Red and white blood cells

The US Food and Drug Administration (FDA) says it is evaluating reports of venous thromboembolism (VTE) in patients treated with the CELLEX Photopheresis System by Therakos, Inc.

This extracorporeal photopheresis (ECP) device system is FDA-approved for use in patients with cutaneous T-cell lymphoma (CTCL).

The system is used to perform ultraviolet-A irradiation of a patient’s own leukocyte-enriched blood that is then used as palliative treatment for skin manifestations of CTCL that are unresponsive to other forms of treatment.

The CELLEX Photopheresis System is also used to treat graft-vs-host disease (GVHD) that is resistant to standard immunosuppressive therapy and acute cardiac allograft rejection that is resistant to standard immunosuppressive therapy.

The CELLEX Photopheresis System uses methoxsalen as a photosensitizing agent and heparin as an anticoagulant.

Since 2012, the FDA has received 7 reports of pulmonary embolism (PE) and 2 reports of deep vein thrombosis (DVT) occurring during or soon after treatment with the CELLEX Photopheresis System.

Two of the patients who developed a PE died, although it’s not clear whether PE was the cause of death.

Four of the 7 PEs occurred in patients undergoing treatment for GVHD, including the 2 patients who died. Both DVTs occurred in patients undergoing treatment for GVHD as well.

The FDA is recommending that healthcare providers inform patients, clinical staff, and technicians that PE and DVT can occur during or after an ECP procedure.

The agency also recommends that healthcare providers consult device labeling regarding anticoagulation and use clinical judgment in adjusting a patient’s heparin dosage.

Finally, providers should report VTEs related to ECP procedures to the FDA’s MedWatch Safety Information and Adverse Event Reporting Program.

If possible, reports should include the following:

• The indication for ECP therapy
• Comorbidities that may predispose a patient to increased coagulation and history of DVT or PE
• The anticoagulation regimen used
• The number of ECP sessions the patient underwent prior to VTE onset, including the date of the first treatment session, frequency of treatment sessions, and timing of the final treatment
• Timing of the VTE in relation to the most recent treatment session
• Interventions required to manage the VTE.
  

Red and white blood cells

The US Food and Drug Administration (FDA) says it is evaluating reports of venous thromboembolism (VTE) in patients treated with the CELLEX Photopheresis System by Therakos, Inc.

This extracorporeal photopheresis (ECP) device system is FDA-approved for use in patients with cutaneous T-cell lymphoma (CTCL).

The system is used to perform ultraviolet-A irradiation of a patient’s own leukocyte-enriched blood that is then used as palliative treatment for skin manifestations of CTCL that are unresponsive to other forms of treatment.

The CELLEX Photopheresis System is also used to treat graft-vs-host disease (GVHD) that is resistant to standard immunosuppressive therapy and acute cardiac allograft rejection that is resistant to standard immunosuppressive therapy.

The CELLEX Photopheresis System uses methoxsalen as a photosensitizing agent and heparin as an anticoagulant.

Since 2012, the FDA has received 7 reports of pulmonary embolism (PE) and 2 reports of deep vein thrombosis (DVT) occurring during or soon after treatment with the CELLEX Photopheresis System.

Two of the patients who developed a PE died, although it’s not clear whether PE was the cause of death.

Four of the 7 PEs occurred in patients undergoing treatment for GVHD, including the 2 patients who died. Both DVTs occurred in patients undergoing treatment for GVHD as well.

The FDA is recommending that healthcare providers inform patients, clinical staff, and technicians that PE and DVT can occur during or after an ECP procedure.

The agency also recommends that healthcare providers consult device labeling regarding anticoagulation and use clinical judgment in adjusting a patient’s heparin dosage.

Finally, providers should report VTEs related to ECP procedures to the FDA’s MedWatch Safety Information and Adverse Event Reporting Program.

If possible, reports should include the following:

• The indication for ECP therapy
• Comorbidities that may predispose a patient to increased coagulation and history of DVT or PE
• The anticoagulation regimen used
• The number of ECP sessions the patient underwent prior to VTE onset, including the date of the first treatment session, frequency of treatment sessions, and timing of the final treatment
• Timing of the VTE in relation to the most recent treatment session
• Interventions required to manage the VTE.
  

Red and white blood cells

The US Food and Drug Administration (FDA) says it is evaluating reports of venous thromboembolism (VTE) in patients treated with the CELLEX Photopheresis System by Therakos, Inc.

This extracorporeal photopheresis (ECP) device system is FDA-approved for use in patients with cutaneous T-cell lymphoma (CTCL).

The system is used to perform ultraviolet-A irradiation of a patient’s own leukocyte-enriched blood that is then used as palliative treatment for skin manifestations of CTCL that are unresponsive to other forms of treatment.

The CELLEX Photopheresis System is also used to treat graft-vs-host disease (GVHD) that is resistant to standard immunosuppressive therapy and acute cardiac allograft rejection that is resistant to standard immunosuppressive therapy.

The CELLEX Photopheresis System uses methoxsalen as a photosensitizing agent and heparin as an anticoagulant.

Since 2012, the FDA has received 7 reports of pulmonary embolism (PE) and 2 reports of deep vein thrombosis (DVT) occurring during or soon after treatment with the CELLEX Photopheresis System.

Two of the patients who developed a PE died, although it’s not clear whether PE was the cause of death.

Four of the 7 PEs occurred in patients undergoing treatment for GVHD, including the 2 patients who died. Both DVTs occurred in patients undergoing treatment for GVHD as well.

The FDA is recommending that healthcare providers inform patients, clinical staff, and technicians that PE and DVT can occur during or after an ECP procedure.

The agency also recommends that healthcare providers consult device labeling regarding anticoagulation and use clinical judgment in adjusting a patient’s heparin dosage.

Finally, providers should report VTEs related to ECP procedures to the FDA’s MedWatch Safety Information and Adverse Event Reporting Program.

If possible, reports should include the following:

• The indication for ECP therapy
• Comorbidities that may predispose a patient to increased coagulation and history of DVT or PE
• The anticoagulation regimen used
• The number of ECP sessions the patient underwent prior to VTE onset, including the date of the first treatment session, frequency of treatment sessions, and timing of the final treatment
• Timing of the VTE in relation to the most recent treatment session
• Interventions required to manage the VTE.
  

The surfaces of the human body exposed to the environment are colonized by microbes—the majority of which reside in the intestinal tract. Collectively, the microbial cells that live in and on us (bacteria, eukaryotes, viruses, fungi, and archaea) make up our microbiota, and their genetic material constitutes our microbiome. There are at least 100 times more genes in the human microbiome than in the human genome.^1,2

With the help of recent technologic advances in genetic sequencing, we’re beginning to understand more about this vast biological habitat. We know that the microbiota plays a role in vitamin production, energy harvest and storage, and fermentation and absorption of undigested carbohydrates. It also has bidirectional influence on the central nervous system and neuropsychologic health and is involved in the maturation and development of the immune system.

A healthy biome is characterized by bacterial diversity and richness. Gut microbiota is mostly comprised of Firmicutes (64%), Bacteroidetes (23%), Proteobacteria (8%), and Actinobacteria (3%).² The distribution of these bacteria is largely determined by diet; individuals who follow a diet high in animal fat have a Bacteroides-dominant pattern, whereas those who follow a carbohydrate-rich diet tend toward a Prevotella-dominant pattern.^1-3

Lack of bacterial diversity and overgrowth of pathobacteria results in dysbiosis, an imbalance in the gut’s microbial composition. Alterations in the proportions of bacteria are thought to result in metabolic disease. As such, dysbiosis is correlated with obesity and diabetes, as well as other diseases (eg, inflammatory bowel disease, multiple sclerosis, Crohn disease, and rheumatoid arthritis).^1-3 At this time, however, it is unclear whether these bacterial imbalances cause or result from disease.

ROLE IN TYPE 2 DIABETES

The microbiome of patients with type 2 diabetes (T2DM) is characterized by reduced levels of Firmicutes and Clostridia and an increased ratio of Bacteroidetes:Firmicutes (this ratio correlates with plasma glucose concentration).^4,5 Interestingly, although T2DM and obesity are closely related, available data indicate that gut microbiome changes are not always identical between these two patient populations. In some studies, the microbiome of obese individuals involves a decreased Bacteroidetes:Firmicutes ratio, in contrast to the increase seen with T2DM—which raises the question of whether the same or different factors cause these two entities.^1,5-7

Patients with T2DM also have decreased amounts of butyrate-producing bacteria in their microbiomes. Butyrate, acetate, and propionate are short-chain fatty acids (­SCFAs) fermented in the large intestine by bacteria from dietary fiber. These SCFAs play an important role in energy metabolism and are critical for modulating immune responses and tumorigenesis in the gut. Butyrate, in particular, provides energy for colonic epithelial cells. By feeding colonic cells, butyrate helps to maintain intestinal integrity and prevent translocation—a process that moves gram-negative intestinal bacteria across the lumen of the gut, causing endotoxemia. Endotoxemia triggers a low-grade inflammatory response, and low-grade inflammation is thought to underlie T2DM.^2,5,6

Therapeutic interventions—such as dietary modifications, prebiotics, probiotics, antibiotics, metformin, fecal transplantation, and bariatric surgery—can effectively alter the composition of gut bacteria. It has been proposed that these interventions could be harnessed to prevent and treat T2DM in the future.² So, what might these interventions have (or not have) to offer?

ANTIBIOTICS

Antibiotics are useful for eradicating pathogenic bacteria, but they can also destroy beneficial intestinal commensals in the process. Therefore, concern about the widespread use of antibiotics in humans and livestock has increased. Subtherapeutic use of antibiotics, which has been common in farm animals throughout the past 50 years to increase growth and food production, has been shown to affect metabolic pathways—particularly with respect to SCFAs—in mouse studies.⁶

Recent data on humans have linked antibiotic treatment in early infancy to long-term effects on microbial diversity and childhood overweight. Similarly, long-term use of IV vancomycin in adults has been linked to an increased obesity risk. But it’s not just long-term exposure that poses a threat; even short courses of oral antibiotics can have profound and irreversible ­effects on intestinal microbial diversity and composition. For example, short-term use of oral vancomycin was found to impair peripheral insulin sensitivity in males with metabolic syndrome associated with ­altered gut microbiota, while amoxicillin did not.⁶

PREBIOTICS AND PROBIOTICS

Prebiotics are indigestible carbohydrates that improve host health by stimulating the growth and activity of colonic bacteria. Most prebiotics are oligosaccharides, which can travel through the upper GI system undigested. When they reach the colon, they are fermented to produce SCFAs that stimulate the growth of microbes that reside there. Prebiotics come from a wide variety of food sources, including asparagus, barley, garlic, onions, and wheat bran.^2,3 Pickled and fermented foods (eg, kimchi, sauerkraut, yogurt, miso) are good sources of both prebiotics and probiotics.²

Bifidobacteria and lactobacilli are the most commonly used strains in foods and supplements containing probiotics. These live microorganisms bring about specific changes in the composition and activity of gut microbiota: they secrete antimicrobial substances, compete with pathogenic bacteria, strengthen the intestinal barrier, and modulate the immune system.^2,3,6 Research on human and animal models suggests that administering probiotics may help manage diabetes.²

DIETARY MODULATION

Dietary changes have been shown to modify the bacterial metabolic activity of the human gut. In one study, obese adults with T2DM were placed on either a fat- or carbohydrate-restricted diet, and it was found that their levels of Bacteroidetes increased and Firmicutes decreased.⁷

In another study, patients with T2DM adhered to one of two calorie-controlled diets: a high-fiber macrobiotic diet or a Mediterranean-style (control) diet. The macrobiotic diet was high in complex carbohydrates, legumes, fermented products, sea salt, and green tea and was free of animal protein, fat, and added sugar. Both diets were effective at improving dysbiosis—ecosystem diversity increased, and health-promoting SCFA producers were replenished. However, the macrobiotic diet was more effective than the control diet at reducing fasting and postprandial glucose, A1C, serum cholesterol, insulin resistance, BMI, and waist and hip circumferences; and only the macrobiotic diet counteracted the inflammation-producing bacterial groups.⁸

METFORMIN

Metformin has therapeutic effects on microbial composition and SCFA synthesis. In a microbiome comparison study, patients with T2DM treated with metformin had more butyrate-producing bacteria than their untreated counterparts. The trend toward increased Lactobacillus seen in the context of T2DM was reduced or reversed by metformin treatment. Researchers were able to tell which patients were (and were not) treated based on their gut microbiome taxonomic signature.⁹

FECAL MICROBIOTA TRANSPLANT

Fecal microbiota transplant, also known as stool transplant or bacteriotherapy, is the process of transferring fecal bacteria from a healthy individual into a recipient. It is used in the treatment of recurrent Clostridium difficile colitis to replenish beneficial bacteria in the digestive tract following use of wide-spectrum antibiotics. In a double-blind randomized controlled trial, insulin-resistant men received either autologous (reinfusion of one’s collected feces) or allogenic (feces from a lean donor) infusions. Allogenic transplantation resulted in significantly increased intestinal microbial diversity and increased levels of butyrate-producing species, accompanied by significantly improved peripheral muscle sensitivity to insulin.^1,6

BARIATRIC SURGERY

Bariatric surgery, specifically Roux-en-Y gastric bypass (RYGBP), is a powerful tool used to treat obesity. In six patients (five of whom had diabetes) treated with RYGBP, dramatic changes to the gut microbiota were seen at three months following surgery. BMI was reduced by 15% to 32%, C-reactive protein decreased in five of six patients, and T2DM was alleviated in all. Postoperatively, there was a striking shift towards higher amounts of Proteobacteria and lower relative amounts of Firmicutes and Bacteroides in the gut phyla. Postoperative increases in certain bacteria were more profound than the amount in lean controls, suggesting these changes are related to alterations in the gut, not lower body weight.^4,6

CONCLUSION

We are just beginning to understand the microbiome and its relationship to health and disease. For patients with T2DM, a variety of interventions may be used to return the gut microbiota to health. Dietary interventions, prebiotics and probiotics, fecal microbial transplant, and bariatric surgery can influence gut microbial composition, with the goal of preventing and/or treating disease. In the future, gut microbial signatures may serve as early diagnostic markers.

The surfaces of the human body exposed to the environment are colonized by microbes—the majority of which reside in the intestinal tract. Collectively, the microbial cells that live in and on us (bacteria, eukaryotes, viruses, fungi, and archaea) make up our microbiota, and their genetic material constitutes our microbiome. There are at least 100 times more genes in the human microbiome than in the human genome.^1,2

With the help of recent technologic advances in genetic sequencing, we’re beginning to understand more about this vast biological habitat. We know that the microbiota plays a role in vitamin production, energy harvest and storage, and fermentation and absorption of undigested carbohydrates. It also has bidirectional influence on the central nervous system and neuropsychologic health and is involved in the maturation and development of the immune system.

A healthy biome is characterized by bacterial diversity and richness. Gut microbiota is mostly comprised of Firmicutes (64%), Bacteroidetes (23%), Proteobacteria (8%), and Actinobacteria (3%).² The distribution of these bacteria is largely determined by diet; individuals who follow a diet high in animal fat have a Bacteroides-dominant pattern, whereas those who follow a carbohydrate-rich diet tend toward a Prevotella-dominant pattern.^1-3

Lack of bacterial diversity and overgrowth of pathobacteria results in dysbiosis, an imbalance in the gut’s microbial composition. Alterations in the proportions of bacteria are thought to result in metabolic disease. As such, dysbiosis is correlated with obesity and diabetes, as well as other diseases (eg, inflammatory bowel disease, multiple sclerosis, Crohn disease, and rheumatoid arthritis).^1-3 At this time, however, it is unclear whether these bacterial imbalances cause or result from disease.

