalized that worsened over a 2-week period. At this point, the bexarotene was discontinued and his WBC count slowly recovered. We believe that one of the initial antibiotics prescribed by the patient’s primary care physician at initial onset of pneumonia symptoms as an outpatient could have acted synergistically with bexarotene to worsen lymphopenia. Specifically, ceftazidime, vancomycin, and ciprofloxacin have all been reported to cause leukopenia; however, it was neutropenia in these cases, not lymphopenia.^17,18 Notwithstanding, the opportunistic pneumonia and therefore CD4 lymphopenia was present prior to any antibiotic use.

The CD4 lymphopenia was unlikely due to underlying infection(s) because an extensive workup was negative, except for the pneumocystis, which likely resulted from the lymphopenia. The CD4 lymphopenia also could be idiopathic, as it has been reported in 3 patients with mycosis fungoides.¹⁹ All 3 patients were erythrodermic at presentation and were noted to have numerous CD4⁺ lymphocytes in the cutaneous lesions but few circulating CD4⁺ T lymphocytes in the blood. The authors attributed the CD4 lymphopenia to cutaneous sequestration of CD4⁺ T lymphocytes.¹⁹ These cases contrast with our patient who was in clinical remission at the time of CD4 lymphopenia, which improved and normalized following discontinuation of bexarotene.

Conclusion

This case emphasizes the importance of monitoring for leukopenia, specifically CD4 lymphopenia, in patients on long-term bexarotene therapy. Routine CBC as well as T-cell subset counts should be performed during treatment. Rotation off bexarotene after several years of therapy should be considered, even in patients with continuous benefit from this systemic therapy.

ORLANDO – A first-in-class antiviral drug was safe and effective when used to prevent clinically significant cytomegalovirus infections in adults undergoing hematopoietic cell transplantation.

At 24 weeks post-transplant, 38% (122/325) of those receiving the novel antiviral letermovir were considered treatment failures, compared with 61% (103/170) of those receiving placebo (P less than .0001). All-cause mortality was 10% (n=32/325) for patients receiving letermovir and 16%, (n=27/170) for the placebo group (log rank two-sided P = 0.0317).

CDC/Dr. Craig Lyerla

This article was updated 2/27/17.

[email protected]

On Twitter @karioakes

ORLANDO – A first-in-class antiviral drug was safe and effective when used to prevent clinically significant cytomegalovirus infections in adults undergoing hematopoietic cell transplantation.

At 24 weeks post-transplant, 38% (122/325) of those receiving the novel antiviral letermovir were considered treatment failures, compared with 61% (103/170) of those receiving placebo (P less than .0001). All-cause mortality was 10% (n=32/325) for patients receiving letermovir and 16%, (n=27/170) for the placebo group (log rank two-sided P = 0.0317).

CDC/Dr. Craig Lyerla

This article was updated 2/27/17.

[email protected]

On Twitter @karioakes

ORLANDO – A first-in-class antiviral drug was safe and effective when used to prevent clinically significant cytomegalovirus infections in adults undergoing hematopoietic cell transplantation.

At 24 weeks post-transplant, 38% (122/325) of those receiving the novel antiviral letermovir were considered treatment failures, compared with 61% (103/170) of those receiving placebo (P less than .0001). All-cause mortality was 10% (n=32/325) for patients receiving letermovir and 16%, (n=27/170) for the placebo group (log rank two-sided P = 0.0317).

CDC/Dr. Craig Lyerla

This article was updated 2/27/17.

[email protected]

On Twitter @karioakes

WAILEA, HAWAII – It is time for a new system of classifying nevi, according to Ashfaq Marghoob, MD, of Memorial Sloan Kettering Cancer Center, New York.

“It was known for the last 30 or 40 years that we do need to subclassify nevi into groups, so as to better stratify for melanoma risk,” identifying groups of individuals who would benefit most from targeted screening, Dr. Marghoob said in a video interview at the meeting, provided by Global Academy for Medical Education/Skin Disease Education Foundation. But it has been clear that there are many flaws in the current classification system, he added.

This is beginning to change as new data emerge about gene mutations and other science that can better stratify “or segregate” the nevi into subsets, and “the hope is we will be better able to predict which subsets are associated with melanoma risk either within the lesion itself or poses an increased risk to the patient,” he explained.

