Infectious Diseases

Antibiotics are associated with increased large intestinal proteolytic activity and gut barrier disruption, thereby raising the risk of chronic colitis in susceptible individuals, a recent study found.

Although the association between antibiotics and chronic colitis has been previously described, this is the first study to demonstrate the causative role of high proteolytic activity, reported lead author Hongsup Yoon, PhD, chair of nutrition and immunology at Technische Universität München in Freising-Weihenstephan, Germany, and colleagues. The team’s experiments support development of antiproteolytic strategies in susceptible humans.

“In the context of IBD, several clinical studies have already revealed that early and frequent antibiotic therapies, especially metronidazole or fluoroquinolone treatments, are associated with increased risk for Crohn’s disease,” the authors wrote in Cellular and Molecular Gastroenterology and Hepatology. “However, the causal role of antibiotic therapies in the disease development and the mechanisms underlying this [potentially] serious long-term adverse effect of antibiotics on the intestinal immune homeostasis remain unknown.”

Previous studies have shown that antibiotic therapy often causes high luminal proteolytic activity in the large intestine, likely because of the elimination of antiproteolytic bacteria that normally control pancreatic protease levels. Other studies have shown that exposing murine colonic mucosa to fecal supernatants with high proteolytic activity increases gut barrier permeability, which triggers chronic inflammation via translocation of luminal antigens.

“In view of these data,” the authors wrote, “we hypothesized that the antibiotic-increased proteolytic activity in the large intestine is a relevant risk factor for the development of colitis in susceptible organisms.”

The first component of the study used transwell experiments to evaluate the impact of high proteolytic activity on gut barrier integrity. High proteolytic activity was induced by several antibiotics, including fluoroquinolones with or without an imidazole (ciprofloxacin and levofloxacin plus or minus metronidazole), a beta-lactam (amoxicillin + clavulanate), cephalosporins with or without a macrolide (azithromycin and ceftriaxone plus or minus azithromycin), and a rifamycin (rifaximin).

“All tested antibiotic classes mediated a major proteolytic activity increase in some patients but not in others,” the authors wrote, “demonstrating individual-specific vulnerability of the intestinal microbiota toward antibiotic therapies, which is likely caused by the high interindividual variability of human microbial ecosystems.”

One-quarter of patients had a 400% or greater increase in large intestinal proteolytic activity following antibiotic therapy, and several had an increase greater than 900%. Analysis indicated that proteolytic activity was caused by pancreatic proteases such as chymotrypsin and trypsin.

Subsequent cell line testing showed that stool supernatants with high proteolytic activity damaged the epithelial barrier, but samples with low proteolytic activity did not. Of note, the negative impact of high proteolytic activity on epithelial cells could be mitigated by incubating stool supernatants with a serine protease inhibitor.

In analogous experiments, mice were given a combination of vancomycin and metronidazole (V/M). In contrast with the various proteolytic activity levels observed in humans, all mice had high proteolytic activity levels following treatment, suggesting that V/M eliminated almost all antiproteolytic bacteria.

The loss of antiproteolytic bacteria was clarified by cecal microbiota transplantation tests. Transplants from untreated mice were capable of normalizing proteolytic activity levels in germ-free mice (which have high proteolytic activity levels), but transplants from V/M-treated mice were ineffective, suggesting a near-total loss of antiproteolytic bacteria. The identity of these antiproteolytic bacteria remains a mystery.

“Although our data are in line with published literature suggesting specific strains of the order Bacteroidales to play a role in the physiological inactivation of pancreatic proteases,” the authors wrote, “the identity of relevant antiproteolytic species/strains remains to be elucidated.”

The next part of the study involved wild-type and interleukin (IL)-10–/– mice, the latter of which serves as a model of human colitis. Both types of mice were given V/M with or without an oral serine protease inhibitor, a potential therapy intended to limit proteolytic activity and associated intestinal barrier damage.

Although both wild-type and IL-10–/– mice had increased intestinal permeability after V/M treatment, only IL-10–/– mice showed lasting inflammation. Of note, coadministration of an oral serine protease inhibitor with V/M protected against colitis in IL-10–/– mice.

The protective benefit of an oral serine protease inhibitor in IL-10–/– mice prompts the development of antiproteolytic strategies in humans. These would target “large intestinal proteolytic activity [e.g., oral administration of encapsulated serine protease inhibitors, commensal antiproteolytic bacteria, or genetically modified bacteria expressing protease inhibitors] to protect the large intestinal mucosa from adverse effects of antibiotic-induced or diarrhea-induced high proteolytic activity,” the authors wrote.

The study was funded by the Deutscher Akademischer Austauschdienst. No conflicts of interest were reported.

SOURCE: Yoon H-S et al. Cell Mol Gastroenterol Hepatol. 2018 May 29. doi: 10.1016/j.jcmgh.2018.05.008.