ROLE IN TYPE 2 DIABETES

The microbiome of patients with type 2 diabetes (T2DM) is characterized by reduced levels of Firmicutes and Clostridia and an increased ratio of Bacteroidetes:Firmicutes (this ratio correlates with plasma glucose concentration).^4,5 Interestingly, although T2DM and obesity are closely related, available data indicate that gut microbiome changes are not always identical between these two patient populations. In some studies, the microbiome of obese individuals involves a decreased Bacteroidetes:Firmicutes ratio, in contrast to the increase seen with T2DM—which raises the question of whether the same or different factors cause these two entities.^1,5-7

Patients with T2DM also have decreased amounts of butyrate-producing bacteria in their microbiomes. Butyrate, acetate, and propionate are short-chain fatty acids (­SCFAs) fermented in the large intestine by bacteria from dietary fiber. These SCFAs play an important role in energy metabolism and are critical for modulating immune responses and tumorigenesis in the gut. Butyrate, in particular, provides energy for colonic epithelial cells. By feeding colonic cells, butyrate helps to maintain intestinal integrity and prevent translocation—a process that moves gram-negative intestinal bacteria across the lumen of the gut, causing endotoxemia. Endotoxemia triggers a low-grade inflammatory response, and low-grade inflammation is thought to underlie T2DM.^2,5,6

Therapeutic interventions—such as dietary modifications, prebiotics, probiotics, antibiotics, metformin, fecal transplantation, and bariatric surgery—can effectively alter the composition of gut bacteria. It has been proposed that these interventions could be harnessed to prevent and treat T2DM in the future.² So, what might these interventions have (or not have) to offer?

ANTIBIOTICS

Antibiotics are useful for eradicating pathogenic bacteria, but they can also destroy beneficial intestinal commensals in the process. Therefore, concern about the widespread use of antibiotics in humans and livestock has increased. Subtherapeutic use of antibiotics, which has been common in farm animals throughout the past 50 years to increase growth and food production, has been shown to affect metabolic pathways—particularly with respect to SCFAs—in mouse studies.⁶

Recent data on humans have linked antibiotic treatment in early infancy to long-term effects on microbial diversity and childhood overweight. Similarly, long-term use of IV vancomycin in adults has been linked to an increased obesity risk. But it’s not just long-term exposure that poses a threat; even short courses of oral antibiotics can have profound and irreversible ­effects on intestinal microbial diversity and composition. For example, short-term use of oral vancomycin was found to impair peripheral insulin sensitivity in males with metabolic syndrome associated with ­altered gut microbiota, while amoxicillin did not.⁶

PREBIOTICS AND PROBIOTICS

Prebiotics are indigestible carbohydrates that improve host health by stimulating the growth and activity of colonic bacteria. Most prebiotics are oligosaccharides, which can travel through the upper GI system undigested. When they reach the colon, they are fermented to produce SCFAs that stimulate the growth of microbes that reside there. Prebiotics come from a wide variety of food sources, including asparagus, barley, garlic, onions, and wheat bran.^2,3 Pickled and fermented foods (eg, kimchi, sauerkraut, yogurt, miso) are good sources of both prebiotics and probiotics.²

Bifidobacteria and lactobacilli are the most commonly used strains in foods and supplements containing probiotics. These live microorganisms bring about specific changes in the composition and activity of gut microbiota: they secrete antimicrobial substances, compete with pathogenic bacteria, strengthen the intestinal barrier, and modulate the immune system.^2,3,6 Research on human and animal models suggests that administering probiotics may help manage diabetes.²

DIETARY MODULATION

Dietary changes have been shown to modify the bacterial metabolic activity of the human gut. In one study, obese adults with T2DM were placed on either a fat- or carbohydrate-restricted diet, and it was found that their levels of Bacteroidetes increased and Firmicutes decreased.⁷

In another study, patients with T2DM adhered to one of two calorie-controlled diets: a high-fiber macrobiotic diet or a Mediterranean-style (control) diet. The macrobiotic diet was high in complex carbohydrates, legumes, fermented products, sea salt, and green tea and was free of animal protein, fat, and added sugar. Both diets were effective at improving dysbiosis—ecosystem diversity increased, and health-promoting SCFA producers were replenished. However, the macrobiotic diet was more effective than the control diet at reducing fasting and postprandial glucose, A1C, serum cholesterol, insulin resistance, BMI, and waist and hip circumferences; and only the macrobiotic diet counteracted the inflammation-producing bacterial groups.⁸

METFORMIN

Metformin has therapeutic effects on microbial composition and SCFA synthesis. In a microbiome comparison study, patients with T2DM treated with metformin had more butyrate-producing bacteria than their untreated counterparts. The trend toward increased Lactobacillus seen in the context of T2DM was reduced or reversed by metformin treatment. Researchers were able to tell which patients were (and were not) treated based on their gut microbiome taxonomic signature.⁹

FECAL MICROBIOTA TRANSPLANT

Fecal microbiota transplant, also known as stool transplant or bacteriotherapy, is the process of transferring fecal bacteria from a healthy individual into a recipient. It is used in the treatment of recurrent Clostridium difficile colitis to replenish beneficial bacteria in the digestive tract following use of wide-spectrum antibiotics. In a double-blind randomized controlled trial, insulin-resistant men received either autologous (reinfusion of one’s collected feces) or allogenic (feces from a lean donor) infusions. Allogenic transplantation resulted in significantly increased intestinal microbial diversity and increased levels of butyrate-producing species, accompanied by significantly improved peripheral muscle sensitivity to insulin.^1,6

BARIATRIC SURGERY

Bariatric surgery, specifically Roux-en-Y gastric bypass (RYGBP), is a powerful tool used to treat obesity. In six patients (five of whom had diabetes) treated with RYGBP, dramatic changes to the gut microbiota were seen at three months following surgery. BMI was reduced by 15% to 32%, C-reactive protein decreased in five of six patients, and T2DM was alleviated in all. Postoperatively, there was a striking shift towards higher amounts of Proteobacteria and lower relative amounts of Firmicutes and Bacteroides in the gut phyla. Postoperative increases in certain bacteria were more profound than the amount in lean controls, suggesting these changes are related to alterations in the gut, not lower body weight.^4,6

CONCLUSION

We are just beginning to understand the microbiome and its relationship to health and disease. For patients with T2DM, a variety of interventions may be used to return the gut microbiota to health. Dietary interventions, prebiotics and probiotics, fecal microbial transplant, and bariatric surgery can influence gut microbial composition, with the goal of preventing and/or treating disease. In the future, gut microbial signatures may serve as early diagnostic markers.

The surfaces of the human body exposed to the environment are colonized by microbes—the majority of which reside in the intestinal tract. Collectively, the microbial cells that live in and on us (bacteria, eukaryotes, viruses, fungi, and archaea) make up our microbiota, and their genetic material constitutes our microbiome. There are at least 100 times more genes in the human microbiome than in the human genome.^1,2

With the help of recent technologic advances in genetic sequencing, we’re beginning to understand more about this vast biological habitat. We know that the microbiota plays a role in vitamin production, energy harvest and storage, and fermentation and absorption of undigested carbohydrates. It also has bidirectional influence on the central nervous system and neuropsychologic health and is involved in the maturation and development of the immune system.

A healthy biome is characterized by bacterial diversity and richness. Gut microbiota is mostly comprised of Firmicutes (64%), Bacteroidetes (23%), Proteobacteria (8%), and Actinobacteria (3%).² The distribution of these bacteria is largely determined by diet; individuals who follow a diet high in animal fat have a Bacteroides-dominant pattern, whereas those who follow a carbohydrate-rich diet tend toward a Prevotella-dominant pattern.^1-3

Lack of bacterial diversity and overgrowth of pathobacteria results in dysbiosis, an imbalance in the gut’s microbial composition. Alterations in the proportions of bacteria are thought to result in metabolic disease. As such, dysbiosis is correlated with obesity and diabetes, as well as other diseases (eg, inflammatory bowel disease, multiple sclerosis, Crohn disease, and rheumatoid arthritis).^1-3 At this time, however, it is unclear whether these bacterial imbalances cause or result from disease.

ROLE IN TYPE 2 DIABETES

The microbiome of patients with type 2 diabetes (T2DM) is characterized by reduced levels of Firmicutes and Clostridia and an increased ratio of Bacteroidetes:Firmicutes (this ratio correlates with plasma glucose concentration).^4,5 Interestingly, although T2DM and obesity are closely related, available data indicate that gut microbiome changes are not always identical between these two patient populations. In some studies, the microbiome of obese individuals involves a decreased Bacteroidetes:Firmicutes ratio, in contrast to the increase seen with T2DM—which raises the question of whether the same or different factors cause these two entities.^1,5-7

Patients with T2DM also have decreased amounts of butyrate-producing bacteria in their microbiomes. Butyrate, acetate, and propionate are short-chain fatty acids (­SCFAs) fermented in the large intestine by bacteria from dietary fiber. These SCFAs play an important role in energy metabolism and are critical for modulating immune responses and tumorigenesis in the gut. Butyrate, in particular, provides energy for colonic epithelial cells. By feeding colonic cells, butyrate helps to maintain intestinal integrity and prevent translocation—a process that moves gram-negative intestinal bacteria across the lumen of the gut, causing endotoxemia. Endotoxemia triggers a low-grade inflammatory response, and low-grade inflammation is thought to underlie T2DM.^2,5,6

Therapeutic interventions—such as dietary modifications, prebiotics, probiotics, antibiotics, metformin, fecal transplantation, and bariatric surgery—can effectively alter the composition of gut bacteria. It has been proposed that these interventions could be harnessed to prevent and treat T2DM in the future.² So, what might these interventions have (or not have) to offer?

ANTIBIOTICS

Antibiotics are useful for eradicating pathogenic bacteria, but they can also destroy beneficial intestinal commensals in the process. Therefore, concern about the widespread use of antibiotics in humans and livestock has increased. Subtherapeutic use of antibiotics, which has been common in farm animals throughout the past 50 years to increase growth and food production, has been shown to affect metabolic pathways—particularly with respect to SCFAs—in mouse studies.⁶

Recent data on humans have linked antibiotic treatment in early infancy to long-term effects on microbial diversity and childhood overweight. Similarly, long-term use of IV vancomycin in adults has been linked to an increased obesity risk. But it’s not just long-term exposure that poses a threat; even short courses of oral antibiotics can have profound and irreversible ­effects on intestinal microbial diversity and composition. For example, short-term use of oral vancomycin was found to impair peripheral insulin sensitivity in males with metabolic syndrome associated with ­altered gut microbiota, while amoxicillin did not.⁶

PREBIOTICS AND PROBIOTICS

Prebiotics are indigestible carbohydrates that improve host health by stimulating the growth and activity of colonic bacteria. Most prebiotics are oligosaccharides, which can travel through the upper GI system undigested. When they reach the colon, they are fermented to produce SCFAs that stimulate the growth of microbes that reside there. Prebiotics come from a wide variety of food sources, including asparagus, barley, garlic, onions, and wheat bran.^2,3 Pickled and fermented foods (eg, kimchi, sauerkraut, yogurt, miso) are good sources of both prebiotics and probiotics.²

Bifidobacteria and lactobacilli are the most commonly used strains in foods and supplements containing probiotics. These live microorganisms bring about specific changes in the composition and activity of gut microbiota: they secrete antimicrobial substances, compete with pathogenic bacteria, strengthen the intestinal barrier, and modulate the immune system.^2,3,6 Research on human and animal models suggests that administering probiotics may help manage diabetes.²

DIETARY MODULATION

Dietary changes have been shown to modify the bacterial metabolic activity of the human gut. In one study, obese adults with T2DM were placed on either a fat- or carbohydrate-restricted diet, and it was found that their levels of Bacteroidetes increased and Firmicutes decreased.⁷

In another study, patients with T2DM adhered to one of two calorie-controlled diets: a high-fiber macrobiotic diet or a Mediterranean-style (control) diet. The macrobiotic diet was high in complex carbohydrates, legumes, fermented products, sea salt, and green tea and was free of animal protein, fat, and added sugar. Both diets were effective at improving dysbiosis—ecosystem diversity increased, and health-promoting SCFA producers were replenished. However, the macrobiotic diet was more effective than the control diet at reducing fasting and postprandial glucose, A1C, serum cholesterol, insulin resistance, BMI, and waist and hip circumferences; and only the macrobiotic diet counteracted the inflammation-producing bacterial groups.⁸

METFORMIN

Metformin has therapeutic effects on microbial composition and SCFA synthesis. In a microbiome comparison study, patients with T2DM treated with metformin had more butyrate-producing bacteria than their untreated counterparts. The trend toward increased Lactobacillus seen in the context of T2DM was reduced or reversed by metformin treatment. Researchers were able to tell which patients were (and were not) treated based on their gut microbiome taxonomic signature.⁹

FECAL MICROBIOTA TRANSPLANT

Fecal microbiota transplant, also known as stool transplant or bacteriotherapy, is the process of transferring fecal bacteria from a healthy individual into a recipient. It is used in the treatment of recurrent Clostridium difficile colitis to replenish beneficial bacteria in the digestive tract following use of wide-spectrum antibiotics. In a double-blind randomized controlled trial, insulin-resistant men received either autologous (reinfusion of one’s collected feces) or allogenic (feces from a lean donor) infusions. Allogenic transplantation resulted in significantly increased intestinal microbial diversity and increased levels of butyrate-producing species, accompanied by significantly improved peripheral muscle sensitivity to insulin.^1,6

BARIATRIC SURGERY

Bariatric surgery, specifically Roux-en-Y gastric bypass (RYGBP), is a powerful tool used to treat obesity. In six patients (five of whom had diabetes) treated with RYGBP, dramatic changes to the gut microbiota were seen at three months following surgery. BMI was reduced by 15% to 32%, C-reactive protein decreased in five of six patients, and T2DM was alleviated in all. Postoperatively, there was a striking shift towards higher amounts of Proteobacteria and lower relative amounts of Firmicutes and Bacteroides in the gut phyla. Postoperative increases in certain bacteria were more profound than the amount in lean controls, suggesting these changes are related to alterations in the gut, not lower body weight.^4,6

CONCLUSION

We are just beginning to understand the microbiome and its relationship to health and disease. For patients with T2DM, a variety of interventions may be used to return the gut microbiota to health. Dietary interventions, prebiotics and probiotics, fecal microbial transplant, and bariatric surgery can influence gut microbial composition, with the goal of preventing and/or treating disease. In the future, gut microbial signatures may serve as early diagnostic markers.

KAUAI, HAWAII – Two keys to effective topical treatment of onychomycosis are treat it early and address coexisting tinea pedis, according to Theodore Rosen, MD.

A third element in achieving treatment success is to use one of the newer topical agents: efinaconazole (Jublia) or tavaborole (Kerydin). The efficacy of efinaconazole approaches that of terbinafine, the most effective and widely prescribed oral agent, which has a 59% rate of almost complete cure, defined as less than 10% residual abnormal nail with no requirement for mycologic cure.

Bruce Jancin/Frontline Medical News

And while tavaborole isn’t quite as effective, it’s definitely better than previous topical agents, Dr. Rosen said at the Hawaii Dermatology Seminar provided by Global Academy for Medical Education/Skin Disease Education Foundation.

Both of these topicals are well tolerated and feature good nail permeation. They also allow for spread to the lateral nail folds and hyponychium. They even penetrate nail polish, although efinaconazole often causes the polish to lose its spiffy gloss, said Dr. Rosen, professor of dermatology at Baylor College of Medicine, Houston.

To underscore the importance of early treatment and addressing concomitant tinea pedis, he cited published secondary analyses of two identical double-blind, multicenter, 48-week clinical trials totaling 1,655 adults with onychomycosis who were randomized 3:1 to once-daily efinaconazole 10% topical solution or its vehicle.
 

Treat early

Phoebe Rich, MD, of the Oregon Dermatology and Research Center, Portland, broke down the outcomes according to disease duration, in a study of more than 1,500 patients with onychomycosis. She found that the complete cure rate at 52 weeks dropped off markedly in patients with a history of onychomycosis for 1 year or longer at baseline.