“As our understanding grows, we will start to come out with subsets of nevi that have a certain clinical and dermoscopic morphology,” to help predict which patients would benefit most from being monitored very closely, with the aim of detecting – and curing – melanomas early, said Dr. Marghoob, director of Memorial Sloan Kettering’s regional skin cancer clinic in Hauppauge, N.Y.

He had no financial conflicts to disclose.

SDEF and this news organization are owned by the same parent organization.

WAILEA, HAWAII – It is time for a new system of classifying nevi, according to Ashfaq Marghoob, MD, of Memorial Sloan Kettering Cancer Center, New York.

“It was known for the last 30 or 40 years that we do need to subclassify nevi into groups, so as to better stratify for melanoma risk,” identifying groups of individuals who would benefit most from targeted screening, Dr. Marghoob said in a video interview at the meeting, provided by Global Academy for Medical Education/Skin Disease Education Foundation. But it has been clear that there are many flaws in the current classification system, he added.

This is beginning to change as new data emerge about gene mutations and other science that can better stratify “or segregate” the nevi into subsets, and “the hope is we will be better able to predict which subsets are associated with melanoma risk either within the lesion itself or poses an increased risk to the patient,” he explained.

“As our understanding grows, we will start to come out with subsets of nevi that have a certain clinical and dermoscopic morphology,” to help predict which patients would benefit most from being monitored very closely, with the aim of detecting – and curing – melanomas early, said Dr. Marghoob, director of Memorial Sloan Kettering’s regional skin cancer clinic in Hauppauge, N.Y.

He had no financial conflicts to disclose.

SDEF and this news organization are owned by the same parent organization.

WAILEA, HAWAII – It is time for a new system of classifying nevi, according to Ashfaq Marghoob, MD, of Memorial Sloan Kettering Cancer Center, New York.

“It was known for the last 30 or 40 years that we do need to subclassify nevi into groups, so as to better stratify for melanoma risk,” identifying groups of individuals who would benefit most from targeted screening, Dr. Marghoob said in a video interview at the meeting, provided by Global Academy for Medical Education/Skin Disease Education Foundation. But it has been clear that there are many flaws in the current classification system, he added.

This is beginning to change as new data emerge about gene mutations and other science that can better stratify “or segregate” the nevi into subsets, and “the hope is we will be better able to predict which subsets are associated with melanoma risk either within the lesion itself or poses an increased risk to the patient,” he explained.

“As our understanding grows, we will start to come out with subsets of nevi that have a certain clinical and dermoscopic morphology,” to help predict which patients would benefit most from being monitored very closely, with the aim of detecting – and curing – melanomas early, said Dr. Marghoob, director of Memorial Sloan Kettering’s regional skin cancer clinic in Hauppauge, N.Y.

He had no financial conflicts to disclose.

SDEF and this news organization are owned by the same parent organization.

Progress continues to be made on creating a Zika vaccine, but taking any of the current candidates all the way through clinical trials and into production could take another few years, according to the latest information presented at a meeting of the Centers for Disease Control and Prevention’s Advisory Committee on Immunization Practices.

“As we all know, there is no vaccine for Zika, but there are a number of vaccines that have been developed over the last century or so for other flaviviruses, [such as] dengue, yellow fever, Japanese encephalitis, [West Nile], and we know a great deal about flaviviruses in general and the pathology that they have,” explained Gerald R. Kovacs, PhD, of the Biomedical Advanced Research and Development Authority (BARDA). “What we’re doing is using our lessons learned and working with the epidemiologists, with the clinicians, with the nonclinical development people, and using those lessons to develop new vaccines for Zika.”

Aunt_Spray/Thinkstock

[email protected]

Progress continues to be made on creating a Zika vaccine, but taking any of the current candidates all the way through clinical trials and into production could take another few years, according to the latest information presented at a meeting of the Centers for Disease Control and Prevention’s Advisory Committee on Immunization Practices.

“As we all know, there is no vaccine for Zika, but there are a number of vaccines that have been developed over the last century or so for other flaviviruses, [such as] dengue, yellow fever, Japanese encephalitis, [West Nile], and we know a great deal about flaviviruses in general and the pathology that they have,” explained Gerald R. Kovacs, PhD, of the Biomedical Advanced Research and Development Authority (BARDA). “What we’re doing is using our lessons learned and working with the epidemiologists, with the clinicians, with the nonclinical development people, and using those lessons to develop new vaccines for Zika.”