Antibiotics are associated with increased large intestinal proteolytic activity and gut barrier disruption, thereby raising the risk of chronic colitis in susceptible individuals, a recent study found.

Although the association between antibiotics and chronic colitis has been previously described, this is the first study to demonstrate the causative role of high proteolytic activity, reported lead author Hongsup Yoon, PhD, chair of nutrition and immunology at Technische Universität München in Freising-Weihenstephan, Germany, and colleagues. The team’s experiments support development of antiproteolytic strategies in susceptible humans.

“In the context of IBD, several clinical studies have already revealed that early and frequent antibiotic therapies, especially metronidazole or fluoroquinolone treatments, are associated with increased risk for Crohn’s disease,” the authors wrote in Cellular and Molecular Gastroenterology and Hepatology. “However, the causal role of antibiotic therapies in the disease development and the mechanisms underlying this [potentially] serious long-term adverse effect of antibiotics on the intestinal immune homeostasis remain unknown.”

Previous studies have shown that antibiotic therapy often causes high luminal proteolytic activity in the large intestine, likely because of the elimination of antiproteolytic bacteria that normally control pancreatic protease levels. Other studies have shown that exposing murine colonic mucosa to fecal supernatants with high proteolytic activity increases gut barrier permeability, which triggers chronic inflammation via translocation of luminal antigens.

“In view of these data,” the authors wrote, “we hypothesized that the antibiotic-increased proteolytic activity in the large intestine is a relevant risk factor for the development of colitis in susceptible organisms.”

The first component of the study used transwell experiments to evaluate the impact of high proteolytic activity on gut barrier integrity. High proteolytic activity was induced by several antibiotics, including fluoroquinolones with or without an imidazole (ciprofloxacin and levofloxacin plus or minus metronidazole), a beta-lactam (amoxicillin + clavulanate), cephalosporins with or without a macrolide (azithromycin and ceftriaxone plus or minus azithromycin), and a rifamycin (rifaximin).

“All tested antibiotic classes mediated a major proteolytic activity increase in some patients but not in others,” the authors wrote, “demonstrating individual-specific vulnerability of the intestinal microbiota toward antibiotic therapies, which is likely caused by the high interindividual variability of human microbial ecosystems.”

One-quarter of patients had a 400% or greater increase in large intestinal proteolytic activity following antibiotic therapy, and several had an increase greater than 900%. Analysis indicated that proteolytic activity was caused by pancreatic proteases such as chymotrypsin and trypsin.

Subsequent cell line testing showed that stool supernatants with high proteolytic activity damaged the epithelial barrier, but samples with low proteolytic activity did not. Of note, the negative impact of high proteolytic activity on epithelial cells could be mitigated by incubating stool supernatants with a serine protease inhibitor.

In analogous experiments, mice were given a combination of vancomycin and metronidazole (V/M). In contrast with the various proteolytic activity levels observed in humans, all mice had high proteolytic activity levels following treatment, suggesting that V/M eliminated almost all antiproteolytic bacteria.

The loss of antiproteolytic bacteria was clarified by cecal microbiota transplantation tests. Transplants from untreated mice were capable of normalizing proteolytic activity levels in germ-free mice (which have high proteolytic activity levels), but transplants from V/M-treated mice were ineffective, suggesting a near-total loss of antiproteolytic bacteria. The identity of these antiproteolytic bacteria remains a mystery.

“Although our data are in line with published literature suggesting specific strains of the order Bacteroidales to play a role in the physiological inactivation of pancreatic proteases,” the authors wrote, “the identity of relevant antiproteolytic species/strains remains to be elucidated.”

The next part of the study involved wild-type and interleukin (IL)-10–/– mice, the latter of which serves as a model of human colitis. Both types of mice were given V/M with or without an oral serine protease inhibitor, a potential therapy intended to limit proteolytic activity and associated intestinal barrier damage.

Although both wild-type and IL-10–/– mice had increased intestinal permeability after V/M treatment, only IL-10–/– mice showed lasting inflammation. Of note, coadministration of an oral serine protease inhibitor with V/M protected against colitis in IL-10–/– mice.

The protective benefit of an oral serine protease inhibitor in IL-10–/– mice prompts the development of antiproteolytic strategies in humans. These would target “large intestinal proteolytic activity [e.g., oral administration of encapsulated serine protease inhibitors, commensal antiproteolytic bacteria, or genetically modified bacteria expressing protease inhibitors] to protect the large intestinal mucosa from adverse effects of antibiotic-induced or diarrhea-induced high proteolytic activity,” the authors wrote.

The study was funded by the Deutscher Akademischer Austauschdienst. No conflicts of interest were reported.

SOURCE: Yoon H-S et al. Cell Mol Gastroenterol Hepatol. 2018 May 29. doi: 10.1016/j.jcmgh.2018.05.008.