Complete cure – defined as no clinical involvement of the target toenail along with both a negative potassium hydroxide examination and a negative fungal culture at 52 weeks – was achieved in 43% of efinaconazole-treated patients with onychomycosis for less than 1 year. The rate then plunged to 17% in those with a disease duration of 1-5 years and 16% in patients with onychomycosis for more than 5 years. Nevertheless, the topical antifungal was significantly more effective than was the vehicle, across the board, with complete cure rates in the vehicle group of roughly 18%, 5%, and 2%, respectively, in patients with onychomycosis for less than 1 year, 1-5 years, and more than 5 years (J Drugs Dermatol. 2015 Jan;14[1]:58-62).
 

Tackle coexisting tinea pedis

Podiatrists analyzed the combined efinaconazole outcome data based on whether participants had no coexisting tinea pedis, baseline tinea pedis treated concomitantly with an investigator-approved topical antifungal, or tinea pedis left untreated. They concluded that treatment of coexisting tinea pedis decisively enhanced the efficacy of efinaconazole for onychomycosis.

A total of 21% of study participants had concomitant tinea pedis, and 61% of them were treated for it. At week 52, the onychomycosis complete cure rate was 29% in the efinaconazole group concurrently treated for tinea pedis, compared with just 16% if their tinea pedis was untreated (J Am Podiatr Med Assoc. 2015 Sep;105[5]:407-11).

“If you see tinea pedis, don’t blow it off. Treat it. Otherwise, you’re not getting rid of the fungal reservoir,” Dr. Rosen emphasized.

He noted that two topical agents approved for tinea pedis – naftifine 2% cream or gel and luliconazole 1% cream – are effective as once-daily therapy for 2 weeks, a considerably briefer regimen than with other approved topicals. And short-course therapy spells improved adherence, he added.

In the pivotal trials, naftifine had an effective treatment rate – a clinically useful endpoint defined as a small amount of residual scaling and/or redness but no itching – of 57%, while for luliconazole the rates were 33%-48%.

These two agents also are approved for treatment of tinea corporis and tinea cruris. Naftifine is approved as a once-daily treatment for 2 weeks, while luliconazole is, notably, a 7-day treatment. Luliconazole, in particular, is a relatively expensive drug, Dr. Rosen added, so insurers may require prior failure on clotrimazole.
 

When to treat onychomycosis topically

The pivotal trials of tavaborole and efinaconazole were conducted in patients with 20%-60% nail involvement. The infection didn’t extend to the matrix, and nail thickness and crumbly subungual debris were modest at baseline.

“There are always potential safety issues – drug interactions, GI disturbance, taste loss, headache, teratogenicity, cardiotoxicity, hepatotoxicity – anytime you put a pill in your mouth. So if you have a patient who’s dedicated enough to use a topical for 48 weeks and it’s a modestly affected nail, think about it,” Dr. Rosen advised.

He reported serving on scientific advisory boards for Aclaris, Anacor, Cipla, and Valeant.

SDEF/Global Academy for Medical Education and this news organization are owned by the same parent company.
 

[email protected]

KAUAI, HAWAII – Two keys to effective topical treatment of onychomycosis are treat it early and address coexisting tinea pedis, according to Theodore Rosen, MD.

A third element in achieving treatment success is to use one of the newer topical agents: efinaconazole (Jublia) or tavaborole (Kerydin). The efficacy of efinaconazole approaches that of terbinafine, the most effective and widely prescribed oral agent, which has a 59% rate of almost complete cure, defined as less than 10% residual abnormal nail with no requirement for mycologic cure.

Bruce Jancin/Frontline Medical News

And while tavaborole isn’t quite as effective, it’s definitely better than previous topical agents, Dr. Rosen said at the Hawaii Dermatology Seminar provided by Global Academy for Medical Education/Skin Disease Education Foundation.

Both of these topicals are well tolerated and feature good nail permeation. They also allow for spread to the lateral nail folds and hyponychium. They even penetrate nail polish, although efinaconazole often causes the polish to lose its spiffy gloss, said Dr. Rosen, professor of dermatology at Baylor College of Medicine, Houston.

To underscore the importance of early treatment and addressing concomitant tinea pedis, he cited published secondary analyses of two identical double-blind, multicenter, 48-week clinical trials totaling 1,655 adults with onychomycosis who were randomized 3:1 to once-daily efinaconazole 10% topical solution or its vehicle.
 

Treat early

Phoebe Rich, MD, of the Oregon Dermatology and Research Center, Portland, broke down the outcomes according to disease duration, in a study of more than 1,500 patients with onychomycosis. She found that the complete cure rate at 52 weeks dropped off markedly in patients with a history of onychomycosis for 1 year or longer at baseline.

Complete cure – defined as no clinical involvement of the target toenail along with both a negative potassium hydroxide examination and a negative fungal culture at 52 weeks – was achieved in 43% of efinaconazole-treated patients with onychomycosis for less than 1 year. The rate then plunged to 17% in those with a disease duration of 1-5 years and 16% in patients with onychomycosis for more than 5 years. Nevertheless, the topical antifungal was significantly more effective than was the vehicle, across the board, with complete cure rates in the vehicle group of roughly 18%, 5%, and 2%, respectively, in patients with onychomycosis for less than 1 year, 1-5 years, and more than 5 years (J Drugs Dermatol. 2015 Jan;14[1]:58-62).
 

Tackle coexisting tinea pedis

Podiatrists analyzed the combined efinaconazole outcome data based on whether participants had no coexisting tinea pedis, baseline tinea pedis treated concomitantly with an investigator-approved topical antifungal, or tinea pedis left untreated. They concluded that treatment of coexisting tinea pedis decisively enhanced the efficacy of efinaconazole for onychomycosis.

A total of 21% of study participants had concomitant tinea pedis, and 61% of them were treated for it. At week 52, the onychomycosis complete cure rate was 29% in the efinaconazole group concurrently treated for tinea pedis, compared with just 16% if their tinea pedis was untreated (J Am Podiatr Med Assoc. 2015 Sep;105[5]:407-11).

“If you see tinea pedis, don’t blow it off. Treat it. Otherwise, you’re not getting rid of the fungal reservoir,” Dr. Rosen emphasized.

He noted that two topical agents approved for tinea pedis – naftifine 2% cream or gel and luliconazole 1% cream – are effective as once-daily therapy for 2 weeks, a considerably briefer regimen than with other approved topicals. And short-course therapy spells improved adherence, he added.

In the pivotal trials, naftifine had an effective treatment rate – a clinically useful endpoint defined as a small amount of residual scaling and/or redness but no itching – of 57%, while for luliconazole the rates were 33%-48%.

These two agents also are approved for treatment of tinea corporis and tinea cruris. Naftifine is approved as a once-daily treatment for 2 weeks, while luliconazole is, notably, a 7-day treatment. Luliconazole, in particular, is a relatively expensive drug, Dr. Rosen added, so insurers may require prior failure on clotrimazole.
 

When to treat onychomycosis topically

The pivotal trials of tavaborole and efinaconazole were conducted in patients with 20%-60% nail involvement. The infection didn’t extend to the matrix, and nail thickness and crumbly subungual debris were modest at baseline.

“There are always potential safety issues – drug interactions, GI disturbance, taste loss, headache, teratogenicity, cardiotoxicity, hepatotoxicity – anytime you put a pill in your mouth. So if you have a patient who’s dedicated enough to use a topical for 48 weeks and it’s a modestly affected nail, think about it,” Dr. Rosen advised.

He reported serving on scientific advisory boards for Aclaris, Anacor, Cipla, and Valeant.

SDEF/Global Academy for Medical Education and this news organization are owned by the same parent company.
 

[email protected]

KAUAI, HAWAII – Two keys to effective topical treatment of onychomycosis are treat it early and address coexisting tinea pedis, according to Theodore Rosen, MD.

A third element in achieving treatment success is to use one of the newer topical agents: efinaconazole (Jublia) or tavaborole (Kerydin). The efficacy of efinaconazole approaches that of terbinafine, the most effective and widely prescribed oral agent, which has a 59% rate of almost complete cure, defined as less than 10% residual abnormal nail with no requirement for mycologic cure.

Bruce Jancin/Frontline Medical News

And while tavaborole isn’t quite as effective, it’s definitely better than previous topical agents, Dr. Rosen said at the Hawaii Dermatology Seminar provided by Global Academy for Medical Education/Skin Disease Education Foundation.

Both of these topicals are well tolerated and feature good nail permeation. They also allow for spread to the lateral nail folds and hyponychium. They even penetrate nail polish, although efinaconazole often causes the polish to lose its spiffy gloss, said Dr. Rosen, professor of dermatology at Baylor College of Medicine, Houston.

To underscore the importance of early treatment and addressing concomitant tinea pedis, he cited published secondary analyses of two identical double-blind, multicenter, 48-week clinical trials totaling 1,655 adults with onychomycosis who were randomized 3:1 to once-daily efinaconazole 10% topical solution or its vehicle.
 

Treat early

Phoebe Rich, MD, of the Oregon Dermatology and Research Center, Portland, broke down the outcomes according to disease duration, in a study of more than 1,500 patients with onychomycosis. She found that the complete cure rate at 52 weeks dropped off markedly in patients with a history of onychomycosis for 1 year or longer at baseline.

Complete cure – defined as no clinical involvement of the target toenail along with both a negative potassium hydroxide examination and a negative fungal culture at 52 weeks – was achieved in 43% of efinaconazole-treated patients with onychomycosis for less than 1 year. The rate then plunged to 17% in those with a disease duration of 1-5 years and 16% in patients with onychomycosis for more than 5 years. Nevertheless, the topical antifungal was significantly more effective than was the vehicle, across the board, with complete cure rates in the vehicle group of roughly 18%, 5%, and 2%, respectively, in patients with onychomycosis for less than 1 year, 1-5 years, and more than 5 years (J Drugs Dermatol. 2015 Jan;14[1]:58-62).
 

Tackle coexisting tinea pedis

Podiatrists analyzed the combined efinaconazole outcome data based on whether participants had no coexisting tinea pedis, baseline tinea pedis treated concomitantly with an investigator-approved topical antifungal, or tinea pedis left untreated. They concluded that treatment of coexisting tinea pedis decisively enhanced the efficacy of efinaconazole for onychomycosis.

A total of 21% of study participants had concomitant tinea pedis, and 61% of them were treated for it. At week 52, the onychomycosis complete cure rate was 29% in the efinaconazole group concurrently treated for tinea pedis, compared with just 16% if their tinea pedis was untreated (J Am Podiatr Med Assoc. 2015 Sep;105[5]:407-11).

“If you see tinea pedis, don’t blow it off. Treat it. Otherwise, you’re not getting rid of the fungal reservoir,” Dr. Rosen emphasized.

He noted that two topical agents approved for tinea pedis – naftifine 2% cream or gel and luliconazole 1% cream – are effective as once-daily therapy for 2 weeks, a considerably briefer regimen than with other approved topicals. And short-course therapy spells improved adherence, he added.

In the pivotal trials, naftifine had an effective treatment rate – a clinically useful endpoint defined as a small amount of residual scaling and/or redness but no itching – of 57%, while for luliconazole the rates were 33%-48%.

These two agents also are approved for treatment of tinea corporis and tinea cruris. Naftifine is approved as a once-daily treatment for 2 weeks, while luliconazole is, notably, a 7-day treatment. Luliconazole, in particular, is a relatively expensive drug, Dr. Rosen added, so insurers may require prior failure on clotrimazole.
 

When to treat onychomycosis topically

The pivotal trials of tavaborole and efinaconazole were conducted in patients with 20%-60% nail involvement. The infection didn’t extend to the matrix, and nail thickness and crumbly subungual debris were modest at baseline.

“There are always potential safety issues – drug interactions, GI disturbance, taste loss, headache, teratogenicity, cardiotoxicity, hepatotoxicity – anytime you put a pill in your mouth. So if you have a patient who’s dedicated enough to use a topical for 48 weeks and it’s a modestly affected nail, think about it,” Dr. Rosen advised.

He reported serving on scientific advisory boards for Aclaris, Anacor, Cipla, and Valeant.

SDEF/Global Academy for Medical Education and this news organization are owned by the same parent company.
 

[email protected]

An international prognostic index for patients with chronic lymphocytic leukemia (CLL), known as CLL-IPI, was predictive of time from diagnosis to first treatment (TTFT) and 5-year median overall survival in patients across different risk categories treated with chemoimmunotherapy, according to a systematic review and meta-analysis published in Blood (2018 Jan 18;131[3]:365-8).

But limited data were available for patients treated with targeted therapies that are likely to have a profound effect on overall survival; thereby restricting the use of CLL-IPI in current clinical practice.

Novel therapies such as ibrutinib, idelalisib, and venetoclax have changed the treatment landscape for CLL, Stefano Molica, MD, of Azienda Ospedaliera Pugliese-Ciaccio, Catanzaro, Italy, and his colleagues wrote. “Because observation remains the standard of care for asymptomatic early-stage patients, the introduction of these agents does not impact the utility of the CLL-IPI for predicting time from diagnosis to first treatment, but it likely has a profound impact on the survival of patients of all risk categories once treatment is indicated.”

The CLL-IPI tool, first published in 2016 to predict clinical outcomes in CLL patients, combines five parameters: age, clinical stage, TP53 status [normal vs. del(17p) and/or TP53 mutation], immunoglobulin heavy chain–variable mutational status, and serum b2-microglobulin. The prognostic tool was validated across several studies conducted in different countries with diverse practice settings, including academic hospitals, national population-based cohorts, and clinical trials.

The researchers conducted a systematic review and meta-analysis to understand the utility of CLL-IPI tool in predicting OS and TTFT across each risk category of CLL patients.

They included nine studies with 7,843 patients to assess the impact of the CLL-IPI on overall survival. The patient distribution into the CLL-IPI risk categories was low risk (median 45.9%), intermediate risk (median 30%), high risk (median 16.5%), and very high risk (median 3.6%).

The researchers relied on 11 series comprising 7,383 patients to assess 5-year survival probability, which was 92% for low risk, 81% for intermediate risk, 60% for high risk, and 34% for very high risk. They used seven studies comprising 5,206 patients to assess TTFT and found that the probability of remaining treatment free at 5 years was 82% in the low-risk group, 45% in the intermediate-risk group, 30% in the high-risk group, and 16% in the very-high-risk group.

Although a significant step toward harmonizing international prognostication for CLL, additional studies validating the utility of the CLL-IPI for predicting OS in patients treated with targeted therapy are needed, they wrote.

The researchers reported having no financial disclosures.

[email protected]

An international prognostic index for patients with chronic lymphocytic leukemia (CLL), known as CLL-IPI, was predictive of time from diagnosis to first treatment (TTFT) and 5-year median overall survival in patients across different risk categories treated with chemoimmunotherapy, according to a systematic review and meta-analysis published in Blood (2018 Jan 18;131[3]:365-8).

But limited data were available for patients treated with targeted therapies that are likely to have a profound effect on overall survival; thereby restricting the use of CLL-IPI in current clinical practice.

Novel therapies such as ibrutinib, idelalisib, and venetoclax have changed the treatment landscape for CLL, Stefano Molica, MD, of Azienda Ospedaliera Pugliese-Ciaccio, Catanzaro, Italy, and his colleagues wrote. “Because observation remains the standard of care for asymptomatic early-stage patients, the introduction of these agents does not impact the utility of the CLL-IPI for predicting time from diagnosis to first treatment, but it likely has a profound impact on the survival of patients of all risk categories once treatment is indicated.”

The CLL-IPI tool, first published in 2016 to predict clinical outcomes in CLL patients, combines five parameters: age, clinical stage, TP53 status [normal vs. del(17p) and/or TP53 mutation], immunoglobulin heavy chain–variable mutational status, and serum b2-microglobulin. The prognostic tool was validated across several studies conducted in different countries with diverse practice settings, including academic hospitals, national population-based cohorts, and clinical trials.

The researchers conducted a systematic review and meta-analysis to understand the utility of CLL-IPI tool in predicting OS and TTFT across each risk category of CLL patients.

They included nine studies with 7,843 patients to assess the impact of the CLL-IPI on overall survival. The patient distribution into the CLL-IPI risk categories was low risk (median 45.9%), intermediate risk (median 30%), high risk (median 16.5%), and very high risk (median 3.6%).