Aunt_Spray/Thinkstock

[email protected]

Progress continues to be made on creating a Zika vaccine, but taking any of the current candidates all the way through clinical trials and into production could take another few years, according to the latest information presented at a meeting of the Centers for Disease Control and Prevention’s Advisory Committee on Immunization Practices.

“As we all know, there is no vaccine for Zika, but there are a number of vaccines that have been developed over the last century or so for other flaviviruses, [such as] dengue, yellow fever, Japanese encephalitis, [West Nile], and we know a great deal about flaviviruses in general and the pathology that they have,” explained Gerald R. Kovacs, PhD, of the Biomedical Advanced Research and Development Authority (BARDA). “What we’re doing is using our lessons learned and working with the epidemiologists, with the clinicians, with the nonclinical development people, and using those lessons to develop new vaccines for Zika.”

Aunt_Spray/Thinkstock

[email protected]

WAILEA, HAWAII – In the past few years, there have been “exciting” advances in noninvasive techniques to permanently remove fat, according to Suzanne Kilmer, MD, of the department of dermatology, University of California, Davis.

There are devices now available to reduce fat “in a permanent way that’s not injurious, it’s not uncomfortable – patients love it,” Dr. Kilmer said in a video interview at the Hawaii Dermatology Seminar provided by Global Academy for Medical Education/Skin Disease Education Foundation.

Currently, the three noninvasive modalities she considers most effective for reducing fat are cryolipolysis, the 1,060-nm laser, and focused pulsed ultrasound. In the interview, she discussed the ways these treatments work and their safety.

With all three, “the fat that goes away stays away,” said Dr. Kilmer, who is director of the Laser and Skin Surgery Center of Northern California, Sacramento. Treatment results in release of fat, which is “cleared like it is as if you ate a cheeseburger,” she added. Interestingly, she said, trials that have looked at whether the fat reduction is accompanied by weight loss have found that, in most cases, the patient’s weight remains stable.

Dr. Kilmer’s disclosures included serving as a consultant and/or researcher for Allergan, Cutera, Cynosure, Cytrellis, Kythera, Lumenis, Merz, Miramar, Sebacia, Sienna Labs, Solta, Zeltiq, and Zift.

SDEF and this news organization are owned by the same parent company.

[email protected]

WAILEA, HAWAII – In the past few years, there have been “exciting” advances in noninvasive techniques to permanently remove fat, according to Suzanne Kilmer, MD, of the department of dermatology, University of California, Davis.

There are devices now available to reduce fat “in a permanent way that’s not injurious, it’s not uncomfortable – patients love it,” Dr. Kilmer said in a video interview at the Hawaii Dermatology Seminar provided by Global Academy for Medical Education/Skin Disease Education Foundation.

Currently, the three noninvasive modalities she considers most effective for reducing fat are cryolipolysis, the 1,060-nm laser, and focused pulsed ultrasound. In the interview, she discussed the ways these treatments work and their safety.

With all three, “the fat that goes away stays away,” said Dr. Kilmer, who is director of the Laser and Skin Surgery Center of Northern California, Sacramento. Treatment results in release of fat, which is “cleared like it is as if you ate a cheeseburger,” she added. Interestingly, she said, trials that have looked at whether the fat reduction is accompanied by weight loss have found that, in most cases, the patient’s weight remains stable.

Dr. Kilmer’s disclosures included serving as a consultant and/or researcher for Allergan, Cutera, Cynosure, Cytrellis, Kythera, Lumenis, Merz, Miramar, Sebacia, Sienna Labs, Solta, Zeltiq, and Zift.

SDEF and this news organization are owned by the same parent company.

[email protected]

WAILEA, HAWAII – In the past few years, there have been “exciting” advances in noninvasive techniques to permanently remove fat, according to Suzanne Kilmer, MD, of the department of dermatology, University of California, Davis.

There are devices now available to reduce fat “in a permanent way that’s not injurious, it’s not uncomfortable – patients love it,” Dr. Kilmer said in a video interview at the Hawaii Dermatology Seminar provided by Global Academy for Medical Education/Skin Disease Education Foundation.

Currently, the three noninvasive modalities she considers most effective for reducing fat are cryolipolysis, the 1,060-nm laser, and focused pulsed ultrasound. In the interview, she discussed the ways these treatments work and their safety.