The researchers relied on 11 series comprising 7,383 patients to assess 5-year survival probability, which was 92% for low risk, 81% for intermediate risk, 60% for high risk, and 34% for very high risk. They used seven studies comprising 5,206 patients to assess TTFT and found that the probability of remaining treatment free at 5 years was 82% in the low-risk group, 45% in the intermediate-risk group, 30% in the high-risk group, and 16% in the very-high-risk group.

Although a significant step toward harmonizing international prognostication for CLL, additional studies validating the utility of the CLL-IPI for predicting OS in patients treated with targeted therapy are needed, they wrote.

The researchers reported having no financial disclosures.

[email protected]

An international prognostic index for patients with chronic lymphocytic leukemia (CLL), known as CLL-IPI, was predictive of time from diagnosis to first treatment (TTFT) and 5-year median overall survival in patients across different risk categories treated with chemoimmunotherapy, according to a systematic review and meta-analysis published in Blood (2018 Jan 18;131[3]:365-8).

But limited data were available for patients treated with targeted therapies that are likely to have a profound effect on overall survival; thereby restricting the use of CLL-IPI in current clinical practice.

Novel therapies such as ibrutinib, idelalisib, and venetoclax have changed the treatment landscape for CLL, Stefano Molica, MD, of Azienda Ospedaliera Pugliese-Ciaccio, Catanzaro, Italy, and his colleagues wrote. “Because observation remains the standard of care for asymptomatic early-stage patients, the introduction of these agents does not impact the utility of the CLL-IPI for predicting time from diagnosis to first treatment, but it likely has a profound impact on the survival of patients of all risk categories once treatment is indicated.”

The CLL-IPI tool, first published in 2016 to predict clinical outcomes in CLL patients, combines five parameters: age, clinical stage, TP53 status [normal vs. del(17p) and/or TP53 mutation], immunoglobulin heavy chain–variable mutational status, and serum b2-microglobulin. The prognostic tool was validated across several studies conducted in different countries with diverse practice settings, including academic hospitals, national population-based cohorts, and clinical trials.

The researchers conducted a systematic review and meta-analysis to understand the utility of CLL-IPI tool in predicting OS and TTFT across each risk category of CLL patients.

They included nine studies with 7,843 patients to assess the impact of the CLL-IPI on overall survival. The patient distribution into the CLL-IPI risk categories was low risk (median 45.9%), intermediate risk (median 30%), high risk (median 16.5%), and very high risk (median 3.6%).

The researchers relied on 11 series comprising 7,383 patients to assess 5-year survival probability, which was 92% for low risk, 81% for intermediate risk, 60% for high risk, and 34% for very high risk. They used seven studies comprising 5,206 patients to assess TTFT and found that the probability of remaining treatment free at 5 years was 82% in the low-risk group, 45% in the intermediate-risk group, 30% in the high-risk group, and 16% in the very-high-risk group.

Although a significant step toward harmonizing international prognostication for CLL, additional studies validating the utility of the CLL-IPI for predicting OS in patients treated with targeted therapy are needed, they wrote.

The researchers reported having no financial disclosures.

[email protected]

Antidepressants and alcohol were each identified in more than 40% of tests performed after suicide deaths in 2014, according to data from the Centers for Disease Control and Prevention’s National Violent Death Reporting System.

Of the 14,834 suicide deaths reported that year in the system’s 18 participating states, tests for alcohol – conducted for 53% (7,883) of decedents – were the most commonly performed and were the second most likely to be positive among drugs with data available: The rate was 40.2%. Among the tests for blood alcohol concentration, a level of 0.08 g/dL or higher, which is over the legal limit in all states, was seen in almost 70% of positive results, Katherine A. Fowler, PhD, and her associates at the CDC’s National Center for Injury Prevention and Control reported in Morbidity and Mortality Weekly Report Surveillance Summaries.

[email protected]

SOURCE: Fowler KA et al. MMWR Surveill Summ. 2018;67(SS-2):1-36. doi: 10.15585/mmwr.ss6702a1.

Antidepressants and alcohol were each identified in more than 40% of tests performed after suicide deaths in 2014, according to data from the Centers for Disease Control and Prevention’s National Violent Death Reporting System.

Of the 14,834 suicide deaths reported that year in the system’s 18 participating states, tests for alcohol – conducted for 53% (7,883) of decedents – were the most commonly performed and were the second most likely to be positive among drugs with data available: The rate was 40.2%. Among the tests for blood alcohol concentration, a level of 0.08 g/dL or higher, which is over the legal limit in all states, was seen in almost 70% of positive results, Katherine A. Fowler, PhD, and her associates at the CDC’s National Center for Injury Prevention and Control reported in Morbidity and Mortality Weekly Report Surveillance Summaries.

[email protected]

SOURCE: Fowler KA et al. MMWR Surveill Summ. 2018;67(SS-2):1-36. doi: 10.15585/mmwr.ss6702a1.

Antidepressants and alcohol were each identified in more than 40% of tests performed after suicide deaths in 2014, according to data from the Centers for Disease Control and Prevention’s National Violent Death Reporting System.

Of the 14,834 suicide deaths reported that year in the system’s 18 participating states, tests for alcohol – conducted for 53% (7,883) of decedents – were the most commonly performed and were the second most likely to be positive among drugs with data available: The rate was 40.2%. Among the tests for blood alcohol concentration, a level of 0.08 g/dL or higher, which is over the legal limit in all states, was seen in almost 70% of positive results, Katherine A. Fowler, PhD, and her associates at the CDC’s National Center for Injury Prevention and Control reported in Morbidity and Mortality Weekly Report Surveillance Summaries.

[email protected]

SOURCE: Fowler KA et al. MMWR Surveill Summ. 2018;67(SS-2):1-36. doi: 10.15585/mmwr.ss6702a1.

The androgen receptor antagonist apalutamide is highly effective for treating nonmetastatic castration-resistant prostate cancer that carries high risk for metastasis based on a rapidly rising prostate-specific antigen (PSA) level, according to results of the randomized phase 3 SPARTAN trial.

“Metastatic castration-resistant prostate cancer is a uniformly fatal disease, with a median survival of around 2.5 years. The aim of this study was to see if the development of metastases in the transition from nonmetastatic to metastatic castration-resistant prostate cancer could be slowed,” lead study author Eric J. Small, MD, professor of medicine at the University of California, San Francisco, commented in a press briefing held in advance of the 2018 Genitourinary Cancers Symposium.

He and his coinvestigators randomized 1,207 men with high-risk nonmetastatic castration-resistant prostate cancer 2:1 to apalutamide (an investigational next-generation competitive inhibitor of the androgen receptor, also known as ARN-509) or placebo, with continuation of androgen-deprivation therapy in both groups. After development of metastases, patients were offered open-label abiraterone (Zytiga), the standard of care for this population, with prednisone.

Main results showed that, compared with placebo, apalutamide prolonged the time to metastasis (ascertained by central review of standard imaging) or death by more than 2 years, Dr. Small reported. The difference translated to a nearly three-fourths reduction in the risk of these events. In addition, the drug was well tolerated and had a rate of serious adverse events similar to that seen with placebo.

“This is a positive trial,” he summarized. “Overall, these data suggest that apalutamide should now be considered as a new standard of care for men with high-risk nonmetastatic castration-resistant prostate cancer.”

The metastasis-free survival findings led to unblinding of the trial in July 2017, and all patients were offered open-label apalutamide. Full results of SPARTAN will be reported later this week at the symposium, which is sponsored by the American Society of Clinical Oncology, ASTRO, and the Society of Urologic Oncology.
 

Parsing the findings

“Until the results of studies presented at this meeting, there was really no obvious standard of care for these patients,” commented ASCO Expert and presscast moderator Sumanta K. Pal, MD. The gain in metastasis-free survival in SPARTAN was “very clinically meaningful.”

Results of the similar PROSPER trial, which compared enzalutamide (Xtandi) with placebo, will also be presented at the symposium, he noted. “We know from a press release issued in September of 2017 that this study also showed a significant delay in the time to onset of metastatic disease. It will be interesting to juxtapose these data once available. Enzalutamide is a drug familiar to the prostate cancer community given existing approvals in the setting of more advanced disease. The familiarity that oncologists already have with enzalutamide may help with clinical adoption.”

Ultimately, imaging advances that allow for earlier detection of metastases may shrink the population of men with nonmetastatic castration-resistant prostate cancer, according to Dr. Pal, who is also a medical oncologist and codirector of the Kidney Cancer Program at City of Hope, Duarte, Calif.

“The SPARTAN trial used a more conventional imaging approach, with CT scans and technetium bone scans,” he pointed out. “While it’s true that this is the current standard, imaging techniques such as fluciclovine PET, PSMA [prostate-specific membrane antigen] PET, may potentially improve our ability to detect disease spread earlier and thereby change our management strategy.”
 

Study details

The patients with nonmetastatic castration-resistant prostate cancer enrolled in SPARTAN had a calculated PSA-doubling time of 10 months or less, a feature identifying those most at risk for developing metastases.

At a median follow-up of 20.3 months, median metastasis-free survival was 40.5 months with apalutamide versus 16.2 months with placebo (hazard ratio, 0.28; P less than .001), Dr. Small reported. An interim analysis of overall survival showed a trend favoring apalutamide (P = .07).

Fully 61% of patients in the apalutamide group were still on treatment at data cutoff, compared with 30% of placebo-treated patients.

Both groups had low rates of discontinuation attributable to adverse events (10.7% and 6.3%). Apalutamide-treated patients did not have any decrease from baseline in patient-reported health-related quality of life scores, which were similar to those of placebo-treated counterparts.

Dr. Small disclosed that he has a consulting or advisory role with Fortis, Gilead Sciences, and Valeant Pharmaceuticals International; has stock and other ownership interests with Fortis and Harpoon Therapeutics; and receives honoraria from Janssen-Cilag; in addition, his institution receives research funding from Janssen. The study was funded by Aragon Pharmaceuticals, a wholly-owned subsidiary of Johnson & Johnson.

[email protected]
 

The androgen receptor antagonist apalutamide is highly effective for treating nonmetastatic castration-resistant prostate cancer that carries high risk for metastasis based on a rapidly rising prostate-specific antigen (PSA) level, according to results of the randomized phase 3 SPARTAN trial.

“Metastatic castration-resistant prostate cancer is a uniformly fatal disease, with a median survival of around 2.5 years. The aim of this study was to see if the development of metastases in the transition from nonmetastatic to metastatic castration-resistant prostate cancer could be slowed,” lead study author Eric J. Small, MD, professor of medicine at the University of California, San Francisco, commented in a press briefing held in advance of the 2018 Genitourinary Cancers Symposium.

He and his coinvestigators randomized 1,207 men with high-risk nonmetastatic castration-resistant prostate cancer 2:1 to apalutamide (an investigational next-generation competitive inhibitor of the androgen receptor, also known as ARN-509) or placebo, with continuation of androgen-deprivation therapy in both groups. After development of metastases, patients were offered open-label abiraterone (Zytiga), the standard of care for this population, with prednisone.

Main results showed that, compared with placebo, apalutamide prolonged the time to metastasis (ascertained by central review of standard imaging) or death by more than 2 years, Dr. Small reported. The difference translated to a nearly three-fourths reduction in the risk of these events. In addition, the drug was well tolerated and had a rate of serious adverse events similar to that seen with placebo.

“This is a positive trial,” he summarized. “Overall, these data suggest that apalutamide should now be considered as a new standard of care for men with high-risk nonmetastatic castration-resistant prostate cancer.”

The metastasis-free survival findings led to unblinding of the trial in July 2017, and all patients were offered open-label apalutamide. Full results of SPARTAN will be reported later this week at the symposium, which is sponsored by the American Society of Clinical Oncology, ASTRO, and the Society of Urologic Oncology.
 

Parsing the findings

“Until the results of studies presented at this meeting, there was really no obvious standard of care for these patients,” commented ASCO Expert and presscast moderator Sumanta K. Pal, MD. The gain in metastasis-free survival in SPARTAN was “very clinically meaningful.”

Results of the similar PROSPER trial, which compared enzalutamide (Xtandi) with placebo, will also be presented at the symposium, he noted. “We know from a press release issued in September of 2017 that this study also showed a significant delay in the time to onset of metastatic disease. It will be interesting to juxtapose these data once available. Enzalutamide is a drug familiar to the prostate cancer community given existing approvals in the setting of more advanced disease. The familiarity that oncologists already have with enzalutamide may help with clinical adoption.”

Ultimately, imaging advances that allow for earlier detection of metastases may shrink the population of men with nonmetastatic castration-resistant prostate cancer, according to Dr. Pal, who is also a medical oncologist and codirector of the Kidney Cancer Program at City of Hope, Duarte, Calif.

“The SPARTAN trial used a more conventional imaging approach, with CT scans and technetium bone scans,” he pointed out. “While it’s true that this is the current standard, imaging techniques such as fluciclovine PET, PSMA [prostate-specific membrane antigen] PET, may potentially improve our ability to detect disease spread earlier and thereby change our management strategy.”
 

Study details

The patients with nonmetastatic castration-resistant prostate cancer enrolled in SPARTAN had a calculated PSA-doubling time of 10 months or less, a feature identifying those most at risk for developing metastases.

At a median follow-up of 20.3 months, median metastasis-free survival was 40.5 months with apalutamide versus 16.2 months with placebo (hazard ratio, 0.28; P less than .001), Dr. Small reported. An interim analysis of overall survival showed a trend favoring apalutamide (P = .07).

Fully 61% of patients in the apalutamide group were still on treatment at data cutoff, compared with 30% of placebo-treated patients.

Both groups had low rates of discontinuation attributable to adverse events (10.7% and 6.3%). Apalutamide-treated patients did not have any decrease from baseline in patient-reported health-related quality of life scores, which were similar to those of placebo-treated counterparts.

Dr. Small disclosed that he has a consulting or advisory role with Fortis, Gilead Sciences, and Valeant Pharmaceuticals International; has stock and other ownership interests with Fortis and Harpoon Therapeutics; and receives honoraria from Janssen-Cilag; in addition, his institution receives research funding from Janssen. The study was funded by Aragon Pharmaceuticals, a wholly-owned subsidiary of Johnson & Johnson.

[email protected]
 

The androgen receptor antagonist apalutamide is highly effective for treating nonmetastatic castration-resistant prostate cancer that carries high risk for metastasis based on a rapidly rising prostate-specific antigen (PSA) level, according to results of the randomized phase 3 SPARTAN trial.

“Metastatic castration-resistant prostate cancer is a uniformly fatal disease, with a median survival of around 2.5 years. The aim of this study was to see if the development of metastases in the transition from nonmetastatic to metastatic castration-resistant prostate cancer could be slowed,” lead study author Eric J. Small, MD, professor of medicine at the University of California, San Francisco, commented in a press briefing held in advance of the 2018 Genitourinary Cancers Symposium.

He and his coinvestigators randomized 1,207 men with high-risk nonmetastatic castration-resistant prostate cancer 2:1 to apalutamide (an investigational next-generation competitive inhibitor of the androgen receptor, also known as ARN-509) or placebo, with continuation of androgen-deprivation therapy in both groups. After development of metastases, patients were offered open-label abiraterone (Zytiga), the standard of care for this population, with prednisone.

Main results showed that, compared with placebo, apalutamide prolonged the time to metastasis (ascertained by central review of standard imaging) or death by more than 2 years, Dr. Small reported. The difference translated to a nearly three-fourths reduction in the risk of these events. In addition, the drug was well tolerated and had a rate of serious adverse events similar to that seen with placebo.

“This is a positive trial,” he summarized. “Overall, these data suggest that apalutamide should now be considered as a new standard of care for men with high-risk nonmetastatic castration-resistant prostate cancer.”

The metastasis-free survival findings led to unblinding of the trial in July 2017, and all patients were offered open-label apalutamide. Full results of SPARTAN will be reported later this week at the symposium, which is sponsored by the American Society of Clinical Oncology, ASTRO, and the Society of Urologic Oncology.
 

Parsing the findings

“Until the results of studies presented at this meeting, there was really no obvious standard of care for these patients,” commented ASCO Expert and presscast moderator Sumanta K. Pal, MD. The gain in metastasis-free survival in SPARTAN was “very clinically meaningful.”

Results of the similar PROSPER trial, which compared enzalutamide (Xtandi) with placebo, will also be presented at the symposium, he noted. “We know from a press release issued in September of 2017 that this study also showed a significant delay in the time to onset of metastatic disease. It will be interesting to juxtapose these data once available. Enzalutamide is a drug familiar to the prostate cancer community given existing approvals in the setting of more advanced disease. The familiarity that oncologists already have with enzalutamide may help with clinical adoption.”

Ultimately, imaging advances that allow for earlier detection of metastases may shrink the population of men with nonmetastatic castration-resistant prostate cancer, according to Dr. Pal, who is also a medical oncologist and codirector of the Kidney Cancer Program at City of Hope, Duarte, Calif.

“The SPARTAN trial used a more conventional imaging approach, with CT scans and technetium bone scans,” he pointed out. “While it’s true that this is the current standard, imaging techniques such as fluciclovine PET, PSMA [prostate-specific membrane antigen] PET, may potentially improve our ability to detect disease spread earlier and thereby change our management strategy.”
 

Study details

The patients with nonmetastatic castration-resistant prostate cancer enrolled in SPARTAN had a calculated PSA-doubling time of 10 months or less, a feature identifying those most at risk for developing metastases.

At a median follow-up of 20.3 months, median metastasis-free survival was 40.5 months with apalutamide versus 16.2 months with placebo (hazard ratio, 0.28; P less than .001), Dr. Small reported. An interim analysis of overall survival showed a trend favoring apalutamide (P = .07).

Fully 61% of patients in the apalutamide group were still on treatment at data cutoff, compared with 30% of placebo-treated patients.

Both groups had low rates of discontinuation attributable to adverse events (10.7% and 6.3%). Apalutamide-treated patients did not have any decrease from baseline in patient-reported health-related quality of life scores, which were similar to those of placebo-treated counterparts.

Dr. Small disclosed that he has a consulting or advisory role with Fortis, Gilead Sciences, and Valeant Pharmaceuticals International; has stock and other ownership interests with Fortis and Harpoon Therapeutics; and receives honoraria from Janssen-Cilag; in addition, his institution receives research funding from Janssen. The study was funded by Aragon Pharmaceuticals, a wholly-owned subsidiary of Johnson & Johnson.

[email protected]
 

DALLAS – Timing of maternal oxytocin administration did not affect total placental transfusion volume accomplished via delayed umbilical cord clamping, according to a recent randomized, controlled trial.

Of 144 infants born to women who consented to randomization, those whose mothers received intravenous oxytocin within 15 seconds of delivery (n = 70) gained a mean 86 g (standard deviation, 48; 95% confidence interval, 74-97) in the 3 minutes after delivery, before umbilical cord clamping. Infants whose mothers received oxytocin when the umbilical cord was clamped 3 minutes after delivery (n = 74) gained 87 g (SD, 50; 95% CI, 75-98; P for difference between groups = .92). The findings were presented during an abstract session at the meeting sponsored by the Society for Maternal-Fetal Medicine.

Kari Oakes/Frontline Medical News

[email protected]

SOURCE: Satragno D et al. Am J Obstet Gynecol. 2018 Jan;218:S26.

DALLAS – Timing of maternal oxytocin administration did not affect total placental transfusion volume accomplished via delayed umbilical cord clamping, according to a recent randomized, controlled trial.

Of 144 infants born to women who consented to randomization, those whose mothers received intravenous oxytocin within 15 seconds of delivery (n = 70) gained a mean 86 g (standard deviation, 48; 95% confidence interval, 74-97) in the 3 minutes after delivery, before umbilical cord clamping. Infants whose mothers received oxytocin when the umbilical cord was clamped 3 minutes after delivery (n = 74) gained 87 g (SD, 50; 95% CI, 75-98; P for difference between groups = .92). The findings were presented during an abstract session at the meeting sponsored by the Society for Maternal-Fetal Medicine.

Kari Oakes/Frontline Medical News

[email protected]

SOURCE: Satragno D et al. Am J Obstet Gynecol. 2018 Jan;218:S26.

DALLAS – Timing of maternal oxytocin administration did not affect total placental transfusion volume accomplished via delayed umbilical cord clamping, according to a recent randomized, controlled trial.

Of 144 infants born to women who consented to randomization, those whose mothers received intravenous oxytocin within 15 seconds of delivery (n = 70) gained a mean 86 g (standard deviation, 48; 95% confidence interval, 74-97) in the 3 minutes after delivery, before umbilical cord clamping. Infants whose mothers received oxytocin when the umbilical cord was clamped 3 minutes after delivery (n = 74) gained 87 g (SD, 50; 95% CI, 75-98; P for difference between groups = .92). The findings were presented during an abstract session at the meeting sponsored by the Society for Maternal-Fetal Medicine.

Kari Oakes/Frontline Medical News

[email protected]

SOURCE: Satragno D et al. Am J Obstet Gynecol. 2018 Jan;218:S26.

Indiana is the second state to win federal approval to add a work requirement for adult Medicaid recipients who gained coverage under the Affordable Care Act, but a less debated “lockout” provision in its new plan could lead to tens of thousands of enrollees losing coverage.

The federal approval was announced Feb. 2 by Health & Human Services Secretary Alex Azar in Indianapolis.

Medicaid participants who fail to submit their paperwork in a timely manner showing that they still qualify for the program will be blocked from enrollment for 3 months, according to the updated rules.

Since November 2015, more than 91,000 enrollees in Indiana were kicked off Medicaid for failing to complete the eligibility redetermination process, according to state records. The process requires applicants to show proof of income and family size, among other things, to see if they still qualify for the coverage. Until now, these enrollees could simply reapply anytime. Although many of those people likely were no longer eligible, state officials estimate about half of those who failed to comply with its reenrollment rules were still qualified.

Indiana’s Medicaid expansion began in February 2015, providing coverage to 240,000 people who were previously uninsured, helping drop the state’s uninsured rate from 14% in 2013 to 8% last year. The HHS approval extends the program, which was expiring this month, through 2020.

The new lockout builds on one already in place for Indiana residents who failed to pay monthly premiums and had annual incomes above the federal poverty level, or about $12,200 for an individual. They are barred for 6 months from coverage. During the first 2 years of the experiment, about 10,000 Indiana Medicaid enrollees were subject to the lockout for failing to pay the premium for 2 months in a row, according to state data.

In addition, more than 25,000 enrollees were dropped from the program after they failed to make the payments, although half of them found another source of coverage, usually through their jobs.

Another 46,000 were blocked from coverage because they failed to make the initial payment.

“The ‘lockout” is one of the worst policies to hit Medicaid in a long time,” said Joan Alker, executive director of the Georgetown University Center for Children and Families, in Washington. “Forcing people to remain uninsured for months because they missed a paperwork deadline or missed a premium payment is too high a price to pay. From a health policy perspective, it makes no sense because during that period, chronic health conditions such as hypertension or diabetes are just likely to worsen.”

Indiana’s Medicaid expansion is being closely watched in part because it was spearheaded by then-governor Mike Pence, who is now vice president, and his top health consultant, Seema Verma, who now heads the federal Centers for Medicare & Medicaid Services.

The expansion, known as Healthy Indiana, enabled nondisabled adults access to Medicaid. It has elicited criticism from patient advocates for complex and onerous rules that require these poor adults to make payments ranging from $1 to $27 per month into health savings accounts or risk losing their vision and dental benefits or even all their coverage, depending on their income level.

Indiana Medicaid officials said they added the newest lockout provision in an effort to prompt enrollees to get their paperwork submitted in time. The state initially requested a 6-month lockout.

“Enforcement may encourage better compliance,” the state officials wrote in their waiver application to CMS in July.

The new rule will lead to a 1% cut in Medicaid enrollment in the first year, state officials said. It will also lead to a $15 million reduction in Medicaid costs in 2018 and about $32 million in savings in 2019, the state estimated.

The number of Medicaid enrollees losing coverage for failing to comply with redetermining their eligibility has varied dramatically each quarter from a peak of 19,197 from February 2016 to April 2017 to 1,165 from November 2015 to January 2016, state reports show. In the latest state report, 12,470 enrollees lost coverage from August to October 2017.

The Kentucky Medicaid waiver approved by the Trump administration in January included a similar lockout provision for both failing to pay the monthly premiums or providing paperwork on time. Penalties there are 6 months for both measures. But the provision was overshadowed because of the attention to the first federal approval for a Medicaid work requirement.

Like Kentucky, Indiana’s Medicaid waiver’s work requirements, which mandate adult enrollees to work an average of 20 hours a month, go into effect in 2019. But Indiana’s waiver is more lenient. It exempts people aged 60 years and older and its work-hour requirements are gradually phased in over 18 months. For example, enrollees need to work only 5 hours per week until their 10th month on the program.

Most Medicaid adult enrollees do work, go to school, or are too sick to work, studies show.

Indiana also has a long list of exemptions and alternatives to employment. This includes attending school or job training, volunteering or caring for a dependent child or disabled parent. Nurses, doctors and physician assistants can give enrollees an exemption due to illness or injury.

Three patient advocacy groups have filed suit in federal court seeking to block the work requirements.

Robin Rudowitz, associate director for the Kaiser Family Foundation’s Program on Medicaid and the Uninsured, said it’s difficult to gauge whether work requirements or renewal lockouts will have more of an impact on coverage. She noted both provisions apply to most demonstration beneficiaries. (KHN is an editorially independent program of the foundation).

“Any documentation requirement could lead to increased complexity in terms of states administering the requirements and individuals complying,” she said, adding that it could result “in potentially eligible people falling off of coverage.”
 

Kaiser Health News (KHN) is a national health policy news service. It is an editorially independent program of the Henry J. Kaiser Family Foundation which is not affiliated with Kaiser Permanente.

Indiana is the second state to win federal approval to add a work requirement for adult Medicaid recipients who gained coverage under the Affordable Care Act, but a less debated “lockout” provision in its new plan could lead to tens of thousands of enrollees losing coverage.

The federal approval was announced Feb. 2 by Health & Human Services Secretary Alex Azar in Indianapolis.

Medicaid participants who fail to submit their paperwork in a timely manner showing that they still qualify for the program will be blocked from enrollment for 3 months, according to the updated rules.

Since November 2015, more than 91,000 enrollees in Indiana were kicked off Medicaid for failing to complete the eligibility redetermination process, according to state records. The process requires applicants to show proof of income and family size, among other things, to see if they still qualify for the coverage. Until now, these enrollees could simply reapply anytime. Although many of those people likely were no longer eligible, state officials estimate about half of those who failed to comply with its reenrollment rules were still qualified.

Indiana’s Medicaid expansion began in February 2015, providing coverage to 240,000 people who were previously uninsured, helping drop the state’s uninsured rate from 14% in 2013 to 8% last year. The HHS approval extends the program, which was expiring this month, through 2020.

The new lockout builds on one already in place for Indiana residents who failed to pay monthly premiums and had annual incomes above the federal poverty level, or about $12,200 for an individual. They are barred for 6 months from coverage. During the first 2 years of the experiment, about 10,000 Indiana Medicaid enrollees were subject to the lockout for failing to pay the premium for 2 months in a row, according to state data.

In addition, more than 25,000 enrollees were dropped from the program after they failed to make the payments, although half of them found another source of coverage, usually through their jobs.

Another 46,000 were blocked from coverage because they failed to make the initial payment.

“The ‘lockout” is one of the worst policies to hit Medicaid in a long time,” said Joan Alker, executive director of the Georgetown University Center for Children and Families, in Washington. “Forcing people to remain uninsured for months because they missed a paperwork deadline or missed a premium payment is too high a price to pay. From a health policy perspective, it makes no sense because during that period, chronic health conditions such as hypertension or diabetes are just likely to worsen.”

Indiana’s Medicaid expansion is being closely watched in part because it was spearheaded by then-governor Mike Pence, who is now vice president, and his top health consultant, Seema Verma, who now heads the federal Centers for Medicare & Medicaid Services.

The expansion, known as Healthy Indiana, enabled nondisabled adults access to Medicaid. It has elicited criticism from patient advocates for complex and onerous rules that require these poor adults to make payments ranging from $1 to $27 per month into health savings accounts or risk losing their vision and dental benefits or even all their coverage, depending on their income level.

Indiana Medicaid officials said they added the newest lockout provision in an effort to prompt enrollees to get their paperwork submitted in time. The state initially requested a 6-month lockout.

“Enforcement may encourage better compliance,” the state officials wrote in their waiver application to CMS in July.

The new rule will lead to a 1% cut in Medicaid enrollment in the first year, state officials said. It will also lead to a $15 million reduction in Medicaid costs in 2018 and about $32 million in savings in 2019, the state estimated.

The number of Medicaid enrollees losing coverage for failing to comply with redetermining their eligibility has varied dramatically each quarter from a peak of 19,197 from February 2016 to April 2017 to 1,165 from November 2015 to January 2016, state reports show. In the latest state report, 12,470 enrollees lost coverage from August to October 2017.

The Kentucky Medicaid waiver approved by the Trump administration in January included a similar lockout provision for both failing to pay the monthly premiums or providing paperwork on time. Penalties there are 6 months for both measures. But the provision was overshadowed because of the attention to the first federal approval for a Medicaid work requirement.

Like Kentucky, Indiana’s Medicaid waiver’s work requirements, which mandate adult enrollees to work an average of 20 hours a month, go into effect in 2019. But Indiana’s waiver is more lenient. It exempts people aged 60 years and older and its work-hour requirements are gradually phased in over 18 months. For example, enrollees need to work only 5 hours per week until their 10th month on the program.

Most Medicaid adult enrollees do work, go to school, or are too sick to work, studies show.

Indiana also has a long list of exemptions and alternatives to employment. This includes attending school or job training, volunteering or caring for a dependent child or disabled parent. Nurses, doctors and physician assistants can give enrollees an exemption due to illness or injury.

Three patient advocacy groups have filed suit in federal court seeking to block the work requirements.

Robin Rudowitz, associate director for the Kaiser Family Foundation’s Program on Medicaid and the Uninsured, said it’s difficult to gauge whether work requirements or renewal lockouts will have more of an impact on coverage. She noted both provisions apply to most demonstration beneficiaries. (KHN is an editorially independent program of the foundation).

“Any documentation requirement could lead to increased complexity in terms of states administering the requirements and individuals complying,” she said, adding that it could result “in potentially eligible people falling off of coverage.”
 

Kaiser Health News (KHN) is a national health policy news service. It is an editorially independent program of the Henry J. Kaiser Family Foundation which is not affiliated with Kaiser Permanente.

Indiana is the second state to win federal approval to add a work requirement for adult Medicaid recipients who gained coverage under the Affordable Care Act, but a less debated “lockout” provision in its new plan could lead to tens of thousands of enrollees losing coverage.

The federal approval was announced Feb. 2 by Health & Human Services Secretary Alex Azar in Indianapolis.

Medicaid participants who fail to submit their paperwork in a timely manner showing that they still qualify for the program will be blocked from enrollment for 3 months, according to the updated rules.

Since November 2015, more than 91,000 enrollees in Indiana were kicked off Medicaid for failing to complete the eligibility redetermination process, according to state records. The process requires applicants to show proof of income and family size, among other things, to see if they still qualify for the coverage. Until now, these enrollees could simply reapply anytime. Although many of those people likely were no longer eligible, state officials estimate about half of those who failed to comply with its reenrollment rules were still qualified.

Indiana’s Medicaid expansion began in February 2015, providing coverage to 240,000 people who were previously uninsured, helping drop the state’s uninsured rate from 14% in 2013 to 8% last year. The HHS approval extends the program, which was expiring this month, through 2020.

The new lockout builds on one already in place for Indiana residents who failed to pay monthly premiums and had annual incomes above the federal poverty level, or about $12,200 for an individual. They are barred for 6 months from coverage. During the first 2 years of the experiment, about 10,000 Indiana Medicaid enrollees were subject to the lockout for failing to pay the premium for 2 months in a row, according to state data.