With all three, “the fat that goes away stays away,” said Dr. Kilmer, who is director of the Laser and Skin Surgery Center of Northern California, Sacramento. Treatment results in release of fat, which is “cleared like it is as if you ate a cheeseburger,” she added. Interestingly, she said, trials that have looked at whether the fat reduction is accompanied by weight loss have found that, in most cases, the patient’s weight remains stable.

Dr. Kilmer’s disclosures included serving as a consultant and/or researcher for Allergan, Cutera, Cynosure, Cytrellis, Kythera, Lumenis, Merz, Miramar, Sebacia, Sienna Labs, Solta, Zeltiq, and Zift.

SDEF and this news organization are owned by the same parent company.

[email protected]

LAS VEGAS – There currently is no Food and Drug Administration–approved medication for the symptomatic treatment of stuttering, but current evidence suggests that second-generation antipsychotics risperidone, olanzapine, and asenapine are beneficial, according to Gerald A. Maguire, MD.

At an annual psychopharmacology update held by the Nevada Psychiatric Association, Dr. Maguire, who is a stutterer himself, said current clinical trials in adults with childhood onset fluency disorder support the dopamine hypothesis of stuttering, where abnormal elevated cerebral dopaminergic activity is implicated.

Courtesy UC Riverside School of Medicine

[email protected]

LAS VEGAS – There currently is no Food and Drug Administration–approved medication for the symptomatic treatment of stuttering, but current evidence suggests that second-generation antipsychotics risperidone, olanzapine, and asenapine are beneficial, according to Gerald A. Maguire, MD.

At an annual psychopharmacology update held by the Nevada Psychiatric Association, Dr. Maguire, who is a stutterer himself, said current clinical trials in adults with childhood onset fluency disorder support the dopamine hypothesis of stuttering, where abnormal elevated cerebral dopaminergic activity is implicated.

Courtesy UC Riverside School of Medicine

[email protected]

LAS VEGAS – There currently is no Food and Drug Administration–approved medication for the symptomatic treatment of stuttering, but current evidence suggests that second-generation antipsychotics risperidone, olanzapine, and asenapine are beneficial, according to Gerald A. Maguire, MD.

At an annual psychopharmacology update held by the Nevada Psychiatric Association, Dr. Maguire, who is a stutterer himself, said current clinical trials in adults with childhood onset fluency disorder support the dopamine hypothesis of stuttering, where abnormal elevated cerebral dopaminergic activity is implicated.

Courtesy UC Riverside School of Medicine

[email protected]

More than 10% of patients developed irritable bowel syndrome (IBS) within a year after infectious enteritis, which gave them a more than fourfold greater risk than that of controls, according to a systematic review and meta-analysis of 45 studies.

“Protozoal and bacterial enteritis confer the greatest overall risk, although the magnitude of increased risk diminishes with time since exposure,” Fabiane B. Klem, MD, and Akhilesh Wadhwa, MD, of Mayo Clinic in Rochester, Minn., and their associates wrote in the April issue of Gastroenterology. Other significant risk factors for postinfectious IBS (PI-IBS) included female sex, clinically severe infections, antibiotic therapy, and comorbid psychological distress, they said.

Postinfectious IBS can last at least a decade after resolution of campylobacteriosis, shigellosis, salmonellosis, giardiasis, and norovirus infections, even when patients have no other risk factors for IBS, the researchers noted. To update and expand the most recent meta-analysis of this topic (Aliment Pharmacol Ther. 2007;26:535-44), the investigators searched Ovid Medline, EMBASE, Web of Science, and Cochrane Database of Systematic Reviews for studies published from 2006 through Aug. 31, 2015. This search yielded 45 studies, including 30 studies comparing infected patients with controls, who were usually matched by age, sex, and geographic location (Gastroenterology. 2017 Jan 6. doi: 10.1053/j.gastro.2016.12.039).

In all, 10.1% of patients with infectious enteritis developed IBS in the next 12 months (95% confidence interval, 7.2-14.1) – a 4.2-fold increase in risk, compared with that of controls (risk ratio, 4.2; 95% CI, 3.2-5.7). This risk subsequently dropped, but remained significantly elevated (RR, 2.3; 95% CI, 1.8-3.0), compared with controls. “Of patients with enteritis caused by protozoa or parasites, 41.9% developed IBS; of patients with enteritis caused by bacterial infection, 13.8% developed IBS,” the researchers emphasized. Patients with these infections remained at elevated risk of PI-IBS even after 1 year. Viral enteritis also significantly increased the risk of PI-IBS, but risk dropped to baseline levels after a year.