In addition, more than 25,000 enrollees were dropped from the program after they failed to make the payments, although half of them found another source of coverage, usually through their jobs.

Another 46,000 were blocked from coverage because they failed to make the initial payment.

“The ‘lockout” is one of the worst policies to hit Medicaid in a long time,” said Joan Alker, executive director of the Georgetown University Center for Children and Families, in Washington. “Forcing people to remain uninsured for months because they missed a paperwork deadline or missed a premium payment is too high a price to pay. From a health policy perspective, it makes no sense because during that period, chronic health conditions such as hypertension or diabetes are just likely to worsen.”

Indiana’s Medicaid expansion is being closely watched in part because it was spearheaded by then-governor Mike Pence, who is now vice president, and his top health consultant, Seema Verma, who now heads the federal Centers for Medicare & Medicaid Services.

The expansion, known as Healthy Indiana, enabled nondisabled adults access to Medicaid. It has elicited criticism from patient advocates for complex and onerous rules that require these poor adults to make payments ranging from $1 to $27 per month into health savings accounts or risk losing their vision and dental benefits or even all their coverage, depending on their income level.

Indiana Medicaid officials said they added the newest lockout provision in an effort to prompt enrollees to get their paperwork submitted in time. The state initially requested a 6-month lockout.

“Enforcement may encourage better compliance,” the state officials wrote in their waiver application to CMS in July.

The new rule will lead to a 1% cut in Medicaid enrollment in the first year, state officials said. It will also lead to a $15 million reduction in Medicaid costs in 2018 and about $32 million in savings in 2019, the state estimated.

The number of Medicaid enrollees losing coverage for failing to comply with redetermining their eligibility has varied dramatically each quarter from a peak of 19,197 from February 2016 to April 2017 to 1,165 from November 2015 to January 2016, state reports show. In the latest state report, 12,470 enrollees lost coverage from August to October 2017.

The Kentucky Medicaid waiver approved by the Trump administration in January included a similar lockout provision for both failing to pay the monthly premiums or providing paperwork on time. Penalties there are 6 months for both measures. But the provision was overshadowed because of the attention to the first federal approval for a Medicaid work requirement.

Like Kentucky, Indiana’s Medicaid waiver’s work requirements, which mandate adult enrollees to work an average of 20 hours a month, go into effect in 2019. But Indiana’s waiver is more lenient. It exempts people aged 60 years and older and its work-hour requirements are gradually phased in over 18 months. For example, enrollees need to work only 5 hours per week until their 10th month on the program.

Most Medicaid adult enrollees do work, go to school, or are too sick to work, studies show.

Indiana also has a long list of exemptions and alternatives to employment. This includes attending school or job training, volunteering or caring for a dependent child or disabled parent. Nurses, doctors and physician assistants can give enrollees an exemption due to illness or injury.

Three patient advocacy groups have filed suit in federal court seeking to block the work requirements.

Robin Rudowitz, associate director for the Kaiser Family Foundation’s Program on Medicaid and the Uninsured, said it’s difficult to gauge whether work requirements or renewal lockouts will have more of an impact on coverage. She noted both provisions apply to most demonstration beneficiaries. (KHN is an editorially independent program of the foundation).

“Any documentation requirement could lead to increased complexity in terms of states administering the requirements and individuals complying,” she said, adding that it could result “in potentially eligible people falling off of coverage.”
 

Kaiser Health News (KHN) is a national health policy news service. It is an editorially independent program of the Henry J. Kaiser Family Foundation which is not affiliated with Kaiser Permanente.

The 2016 Magnetic Resonance Imaging in Multiple Sclerosis (MAGNIMS) criteria have accuracy similar to that of the 2010 McDonald criteria in predicting the development of clinically definite multiple sclerosis (MS), according to a retrospective study.

“Among the different modifications proposed, our results support removal of the distinction between symptomatic and asymptomatic lesions, which simplifies the clinical use of MRI criteria, and suggest that further consideration be given to increasing the number of lesions needed to define periventricular involvement from one to three, because this might slightly increase specificity,” said Massimo Filippi, MD, of the neuroimaging research unit in the division of neuroscience at San Raffaele Scientific Institute at Vita-Salute San Raffaele University in Milan, and colleagues. The report was published online ahead of print December 21, 2017, in Lancet Neurology. “Further effort is still needed to improve cortical lesion assessment, and more studies should be done to evaluate the effect of including optic nerve assessment as an additional dissemination in space [DIS] criterion.”

An Effort to Draft Revisions

In an effort to guide revisions of MS diagnostic criteria, Dr. Filippi and other members of the MAGNIMS network compared the performance of the 2010 McDonald and 2016 MAGNIMS criteria for MS in a cohort of 368 patients with clinically isolated syndrome (CIS) who were screened between June 16, 1995, and January 27, 2017. They used a time-dependent receiver operating characteristic curve analysis to evaluate MRI criteria performance for DIS, dissemination in time (DIT), and DIS plus DIT. Changes to the DIS definition contained in the 2016 MAGNIMS criteria included removal of the distinction between symptomatic and asymptomatic lesions, increasing the number of lesions needed to define periventricular involvement to three, combining cortical and juxtacortical lesions, and inclusion of optic nerve evaluation. For DIT, removal of the distinction between symptomatic and asymptomatic lesions was suggested.

Dr. Filippi and his coauthors at eight centers reported that 189 (51%) of the 368 patients had developed clinically definite MS by the last evaluation, which occurred at a median of 50 months from baseline. At 36 months, DIS alone showed high sensitivity in the 2010 McDonald and 2016 MAGNIMS criteria (91% vs 93%, respectively), similar specificity (33% vs 32%), and similar area under the curve values (AUC, 0.62 vs 0.63). Inclusion of symptomatic lesions did not alter performance. The researchers also found that requiring three periventricular lesions reduced sensitivity to 85% and increased specificity to 40%, but did not affect AUC values (AUC, 0.63). When optic nerve evaluation was included, sensitivity was similar (92%), while specificity decreased to 26%, and AUC declined to 0.59.

The 2016 MAGNIMS and 2010 McDonald criteria achieved similar sensitivity, specificity, and AUC values when compared on the performance of DIT criteria and DIS plus DIT criteria.

“For both sets of criteria, specificity was lower than that of previous studies that evaluated the diagnostic performance of the 2010 McDonald criteria,” the authors wrote. “Several factors could help explain our findings, including the different follow-up durations, the statistical methods (eg, using a time-to-event analysis in our study), and the effect of treatment, which might have delayed or prevented the occurrence of the second attack during the study period.” They acknowledged certain limitations of the study, including its retrospective design and the fact that patients were recruited in highly specialized centers, which may have resulted in the selection of patients at higher risk of conversion to clinically definite MS.

MRI Abnormalities May Not Indicate MS

As MS diagnosis evolves, revisions to existing diagnostic criteria have increased sensitivity, thus helping clinicians establish earlier diagnoses. Although the study by Dr. Filippi et al showed that for both sets of MRI criteria, sensitivity was greater than specificity for predicting clinically definite MS, the modest specificity is cause for concern, said Anne H. Cross, MD, Head of the Neuroimmunology (MS) Section, and Robert N. Naismith, MD, Associate Professor of Neurology, both at Washington University in St. Louis, in an accompanying editorial. They cited one study that emphasized the importance of not misdiagnosing other CNS diseases as MS. “In that study at four academic medical centers, 110 people seen over a period of less than 1.5 years were found to have been misdiagnosed,” said Drs. Cross and Naismith. “[Seventy percent] of the 110 individuals had received disease-modifying therapy, and 31% had unnecessary morbidity. Leading factors contributing to erroneous diagnosis in the study included overreliance on MRI abnormalities in patients with nonspecific neurologic symptoms.”

Vascular and other diseases can cause MRI abnormalities that could meet the 2016 MAGNIMS recommendations or the 2010 and 2017 McDonald MRI criteria, the authors continued. For example, patients with monophasic inflammatory and infectious diseases might have gadolinium-enhancing lesions that meet the 2017 McDonald criteria for DIT, which require only the simultaneous presence of gadolinium-enhancing and gadolinium-negative lesions in the proper locations. For patients with an atypical presentation who meet the 2010 and 2017 McDonald or 2016 MAGNIMS recommendations, clinicians should weigh all of the observed imaging features (including the number of periventricular lesions, along with lesion size, shape, and location) to improve diagnostic specificity and help to limit misdiagnoses, they concluded.

—Doug Brunk

Suggested Reading

Cross AH, Naismith RT. Refining the use of MRI to predict multiple sclerosis. Lancet Neurol. 2017 Dec 21 [Epub ahead of print].

Filippi M, Preziosa P, Meani A, et al. Prediction of a multiple sclerosis diagnosis in patients with clinically isolated syndrome using the 2016 MAGNIMS and 2010 McDonald criteria: a retrospective study. Lancet Neurol. 2017 Dec 21 [Epub ahead of print].

The 2016 Magnetic Resonance Imaging in Multiple Sclerosis (MAGNIMS) criteria have accuracy similar to that of the 2010 McDonald criteria in predicting the development of clinically definite multiple sclerosis (MS), according to a retrospective study.

“Among the different modifications proposed, our results support removal of the distinction between symptomatic and asymptomatic lesions, which simplifies the clinical use of MRI criteria, and suggest that further consideration be given to increasing the number of lesions needed to define periventricular involvement from one to three, because this might slightly increase specificity,” said Massimo Filippi, MD, of the neuroimaging research unit in the division of neuroscience at San Raffaele Scientific Institute at Vita-Salute San Raffaele University in Milan, and colleagues. The report was published online ahead of print December 21, 2017, in Lancet Neurology. “Further effort is still needed to improve cortical lesion assessment, and more studies should be done to evaluate the effect of including optic nerve assessment as an additional dissemination in space [DIS] criterion.”

An Effort to Draft Revisions

In an effort to guide revisions of MS diagnostic criteria, Dr. Filippi and other members of the MAGNIMS network compared the performance of the 2010 McDonald and 2016 MAGNIMS criteria for MS in a cohort of 368 patients with clinically isolated syndrome (CIS) who were screened between June 16, 1995, and January 27, 2017. They used a time-dependent receiver operating characteristic curve analysis to evaluate MRI criteria performance for DIS, dissemination in time (DIT), and DIS plus DIT. Changes to the DIS definition contained in the 2016 MAGNIMS criteria included removal of the distinction between symptomatic and asymptomatic lesions, increasing the number of lesions needed to define periventricular involvement to three, combining cortical and juxtacortical lesions, and inclusion of optic nerve evaluation. For DIT, removal of the distinction between symptomatic and asymptomatic lesions was suggested.

Dr. Filippi and his coauthors at eight centers reported that 189 (51%) of the 368 patients had developed clinically definite MS by the last evaluation, which occurred at a median of 50 months from baseline. At 36 months, DIS alone showed high sensitivity in the 2010 McDonald and 2016 MAGNIMS criteria (91% vs 93%, respectively), similar specificity (33% vs 32%), and similar area under the curve values (AUC, 0.62 vs 0.63). Inclusion of symptomatic lesions did not alter performance. The researchers also found that requiring three periventricular lesions reduced sensitivity to 85% and increased specificity to 40%, but did not affect AUC values (AUC, 0.63). When optic nerve evaluation was included, sensitivity was similar (92%), while specificity decreased to 26%, and AUC declined to 0.59.

The 2016 MAGNIMS and 2010 McDonald criteria achieved similar sensitivity, specificity, and AUC values when compared on the performance of DIT criteria and DIS plus DIT criteria.

“For both sets of criteria, specificity was lower than that of previous studies that evaluated the diagnostic performance of the 2010 McDonald criteria,” the authors wrote. “Several factors could help explain our findings, including the different follow-up durations, the statistical methods (eg, using a time-to-event analysis in our study), and the effect of treatment, which might have delayed or prevented the occurrence of the second attack during the study period.” They acknowledged certain limitations of the study, including its retrospective design and the fact that patients were recruited in highly specialized centers, which may have resulted in the selection of patients at higher risk of conversion to clinically definite MS.

MRI Abnormalities May Not Indicate MS

As MS diagnosis evolves, revisions to existing diagnostic criteria have increased sensitivity, thus helping clinicians establish earlier diagnoses. Although the study by Dr. Filippi et al showed that for both sets of MRI criteria, sensitivity was greater than specificity for predicting clinically definite MS, the modest specificity is cause for concern, said Anne H. Cross, MD, Head of the Neuroimmunology (MS) Section, and Robert N. Naismith, MD, Associate Professor of Neurology, both at Washington University in St. Louis, in an accompanying editorial. They cited one study that emphasized the importance of not misdiagnosing other CNS diseases as MS. “In that study at four academic medical centers, 110 people seen over a period of less than 1.5 years were found to have been misdiagnosed,” said Drs. Cross and Naismith. “[Seventy percent] of the 110 individuals had received disease-modifying therapy, and 31% had unnecessary morbidity. Leading factors contributing to erroneous diagnosis in the study included overreliance on MRI abnormalities in patients with nonspecific neurologic symptoms.”

Vascular and other diseases can cause MRI abnormalities that could meet the 2016 MAGNIMS recommendations or the 2010 and 2017 McDonald MRI criteria, the authors continued. For example, patients with monophasic inflammatory and infectious diseases might have gadolinium-enhancing lesions that meet the 2017 McDonald criteria for DIT, which require only the simultaneous presence of gadolinium-enhancing and gadolinium-negative lesions in the proper locations. For patients with an atypical presentation who meet the 2010 and 2017 McDonald or 2016 MAGNIMS recommendations, clinicians should weigh all of the observed imaging features (including the number of periventricular lesions, along with lesion size, shape, and location) to improve diagnostic specificity and help to limit misdiagnoses, they concluded.

—Doug Brunk

Suggested Reading

Cross AH, Naismith RT. Refining the use of MRI to predict multiple sclerosis. Lancet Neurol. 2017 Dec 21 [Epub ahead of print].

Filippi M, Preziosa P, Meani A, et al. Prediction of a multiple sclerosis diagnosis in patients with clinically isolated syndrome using the 2016 MAGNIMS and 2010 McDonald criteria: a retrospective study. Lancet Neurol. 2017 Dec 21 [Epub ahead of print].

The 2016 Magnetic Resonance Imaging in Multiple Sclerosis (MAGNIMS) criteria have accuracy similar to that of the 2010 McDonald criteria in predicting the development of clinically definite multiple sclerosis (MS), according to a retrospective study.

“Among the different modifications proposed, our results support removal of the distinction between symptomatic and asymptomatic lesions, which simplifies the clinical use of MRI criteria, and suggest that further consideration be given to increasing the number of lesions needed to define periventricular involvement from one to three, because this might slightly increase specificity,” said Massimo Filippi, MD, of the neuroimaging research unit in the division of neuroscience at San Raffaele Scientific Institute at Vita-Salute San Raffaele University in Milan, and colleagues. The report was published online ahead of print December 21, 2017, in Lancet Neurology. “Further effort is still needed to improve cortical lesion assessment, and more studies should be done to evaluate the effect of including optic nerve assessment as an additional dissemination in space [DIS] criterion.”

An Effort to Draft Revisions

In an effort to guide revisions of MS diagnostic criteria, Dr. Filippi and other members of the MAGNIMS network compared the performance of the 2010 McDonald and 2016 MAGNIMS criteria for MS in a cohort of 368 patients with clinically isolated syndrome (CIS) who were screened between June 16, 1995, and January 27, 2017. They used a time-dependent receiver operating characteristic curve analysis to evaluate MRI criteria performance for DIS, dissemination in time (DIT), and DIS plus DIT. Changes to the DIS definition contained in the 2016 MAGNIMS criteria included removal of the distinction between symptomatic and asymptomatic lesions, increasing the number of lesions needed to define periventricular involvement to three, combining cortical and juxtacortical lesions, and inclusion of optic nerve evaluation. For DIT, removal of the distinction between symptomatic and asymptomatic lesions was suggested.

Dr. Filippi and his coauthors at eight centers reported that 189 (51%) of the 368 patients had developed clinically definite MS by the last evaluation, which occurred at a median of 50 months from baseline. At 36 months, DIS alone showed high sensitivity in the 2010 McDonald and 2016 MAGNIMS criteria (91% vs 93%, respectively), similar specificity (33% vs 32%), and similar area under the curve values (AUC, 0.62 vs 0.63). Inclusion of symptomatic lesions did not alter performance. The researchers also found that requiring three periventricular lesions reduced sensitivity to 85% and increased specificity to 40%, but did not affect AUC values (AUC, 0.63). When optic nerve evaluation was included, sensitivity was similar (92%), while specificity decreased to 26%, and AUC declined to 0.59.

The 2016 MAGNIMS and 2010 McDonald criteria achieved similar sensitivity, specificity, and AUC values when compared on the performance of DIT criteria and DIS plus DIT criteria.

“For both sets of criteria, specificity was lower than that of previous studies that evaluated the diagnostic performance of the 2010 McDonald criteria,” the authors wrote. “Several factors could help explain our findings, including the different follow-up durations, the statistical methods (eg, using a time-to-event analysis in our study), and the effect of treatment, which might have delayed or prevented the occurrence of the second attack during the study period.” They acknowledged certain limitations of the study, including its retrospective design and the fact that patients were recruited in highly specialized centers, which may have resulted in the selection of patients at higher risk of conversion to clinically definite MS.

MRI Abnormalities May Not Indicate MS

As MS diagnosis evolves, revisions to existing diagnostic criteria have increased sensitivity, thus helping clinicians establish earlier diagnoses. Although the study by Dr. Filippi et al showed that for both sets of MRI criteria, sensitivity was greater than specificity for predicting clinically definite MS, the modest specificity is cause for concern, said Anne H. Cross, MD, Head of the Neuroimmunology (MS) Section, and Robert N. Naismith, MD, Associate Professor of Neurology, both at Washington University in St. Louis, in an accompanying editorial. They cited one study that emphasized the importance of not misdiagnosing other CNS diseases as MS. “In that study at four academic medical centers, 110 people seen over a period of less than 1.5 years were found to have been misdiagnosed,” said Drs. Cross and Naismith. “[Seventy percent] of the 110 individuals had received disease-modifying therapy, and 31% had unnecessary morbidity. Leading factors contributing to erroneous diagnosis in the study included overreliance on MRI abnormalities in patients with nonspecific neurologic symptoms.”

Vascular and other diseases can cause MRI abnormalities that could meet the 2016 MAGNIMS recommendations or the 2010 and 2017 McDonald MRI criteria, the authors continued. For example, patients with monophasic inflammatory and infectious diseases might have gadolinium-enhancing lesions that meet the 2017 McDonald criteria for DIT, which require only the simultaneous presence of gadolinium-enhancing and gadolinium-negative lesions in the proper locations. For patients with an atypical presentation who meet the 2010 and 2017 McDonald or 2016 MAGNIMS recommendations, clinicians should weigh all of the observed imaging features (including the number of periventricular lesions, along with lesion size, shape, and location) to improve diagnostic specificity and help to limit misdiagnoses, they concluded.

—Doug Brunk

Suggested Reading

Cross AH, Naismith RT. Refining the use of MRI to predict multiple sclerosis. Lancet Neurol. 2017 Dec 21 [Epub ahead of print].

Filippi M, Preziosa P, Meani A, et al. Prediction of a multiple sclerosis diagnosis in patients with clinically isolated syndrome using the 2016 MAGNIMS and 2010 McDonald criteria: a retrospective study. Lancet Neurol. 2017 Dec 21 [Epub ahead of print].

The term blueberry muffin rash historically was used to describe the cutaneous manifestations observed in congenital rubella. The term traditionally describes the result of a postnatal dermal extramedullary hematopoiesis. Today, TORCH (toxoplasmosis, other agents, rubella, cytomegalovirus, herpes) infections and plasma cell dyscrasias are all potential causes of extramedullary hematopoiesis. Herein, we present a unique case of a neonate born with a blueberry muffin rash secondary to extramedullary hematopoiesis induced by hereditary spherocytosis.

Case Report

The dermatology department was consulted to evaluate a 2-day-old male neonate born with a “rash.” The patient was born to a 34-year-old gravida 3, para 2, woman at 39 weeks’ gestation. The mother’s prenatal laboratory values were within reference range and ultrasounds were normal, and she was compliant with her prenatal care. She underwent a normal spontaneous vaginal delivery 3 hours after rupture of membranes without complication. The amniotic fluid and umbilical cord both were clear. There was no use of forceps or any other external aiding devices during the delivery. At the time of delivery, the consulting physician noted that the patient had “skin lesions from head to toe.”

The patient’s parents reported that the rash did not seem to cause any discomfort for the patient. In the 24 hours after birth, the parents reported that the erythema seemed to slightly fade. Physical examination revealed many scattered erythematous to violaceous, nonblanching papulonodules affecting the scalp (Figure 1), face, arms, hands (Figure 2A), back (Figure 2B), buttocks, legs, and feet. Some of the papulonodules were soft while others were firm and indurated. Several lesions had a yellowish hue with some overlying crust. There was no mucosal, genital, or ocular involvement. No erosions, ulcerations, petechiae, ecchymoses, or hepatosplenomegaly were noted on examination.

The patient was otherwise healthy with an Apgar score of 8/9 at 1 and 5 minutes. His birth weight, length, and head circumference were within normal limits. There was no evidence of ABO blood group or Rhesus factor incompatibility. His temperature, vital signs, laboratory values (including calcium level and TORCH titers, which included cytomegalovirus, rubella, toxoplasmosis, and herpes simplex virus), and review of systems all were within reference range. A bone survey of the skull, spine, ribs, arms, pelvis, legs, and feet was within normal limits.

The mother’s placenta was sent for pathology and revealed a lymphoplasmacytic chronic deciduitis and acute subchorionitis consistent with a nonspecific inflammatory response, unlikely to be from an infectious etiology.

A 4-mm punch biopsy was taken from the left thigh and revealed a predominately lymphocytic infiltrate with rare eosinophils and erythrocyte precursors (Figure 3). Immunohistochemical staining was performed showing that the majority of the lymphocytes represented T lymphocytes, which stained positive for CD45 and CD3 and negative for S-100, CD1a, CD30, and CD117. There were scattered CD34⁺ cells, and scattered cells stained positive for myeloperoxidase. No significant CD20 immunoreactivity was noted. There were scattered eosinophils and rare normoblasts but no megakaryocytes. A complete blood cell count (CBC) with differential and reticulocyte count was within reference range.

At 1-, 3-, 8-, 12-, and 28-week follow-up visits, the patient continued to grow and feed appropriately. No new lesions developed during this time, and the preexisting lesions continued to fade into slightly hyperpigmented patches without induration (Figure 4). At 6 months of age, a CBC performed at the time of an upper respiratory infection and otitis media revealed normocytic anemia with a hemoglobin level of 9.9 g/dL (reference range, 14.0–17.5 g/dL), a reticulocyte count of 0.8% (reference range, 0.5%–1.5%), and a lactate dehydrogenase level of 424 U/L (reference range, 100–200 U/L). All red blood cell (RBC) indices were within reference range. Flow cytometry, eosin-5-maleimide, and ektacytometry were performed with results consistent with mild hereditary spherocytosis.

Comment

Dermal extramedullary hematopoiesis is a normal component of embryologic development up until the fifth month of gestation.¹ The term blueberry muffin rash typically is used to describe the cutaneous manifestations of extramedullary hematopoiesis, which commonly is caused by a TORCH infection or hematologic dyscrasia.² It has been suggested that the term be expanded to include neoplastic processes (eg, neuroblastomas) and vascular processes (eg, multiple hemangiomas, blue rubber bleb nevus syndrome, glomangiomas, multifocal lymphangionendotheliomatosis), which although not associated with an extramedullary hematopoiesis, can clinically resemble a blueberry muffin rash.

Because of the potential for serious systemic complications, a cause must be sought for all newborns presenting with a blueberry muffin rash. Our patient’s lack of cardiovascular, otic, and ocular involvement combined with a negative TORCH screen and normal CBC strongly suggested against a TORCH infection. In addition, a normal bone survey and CBC, as well as a lack of petechiae, ecchymoses, and hepatosplenomegaly, were evidence against congenital leukemia.³ With the spontaneously resolving lesions and apparent clinical resolution, a bone marrow biopsy was not performed. The skin biopsy revealed negative staining for S-100 and CD1a, making the diagnosis of congenital self-healing reticulohistiocytosis unlikely. No panniculitis was noted and calcium levels were normal, ruling out subcutaneous fat necrosis of the newborn. The predominantly T-cell lymphocytic infiltrate demonstrated on skin biopsy led us to a differential diagnosis of aleukemic leukemia cutis versus idiopathic dermal extramedullary hematopoiesis; however, normocytic anemia was later identified when the patient’s hemoglobin level dropped to 9.9 g/dL. The abnormal eosin-5-maleimide and ektacytometry results unmasked a hereditary spherocytosis.

Hereditary spherocytosis typically is inherited in an autosomal-dominant manner and may be caused by mutations in ankyrin-1, band 3, spectrin, or protein 4.2 on the erythrocyte membrane. It is the third leading cause of hemolytic anemia in newborns and the leading cause of direct Coombs-negative hemolytic anemia requiring blood transfusion in neonates. It is most common in neonates of Northern European ancestry, affecting 1 in every 1000 to 2000 births.⁴ Presentation may range from asymptomatic to severe anemia with hydrops fetalis. Most neonates have an elevated mean corpuscular hemoglobin and low mean corpuscular volume. Acute illness may cause hemolytic or aplastic crises, possibly explaining our patient’s normocytic anemia discovered on a CBC during an episode of an upper respiratory infection and otitis media.

Treatment options for hereditary spherocytosis include phototherapy for jaundiced neonates, folate supplementation, packed erythrocyte transfusions for symptomatic anemia, and recombinant erythropoietin in neonates.⁴ Splenectomy is curative for the majority of patients and requires immunization against Streptococcus pneumoniae, Haemophilus influenzae type b, and Neisseria meningitidis several weeks preoperatively. Patients with symptomatic gallstones may be treated with cholecystectomy at the time of splenectomy or by laparoscopic cholecystectomy, endoscopic sphincterotomy, cholecystostomy, or extracorporeal cholecystolithotripsy.⁵

Although a PubMed search of articles indexed for MEDLINE using the terms dermal hematopoiesis, extramedullary hematopoiesis, hereditary spherocytosis, and blueberry muffin rash yielded only 1 other known case of blueberry muffin rash caused by hereditary spherocytosis,⁶ other case reports demonstrate extramedullary hematopoiesis in hereditary spherocytosis patients in locations other than the skin. Calhoun et al⁷ described a case of a 9-year-old boy with hereditary spherocytosis who presented with jaundice. Pathologic examination revealed a 5-cm suprarenal mass demonstrating extramedullary hematopoiesis.⁷ A case reported by Xiros et al⁸ described a 64-year-old man with a history of hereditary spherocytosis who presented with hemothorax from paravertebral extramedullary hematopoiesis. De Backer et al⁹ reported a case of a 60-year-old man diagnosed with hereditary spherocytosis after an abnormal CBC who was subsequently found to have paravertebral masses containing extramedullary hematopoiesis.

There is one known case of a blueberry muffin rash caused by hereditary spherocytosis.⁶ A female neonate was born at 38 weeks’ gestation with multiple petechiae and faint purpuric papules. Initial complications included intracranial ventricular hemorrhage, hyperbilirubinemia, and anemia requiring blood transfusions on the first day of life. TORCH titers were negative and a skin biopsy demonstrated a diffuse infiltrate of mature RBCs, normoblasts, and pronormoblasts in the reticular dermis. She was healthy until 3 months of age when she had several days of vomiting and diarrhea. Laboratory workup revealed a hematocrit level of 20.5% (reference range, 41%–50%); a reticulocyte count of 22.6% (reference range, 0.5%–1.5%); and a peripheral blood smear demonstrating polychromatophilia, anisocytosis, and spherocytosis. She was then diagnosed with hereditary spherocytosis.⁶

Hereditary spherocytosis is a known, albeit rare, cause of extramedullary hematopoiesis presenting as blueberry muffin rash. Patients with mild hereditary spherocytosis may have a compensated hemolysis without anemia or spherocytes on peripheral smear, which may explain the lack of severe hemolytic anemia or RBC-predominant pathology in our patient.⁵ Argyle and Zone⁶ proposed that severe hemolysis and hypoxia were the cause of extramedullary hematopoiesis in their patient. Because our patient did not experience a notable hemolytic episode until he had an upper respiratory infection and otitis media at 6 months of age, the pathophysiology is less clear; a compensated hemolytic process may underlie the extramedullary hematopoiesis and normal RBC indices.

Regardless of the precise cause of extramedullary hematopoiesis in our patient, this case of a T lymphocyte–dominant cutaneous infiltrate in a patient with mild hereditary spherocytosis is exceptionally rare and leads us to consider that perhaps there are causes of this pathology that are unknown to us.

The term blueberry muffin rash historically was used to describe the cutaneous manifestations observed in congenital rubella. The term traditionally describes the result of a postnatal dermal extramedullary hematopoiesis. Today, TORCH (toxoplasmosis, other agents, rubella, cytomegalovirus, herpes) infections and plasma cell dyscrasias are all potential causes of extramedullary hematopoiesis. Herein, we present a unique case of a neonate born with a blueberry muffin rash secondary to extramedullary hematopoiesis induced by hereditary spherocytosis.

Case Report

The dermatology department was consulted to evaluate a 2-day-old male neonate born with a “rash.” The patient was born to a 34-year-old gravida 3, para 2, woman at 39 weeks’ gestation. The mother’s prenatal laboratory values were within reference range and ultrasounds were normal, and she was compliant with her prenatal care. She underwent a normal spontaneous vaginal delivery 3 hours after rupture of membranes without complication. The amniotic fluid and umbilical cord both were clear. There was no use of forceps or any other external aiding devices during the delivery. At the time of delivery, the consulting physician noted that the patient had “skin lesions from head to toe.”

The patient’s parents reported that the rash did not seem to cause any discomfort for the patient. In the 24 hours after birth, the parents reported that the erythema seemed to slightly fade. Physical examination revealed many scattered erythematous to violaceous, nonblanching papulonodules affecting the scalp (Figure 1), face, arms, hands (Figure 2A), back (Figure 2B), buttocks, legs, and feet. Some of the papulonodules were soft while others were firm and indurated. Several lesions had a yellowish hue with some overlying crust. There was no mucosal, genital, or ocular involvement. No erosions, ulcerations, petechiae, ecchymoses, or hepatosplenomegaly were noted on examination.

The patient was otherwise healthy with an Apgar score of 8/9 at 1 and 5 minutes. His birth weight, length, and head circumference were within normal limits. There was no evidence of ABO blood group or Rhesus factor incompatibility. His temperature, vital signs, laboratory values (including calcium level and TORCH titers, which included cytomegalovirus, rubella, toxoplasmosis, and herpes simplex virus), and review of systems all were within reference range. A bone survey of the skull, spine, ribs, arms, pelvis, legs, and feet was within normal limits.

The mother’s placenta was sent for pathology and revealed a lymphoplasmacytic chronic deciduitis and acute subchorionitis consistent with a nonspecific inflammatory response, unlikely to be from an infectious etiology.

A 4-mm punch biopsy was taken from the left thigh and revealed a predominately lymphocytic infiltrate with rare eosinophils and erythrocyte precursors (Figure 3). Immunohistochemical staining was performed showing that the majority of the lymphocytes represented T lymphocytes, which stained positive for CD45 and CD3 and negative for S-100, CD1a, CD30, and CD117. There were scattered CD34⁺ cells, and scattered cells stained positive for myeloperoxidase. No significant CD20 immunoreactivity was noted. There were scattered eosinophils and rare normoblasts but no megakaryocytes. A complete blood cell count (CBC) with differential and reticulocyte count was within reference range.