Among 10 pooled studies of IBS subtypes, 46% of patients had mixed IBS, 39% had diarrhea-predominant IBS, and 15% had constipation-predominant IBS. Female sex doubled the odds of PI-IBS (odds ratio, 2.2; 95% CI, 1.6-3.1) in 11 pooled studies. Significant clinical risk factors for PI-IBS included diarrhea lasting more than 7 days (eight studies; OR, 2.6; 95% CI, 1.5-4.6), bloody stool (four studies; OR, 1.9; 95% CI, 1.1-3.0), and antibiotic therapy during infectious enteritis (seven studies; OR, 1.7; 95% CI, 1.2-2.4).

Multiple reports linked PI-IBS to clinical psychological distress at the time of infectious enteritis. Specific risk factors included depression based on the Hospitalization Anxiety and Depression Scale (five studies; OR, 1.5; 95% CI, 1.2-1.9), anxiety based on the Hospital Anxiety and Depression Scale (four studies; OR, 2.0; 95% CI, 1.3-2.9), somatization (four studies; OR, 4.1; 95% CI, 2.7-6.0), and neuroticism (two studies; OR, 3.3; 95% CI, 1.6-6.6). Isolated studies also implicated hypochondriasis, extroversion, negative illness beliefs, stress, sleep disturbance, and adverse life events in the preceding year, the researchers said.

They found no evidence of publication bias, but noted a substantial amount of heterogeneity among studies. Also, some studies did not report multivariate analyses, so individual odds ratios might reflect “a conglomeration of factors,” they said.

The National Institutes of Health and the American Gastroenterological Association funded the work. The investigators reported having no conflicts of interest.

Source: American Gastroenterological Association

More than 10% of patients developed irritable bowel syndrome (IBS) within a year after infectious enteritis, which gave them a more than fourfold greater risk than that of controls, according to a systematic review and meta-analysis of 45 studies.

“Protozoal and bacterial enteritis confer the greatest overall risk, although the magnitude of increased risk diminishes with time since exposure,” Fabiane B. Klem, MD, and Akhilesh Wadhwa, MD, of Mayo Clinic in Rochester, Minn., and their associates wrote in the April issue of Gastroenterology. Other significant risk factors for postinfectious IBS (PI-IBS) included female sex, clinically severe infections, antibiotic therapy, and comorbid psychological distress, they said.

Postinfectious IBS can last at least a decade after resolution of campylobacteriosis, shigellosis, salmonellosis, giardiasis, and norovirus infections, even when patients have no other risk factors for IBS, the researchers noted. To update and expand the most recent meta-analysis of this topic (Aliment Pharmacol Ther. 2007;26:535-44), the investigators searched Ovid Medline, EMBASE, Web of Science, and Cochrane Database of Systematic Reviews for studies published from 2006 through Aug. 31, 2015. This search yielded 45 studies, including 30 studies comparing infected patients with controls, who were usually matched by age, sex, and geographic location (Gastroenterology. 2017 Jan 6. doi: 10.1053/j.gastro.2016.12.039).

In all, 10.1% of patients with infectious enteritis developed IBS in the next 12 months (95% confidence interval, 7.2-14.1) – a 4.2-fold increase in risk, compared with that of controls (risk ratio, 4.2; 95% CI, 3.2-5.7). This risk subsequently dropped, but remained significantly elevated (RR, 2.3; 95% CI, 1.8-3.0), compared with controls. “Of patients with enteritis caused by protozoa or parasites, 41.9% developed IBS; of patients with enteritis caused by bacterial infection, 13.8% developed IBS,” the researchers emphasized. Patients with these infections remained at elevated risk of PI-IBS even after 1 year. Viral enteritis also significantly increased the risk of PI-IBS, but risk dropped to baseline levels after a year.

Among 10 pooled studies of IBS subtypes, 46% of patients had mixed IBS, 39% had diarrhea-predominant IBS, and 15% had constipation-predominant IBS. Female sex doubled the odds of PI-IBS (odds ratio, 2.2; 95% CI, 1.6-3.1) in 11 pooled studies. Significant clinical risk factors for PI-IBS included diarrhea lasting more than 7 days (eight studies; OR, 2.6; 95% CI, 1.5-4.6), bloody stool (four studies; OR, 1.9; 95% CI, 1.1-3.0), and antibiotic therapy during infectious enteritis (seven studies; OR, 1.7; 95% CI, 1.2-2.4).