At 1-, 3-, 8-, 12-, and 28-week follow-up visits, the patient continued to grow and feed appropriately. No new lesions developed during this time, and the preexisting lesions continued to fade into slightly hyperpigmented patches without induration (Figure 4). At 6 months of age, a CBC performed at the time of an upper respiratory infection and otitis media revealed normocytic anemia with a hemoglobin level of 9.9 g/dL (reference range, 14.0–17.5 g/dL), a reticulocyte count of 0.8% (reference range, 0.5%–1.5%), and a lactate dehydrogenase level of 424 U/L (reference range, 100–200 U/L). All red blood cell (RBC) indices were within reference range. Flow cytometry, eosin-5-maleimide, and ektacytometry were performed with results consistent with mild hereditary spherocytosis.

Comment

Dermal extramedullary hematopoiesis is a normal component of embryologic development up until the fifth month of gestation.¹ The term blueberry muffin rash typically is used to describe the cutaneous manifestations of extramedullary hematopoiesis, which commonly is caused by a TORCH infection or hematologic dyscrasia.² It has been suggested that the term be expanded to include neoplastic processes (eg, neuroblastomas) and vascular processes (eg, multiple hemangiomas, blue rubber bleb nevus syndrome, glomangiomas, multifocal lymphangionendotheliomatosis), which although not associated with an extramedullary hematopoiesis, can clinically resemble a blueberry muffin rash.

Because of the potential for serious systemic complications, a cause must be sought for all newborns presenting with a blueberry muffin rash. Our patient’s lack of cardiovascular, otic, and ocular involvement combined with a negative TORCH screen and normal CBC strongly suggested against a TORCH infection. In addition, a normal bone survey and CBC, as well as a lack of petechiae, ecchymoses, and hepatosplenomegaly, were evidence against congenital leukemia.³ With the spontaneously resolving lesions and apparent clinical resolution, a bone marrow biopsy was not performed. The skin biopsy revealed negative staining for S-100 and CD1a, making the diagnosis of congenital self-healing reticulohistiocytosis unlikely. No panniculitis was noted and calcium levels were normal, ruling out subcutaneous fat necrosis of the newborn. The predominantly T-cell lymphocytic infiltrate demonstrated on skin biopsy led us to a differential diagnosis of aleukemic leukemia cutis versus idiopathic dermal extramedullary hematopoiesis; however, normocytic anemia was later identified when the patient’s hemoglobin level dropped to 9.9 g/dL. The abnormal eosin-5-maleimide and ektacytometry results unmasked a hereditary spherocytosis.

Hereditary spherocytosis typically is inherited in an autosomal-dominant manner and may be caused by mutations in ankyrin-1, band 3, spectrin, or protein 4.2 on the erythrocyte membrane. It is the third leading cause of hemolytic anemia in newborns and the leading cause of direct Coombs-negative hemolytic anemia requiring blood transfusion in neonates. It is most common in neonates of Northern European ancestry, affecting 1 in every 1000 to 2000 births.⁴ Presentation may range from asymptomatic to severe anemia with hydrops fetalis. Most neonates have an elevated mean corpuscular hemoglobin and low mean corpuscular volume. Acute illness may cause hemolytic or aplastic crises, possibly explaining our patient’s normocytic anemia discovered on a CBC during an episode of an upper respiratory infection and otitis media.

Treatment options for hereditary spherocytosis include phototherapy for jaundiced neonates, folate supplementation, packed erythrocyte transfusions for symptomatic anemia, and recombinant erythropoietin in neonates.⁴ Splenectomy is curative for the majority of patients and requires immunization against Streptococcus pneumoniae, Haemophilus influenzae type b, and Neisseria meningitidis several weeks preoperatively. Patients with symptomatic gallstones may be treated with cholecystectomy at the time of splenectomy or by laparoscopic cholecystectomy, endoscopic sphincterotomy, cholecystostomy, or extracorporeal cholecystolithotripsy.⁵

Although a PubMed search of articles indexed for MEDLINE using the terms dermal hematopoiesis, extramedullary hematopoiesis, hereditary spherocytosis, and blueberry muffin rash yielded only 1 other known case of blueberry muffin rash caused by hereditary spherocytosis,⁶ other case reports demonstrate extramedullary hematopoiesis in hereditary spherocytosis patients in locations other than the skin. Calhoun et al⁷ described a case of a 9-year-old boy with hereditary spherocytosis who presented with jaundice. Pathologic examination revealed a 5-cm suprarenal mass demonstrating extramedullary hematopoiesis.⁷ A case reported by Xiros et al⁸ described a 64-year-old man with a history of hereditary spherocytosis who presented with hemothorax from paravertebral extramedullary hematopoiesis. De Backer et al⁹ reported a case of a 60-year-old man diagnosed with hereditary spherocytosis after an abnormal CBC who was subsequently found to have paravertebral masses containing extramedullary hematopoiesis.

There is one known case of a blueberry muffin rash caused by hereditary spherocytosis.⁶ A female neonate was born at 38 weeks’ gestation with multiple petechiae and faint purpuric papules. Initial complications included intracranial ventricular hemorrhage, hyperbilirubinemia, and anemia requiring blood transfusions on the first day of life. TORCH titers were negative and a skin biopsy demonstrated a diffuse infiltrate of mature RBCs, normoblasts, and pronormoblasts in the reticular dermis. She was healthy until 3 months of age when she had several days of vomiting and diarrhea. Laboratory workup revealed a hematocrit level of 20.5% (reference range, 41%–50%); a reticulocyte count of 22.6% (reference range, 0.5%–1.5%); and a peripheral blood smear demonstrating polychromatophilia, anisocytosis, and spherocytosis. She was then diagnosed with hereditary spherocytosis.⁶

Hereditary spherocytosis is a known, albeit rare, cause of extramedullary hematopoiesis presenting as blueberry muffin rash. Patients with mild hereditary spherocytosis may have a compensated hemolysis without anemia or spherocytes on peripheral smear, which may explain the lack of severe hemolytic anemia or RBC-predominant pathology in our patient.⁵ Argyle and Zone⁶ proposed that severe hemolysis and hypoxia were the cause of extramedullary hematopoiesis in their patient. Because our patient did not experience a notable hemolytic episode until he had an upper respiratory infection and otitis media at 6 months of age, the pathophysiology is less clear; a compensated hemolytic process may underlie the extramedullary hematopoiesis and normal RBC indices.

Regardless of the precise cause of extramedullary hematopoiesis in our patient, this case of a T lymphocyte–dominant cutaneous infiltrate in a patient with mild hereditary spherocytosis is exceptionally rare and leads us to consider that perhaps there are causes of this pathology that are unknown to us.

The term blueberry muffin rash historically was used to describe the cutaneous manifestations observed in congenital rubella. The term traditionally describes the result of a postnatal dermal extramedullary hematopoiesis. Today, TORCH (toxoplasmosis, other agents, rubella, cytomegalovirus, herpes) infections and plasma cell dyscrasias are all potential causes of extramedullary hematopoiesis. Herein, we present a unique case of a neonate born with a blueberry muffin rash secondary to extramedullary hematopoiesis induced by hereditary spherocytosis.

Case Report

The dermatology department was consulted to evaluate a 2-day-old male neonate born with a “rash.” The patient was born to a 34-year-old gravida 3, para 2, woman at 39 weeks’ gestation. The mother’s prenatal laboratory values were within reference range and ultrasounds were normal, and she was compliant with her prenatal care. She underwent a normal spontaneous vaginal delivery 3 hours after rupture of membranes without complication. The amniotic fluid and umbilical cord both were clear. There was no use of forceps or any other external aiding devices during the delivery. At the time of delivery, the consulting physician noted that the patient had “skin lesions from head to toe.”

The patient’s parents reported that the rash did not seem to cause any discomfort for the patient. In the 24 hours after birth, the parents reported that the erythema seemed to slightly fade. Physical examination revealed many scattered erythematous to violaceous, nonblanching papulonodules affecting the scalp (Figure 1), face, arms, hands (Figure 2A), back (Figure 2B), buttocks, legs, and feet. Some of the papulonodules were soft while others were firm and indurated. Several lesions had a yellowish hue with some overlying crust. There was no mucosal, genital, or ocular involvement. No erosions, ulcerations, petechiae, ecchymoses, or hepatosplenomegaly were noted on examination.

The patient was otherwise healthy with an Apgar score of 8/9 at 1 and 5 minutes. His birth weight, length, and head circumference were within normal limits. There was no evidence of ABO blood group or Rhesus factor incompatibility. His temperature, vital signs, laboratory values (including calcium level and TORCH titers, which included cytomegalovirus, rubella, toxoplasmosis, and herpes simplex virus), and review of systems all were within reference range. A bone survey of the skull, spine, ribs, arms, pelvis, legs, and feet was within normal limits.

The mother’s placenta was sent for pathology and revealed a lymphoplasmacytic chronic deciduitis and acute subchorionitis consistent with a nonspecific inflammatory response, unlikely to be from an infectious etiology.

A 4-mm punch biopsy was taken from the left thigh and revealed a predominately lymphocytic infiltrate with rare eosinophils and erythrocyte precursors (Figure 3). Immunohistochemical staining was performed showing that the majority of the lymphocytes represented T lymphocytes, which stained positive for CD45 and CD3 and negative for S-100, CD1a, CD30, and CD117. There were scattered CD34⁺ cells, and scattered cells stained positive for myeloperoxidase. No significant CD20 immunoreactivity was noted. There were scattered eosinophils and rare normoblasts but no megakaryocytes. A complete blood cell count (CBC) with differential and reticulocyte count was within reference range.

At 1-, 3-, 8-, 12-, and 28-week follow-up visits, the patient continued to grow and feed appropriately. No new lesions developed during this time, and the preexisting lesions continued to fade into slightly hyperpigmented patches without induration (Figure 4). At 6 months of age, a CBC performed at the time of an upper respiratory infection and otitis media revealed normocytic anemia with a hemoglobin level of 9.9 g/dL (reference range, 14.0–17.5 g/dL), a reticulocyte count of 0.8% (reference range, 0.5%–1.5%), and a lactate dehydrogenase level of 424 U/L (reference range, 100–200 U/L). All red blood cell (RBC) indices were within reference range. Flow cytometry, eosin-5-maleimide, and ektacytometry were performed with results consistent with mild hereditary spherocytosis.

Comment

Dermal extramedullary hematopoiesis is a normal component of embryologic development up until the fifth month of gestation.¹ The term blueberry muffin rash typically is used to describe the cutaneous manifestations of extramedullary hematopoiesis, which commonly is caused by a TORCH infection or hematologic dyscrasia.² It has been suggested that the term be expanded to include neoplastic processes (eg, neuroblastomas) and vascular processes (eg, multiple hemangiomas, blue rubber bleb nevus syndrome, glomangiomas, multifocal lymphangionendotheliomatosis), which although not associated with an extramedullary hematopoiesis, can clinically resemble a blueberry muffin rash.

Because of the potential for serious systemic complications, a cause must be sought for all newborns presenting with a blueberry muffin rash. Our patient’s lack of cardiovascular, otic, and ocular involvement combined with a negative TORCH screen and normal CBC strongly suggested against a TORCH infection. In addition, a normal bone survey and CBC, as well as a lack of petechiae, ecchymoses, and hepatosplenomegaly, were evidence against congenital leukemia.³ With the spontaneously resolving lesions and apparent clinical resolution, a bone marrow biopsy was not performed. The skin biopsy revealed negative staining for S-100 and CD1a, making the diagnosis of congenital self-healing reticulohistiocytosis unlikely. No panniculitis was noted and calcium levels were normal, ruling out subcutaneous fat necrosis of the newborn. The predominantly T-cell lymphocytic infiltrate demonstrated on skin biopsy led us to a differential diagnosis of aleukemic leukemia cutis versus idiopathic dermal extramedullary hematopoiesis; however, normocytic anemia was later identified when the patient’s hemoglobin level dropped to 9.9 g/dL. The abnormal eosin-5-maleimide and ektacytometry results unmasked a hereditary spherocytosis.

Hereditary spherocytosis typically is inherited in an autosomal-dominant manner and may be caused by mutations in ankyrin-1, band 3, spectrin, or protein 4.2 on the erythrocyte membrane. It is the third leading cause of hemolytic anemia in newborns and the leading cause of direct Coombs-negative hemolytic anemia requiring blood transfusion in neonates. It is most common in neonates of Northern European ancestry, affecting 1 in every 1000 to 2000 births.⁴ Presentation may range from asymptomatic to severe anemia with hydrops fetalis. Most neonates have an elevated mean corpuscular hemoglobin and low mean corpuscular volume. Acute illness may cause hemolytic or aplastic crises, possibly explaining our patient’s normocytic anemia discovered on a CBC during an episode of an upper respiratory infection and otitis media.

Treatment options for hereditary spherocytosis include phototherapy for jaundiced neonates, folate supplementation, packed erythrocyte transfusions for symptomatic anemia, and recombinant erythropoietin in neonates.⁴ Splenectomy is curative for the majority of patients and requires immunization against Streptococcus pneumoniae, Haemophilus influenzae type b, and Neisseria meningitidis several weeks preoperatively. Patients with symptomatic gallstones may be treated with cholecystectomy at the time of splenectomy or by laparoscopic cholecystectomy, endoscopic sphincterotomy, cholecystostomy, or extracorporeal cholecystolithotripsy.⁵

Although a PubMed search of articles indexed for MEDLINE using the terms dermal hematopoiesis, extramedullary hematopoiesis, hereditary spherocytosis, and blueberry muffin rash yielded only 1 other known case of blueberry muffin rash caused by hereditary spherocytosis,⁶ other case reports demonstrate extramedullary hematopoiesis in hereditary spherocytosis patients in locations other than the skin. Calhoun et al⁷ described a case of a 9-year-old boy with hereditary spherocytosis who presented with jaundice. Pathologic examination revealed a 5-cm suprarenal mass demonstrating extramedullary hematopoiesis.⁷ A case reported by Xiros et al⁸ described a 64-year-old man with a history of hereditary spherocytosis who presented with hemothorax from paravertebral extramedullary hematopoiesis. De Backer et al⁹ reported a case of a 60-year-old man diagnosed with hereditary spherocytosis after an abnormal CBC who was subsequently found to have paravertebral masses containing extramedullary hematopoiesis.

There is one known case of a blueberry muffin rash caused by hereditary spherocytosis.⁶ A female neonate was born at 38 weeks’ gestation with multiple petechiae and faint purpuric papules. Initial complications included intracranial ventricular hemorrhage, hyperbilirubinemia, and anemia requiring blood transfusions on the first day of life. TORCH titers were negative and a skin biopsy demonstrated a diffuse infiltrate of mature RBCs, normoblasts, and pronormoblasts in the reticular dermis. She was healthy until 3 months of age when she had several days of vomiting and diarrhea. Laboratory workup revealed a hematocrit level of 20.5% (reference range, 41%–50%); a reticulocyte count of 22.6% (reference range, 0.5%–1.5%); and a peripheral blood smear demonstrating polychromatophilia, anisocytosis, and spherocytosis. She was then diagnosed with hereditary spherocytosis.⁶

Hereditary spherocytosis is a known, albeit rare, cause of extramedullary hematopoiesis presenting as blueberry muffin rash. Patients with mild hereditary spherocytosis may have a compensated hemolysis without anemia or spherocytes on peripheral smear, which may explain the lack of severe hemolytic anemia or RBC-predominant pathology in our patient.⁵ Argyle and Zone⁶ proposed that severe hemolysis and hypoxia were the cause of extramedullary hematopoiesis in their patient. Because our patient did not experience a notable hemolytic episode until he had an upper respiratory infection and otitis media at 6 months of age, the pathophysiology is less clear; a compensated hemolytic process may underlie the extramedullary hematopoiesis and normal RBC indices.

Regardless of the precise cause of extramedullary hematopoiesis in our patient, this case of a T lymphocyte–dominant cutaneous infiltrate in a patient with mild hereditary spherocytosis is exceptionally rare and leads us to consider that perhaps there are causes of this pathology that are unknown to us.