Multiple reports linked PI-IBS to clinical psychological distress at the time of infectious enteritis. Specific risk factors included depression based on the Hospitalization Anxiety and Depression Scale (five studies; OR, 1.5; 95% CI, 1.2-1.9), anxiety based on the Hospital Anxiety and Depression Scale (four studies; OR, 2.0; 95% CI, 1.3-2.9), somatization (four studies; OR, 4.1; 95% CI, 2.7-6.0), and neuroticism (two studies; OR, 3.3; 95% CI, 1.6-6.6). Isolated studies also implicated hypochondriasis, extroversion, negative illness beliefs, stress, sleep disturbance, and adverse life events in the preceding year, the researchers said.

They found no evidence of publication bias, but noted a substantial amount of heterogeneity among studies. Also, some studies did not report multivariate analyses, so individual odds ratios might reflect “a conglomeration of factors,” they said.

The National Institutes of Health and the American Gastroenterological Association funded the work. The investigators reported having no conflicts of interest.

Source: American Gastroenterological Association

More than 10% of patients developed irritable bowel syndrome (IBS) within a year after infectious enteritis, which gave them a more than fourfold greater risk than that of controls, according to a systematic review and meta-analysis of 45 studies.

“Protozoal and bacterial enteritis confer the greatest overall risk, although the magnitude of increased risk diminishes with time since exposure,” Fabiane B. Klem, MD, and Akhilesh Wadhwa, MD, of Mayo Clinic in Rochester, Minn., and their associates wrote in the April issue of Gastroenterology. Other significant risk factors for postinfectious IBS (PI-IBS) included female sex, clinically severe infections, antibiotic therapy, and comorbid psychological distress, they said.

Postinfectious IBS can last at least a decade after resolution of campylobacteriosis, shigellosis, salmonellosis, giardiasis, and norovirus infections, even when patients have no other risk factors for IBS, the researchers noted. To update and expand the most recent meta-analysis of this topic (Aliment Pharmacol Ther. 2007;26:535-44), the investigators searched Ovid Medline, EMBASE, Web of Science, and Cochrane Database of Systematic Reviews for studies published from 2006 through Aug. 31, 2015. This search yielded 45 studies, including 30 studies comparing infected patients with controls, who were usually matched by age, sex, and geographic location (Gastroenterology. 2017 Jan 6. doi: 10.1053/j.gastro.2016.12.039).

In all, 10.1% of patients with infectious enteritis developed IBS in the next 12 months (95% confidence interval, 7.2-14.1) – a 4.2-fold increase in risk, compared with that of controls (risk ratio, 4.2; 95% CI, 3.2-5.7). This risk subsequently dropped, but remained significantly elevated (RR, 2.3; 95% CI, 1.8-3.0), compared with controls. “Of patients with enteritis caused by protozoa or parasites, 41.9% developed IBS; of patients with enteritis caused by bacterial infection, 13.8% developed IBS,” the researchers emphasized. Patients with these infections remained at elevated risk of PI-IBS even after 1 year. Viral enteritis also significantly increased the risk of PI-IBS, but risk dropped to baseline levels after a year.

Among 10 pooled studies of IBS subtypes, 46% of patients had mixed IBS, 39% had diarrhea-predominant IBS, and 15% had constipation-predominant IBS. Female sex doubled the odds of PI-IBS (odds ratio, 2.2; 95% CI, 1.6-3.1) in 11 pooled studies. Significant clinical risk factors for PI-IBS included diarrhea lasting more than 7 days (eight studies; OR, 2.6; 95% CI, 1.5-4.6), bloody stool (four studies; OR, 1.9; 95% CI, 1.1-3.0), and antibiotic therapy during infectious enteritis (seven studies; OR, 1.7; 95% CI, 1.2-2.4).

Multiple reports linked PI-IBS to clinical psychological distress at the time of infectious enteritis. Specific risk factors included depression based on the Hospitalization Anxiety and Depression Scale (five studies; OR, 1.5; 95% CI, 1.2-1.9), anxiety based on the Hospital Anxiety and Depression Scale (four studies; OR, 2.0; 95% CI, 1.3-2.9), somatization (four studies; OR, 4.1; 95% CI, 2.7-6.0), and neuroticism (two studies; OR, 3.3; 95% CI, 1.6-6.6). Isolated studies also implicated hypochondriasis, extroversion, negative illness beliefs, stress, sleep disturbance, and adverse life events in the preceding year, the researchers said.

They found no evidence of publication bias, but noted a substantial amount of heterogeneity among studies. Also, some studies did not report multivariate analyses, so individual odds ratios might reflect “a conglomeration of factors,” they said.

The National Institutes of Health and the American Gastroenterological Association funded the work. The investigators reported having no conflicts of interest.

Source: American Gastroenterological Association

SNOWMASS, COLO. – Familial hypercholesterolemia (FH), the most common genetic cause of premature atherosclerotic cardiovascular disease, affects an estimated 1 in 250 Americans. It doesn’t help that physicians are doing a terrible job of finding and treating them, Robert A. Vogel, MD, said at the Annual Cardiovascular Conference at Snowmass.

Indeed, it’s estimated that U.S. physicians diagnose fewer than 1% of affected individuals, as compared with a world’s-best 71% rate in the Netherlands, 43% in Norway, 13% in Sweden, and 12% in the United Kingdom (Eur Heart J. 2013 Dec 1;34[45]:3478-90a).

[email protected]


 

SNOWMASS, COLO. – Familial hypercholesterolemia (FH), the most common genetic cause of premature atherosclerotic cardiovascular disease, affects an estimated 1 in 250 Americans. It doesn’t help that physicians are doing a terrible job of finding and treating them, Robert A. Vogel, MD, said at the Annual Cardiovascular Conference at Snowmass.

Indeed, it’s estimated that U.S. physicians diagnose fewer than 1% of affected individuals, as compared with a world’s-best 71% rate in the Netherlands, 43% in Norway, 13% in Sweden, and 12% in the United Kingdom (Eur Heart J. 2013 Dec 1;34[45]:3478-90a).

[email protected]


 

SNOWMASS, COLO. – Familial hypercholesterolemia (FH), the most common genetic cause of premature atherosclerotic cardiovascular disease, affects an estimated 1 in 250 Americans. It doesn’t help that physicians are doing a terrible job of finding and treating them, Robert A. Vogel, MD, said at the Annual Cardiovascular Conference at Snowmass.

Indeed, it’s estimated that U.S. physicians diagnose fewer than 1% of affected individuals, as compared with a world’s-best 71% rate in the Netherlands, 43% in Norway, 13% in Sweden, and 12% in the United Kingdom (Eur Heart J. 2013 Dec 1;34[45]:3478-90a).

[email protected]


 

LAS VEGAS – Delivery at 38 weeks’ gestation is linked with improved perinatal survival among singleton infants born to morbidly obese mothers in a retrospective review of more than 2 million U.S. births.

“If reasonable, consider delivery at 38 weeks in morbidly obese mothers” delivering singleton pregnancies, Ruofan Yao, MD, said at the annual Pregnancy Meeting sponsored by the Society for Maternal-Fetal Medicine.

Mitchel L. Zoler/Frontline Medical News

[email protected]

On Twitter @mitchelzoler

LAS VEGAS – Delivery at 38 weeks’ gestation is linked with improved perinatal survival among singleton infants born to morbidly obese mothers in a retrospective review of more than 2 million U.S. births.

“If reasonable, consider delivery at 38 weeks in morbidly obese mothers” delivering singleton pregnancies, Ruofan Yao, MD, said at the annual Pregnancy Meeting sponsored by the Society for Maternal-Fetal Medicine.

Mitchel L. Zoler/Frontline Medical News

[email protected]

On Twitter @mitchelzoler

LAS VEGAS – Delivery at 38 weeks’ gestation is linked with improved perinatal survival among singleton infants born to morbidly obese mothers in a retrospective review of more than 2 million U.S. births.

“If reasonable, consider delivery at 38 weeks in morbidly obese mothers” delivering singleton pregnancies, Ruofan Yao, MD, said at the annual Pregnancy Meeting sponsored by the Society for Maternal-Fetal Medicine.

Mitchel L. Zoler/Frontline Medical News

[email protected]

On Twitter @mitchelzoler