Antibiotics are associated with increased large intestinal proteolytic activity and gut barrier disruption, thereby raising the risk of chronic colitis in susceptible individuals, a recent study found.

Although the association between antibiotics and chronic colitis has been previously described, this is the first study to demonstrate the causative role of high proteolytic activity, reported lead author Hongsup Yoon, PhD, chair of nutrition and immunology at Technische Universität München in Freising-Weihenstephan, Germany, and colleagues. The team’s experiments support development of antiproteolytic strategies in susceptible humans.

“In the context of IBD, several clinical studies have already revealed that early and frequent antibiotic therapies, especially metronidazole or fluoroquinolone treatments, are associated with increased risk for Crohn’s disease,” the authors wrote in Cellular and Molecular Gastroenterology and Hepatology. “However, the causal role of antibiotic therapies in the disease development and the mechanisms underlying this [potentially] serious long-term adverse effect of antibiotics on the intestinal immune homeostasis remain unknown.”

Previous studies have shown that antibiotic therapy often causes high luminal proteolytic activity in the large intestine, likely because of the elimination of antiproteolytic bacteria that normally control pancreatic protease levels. Other studies have shown that exposing murine colonic mucosa to fecal supernatants with high proteolytic activity increases gut barrier permeability, which triggers chronic inflammation via translocation of luminal antigens.

“In view of these data,” the authors wrote, “we hypothesized that the antibiotic-increased proteolytic activity in the large intestine is a relevant risk factor for the development of colitis in susceptible organisms.”

The first component of the study used transwell experiments to evaluate the impact of high proteolytic activity on gut barrier integrity. High proteolytic activity was induced by several antibiotics, including fluoroquinolones with or without an imidazole (ciprofloxacin and levofloxacin plus or minus metronidazole), a beta-lactam (amoxicillin + clavulanate), cephalosporins with or without a macrolide (azithromycin and ceftriaxone plus or minus azithromycin), and a rifamycin (rifaximin).

“All tested antibiotic classes mediated a major proteolytic activity increase in some patients but not in others,” the authors wrote, “demonstrating individual-specific vulnerability of the intestinal microbiota toward antibiotic therapies, which is likely caused by the high interindividual variability of human microbial ecosystems.”

One-quarter of patients had a 400% or greater increase in large intestinal proteolytic activity following antibiotic therapy, and several had an increase greater than 900%. Analysis indicated that proteolytic activity was caused by pancreatic proteases such as chymotrypsin and trypsin.

Subsequent cell line testing showed that stool supernatants with high proteolytic activity damaged the epithelial barrier, but samples with low proteolytic activity did not. Of note, the negative impact of high proteolytic activity on epithelial cells could be mitigated by incubating stool supernatants with a serine protease inhibitor.

In analogous experiments, mice were given a combination of vancomycin and metronidazole (V/M). In contrast with the various proteolytic activity levels observed in humans, all mice had high proteolytic activity levels following treatment, suggesting that V/M eliminated almost all antiproteolytic bacteria.

The loss of antiproteolytic bacteria was clarified by cecal microbiota transplantation tests. Transplants from untreated mice were capable of normalizing proteolytic activity levels in germ-free mice (which have high proteolytic activity levels), but transplants from V/M-treated mice were ineffective, suggesting a near-total loss of antiproteolytic bacteria. The identity of these antiproteolytic bacteria remains a mystery.

“Although our data are in line with published literature suggesting specific strains of the order Bacteroidales to play a role in the physiological inactivation of pancreatic proteases,” the authors wrote, “the identity of relevant antiproteolytic species/strains remains to be elucidated.”

The next part of the study involved wild-type and interleukin (IL)-10–/– mice, the latter of which serves as a model of human colitis. Both types of mice were given V/M with or without an oral serine protease inhibitor, a potential therapy intended to limit proteolytic activity and associated intestinal barrier damage.

Although both wild-type and IL-10–/– mice had increased intestinal permeability after V/M treatment, only IL-10–/– mice showed lasting inflammation. Of note, coadministration of an oral serine protease inhibitor with V/M protected against colitis in IL-10–/– mice.

The protective benefit of an oral serine protease inhibitor in IL-10–/– mice prompts the development of antiproteolytic strategies in humans. These would target “large intestinal proteolytic activity [e.g., oral administration of encapsulated serine protease inhibitors, commensal antiproteolytic bacteria, or genetically modified bacteria expressing protease inhibitors] to protect the large intestinal mucosa from adverse effects of antibiotic-induced or diarrhea-induced high proteolytic activity,” the authors wrote.

The study was funded by the Deutscher Akademischer Austauschdienst. No conflicts of interest were reported.

SOURCE: Yoon H-S et al. Cell Mol Gastroenterol Hepatol. 2018 May 29. doi: 10.1016/j.jcmgh.2018.05.008.

Case Report

An 82-year-old woman presented to the clinic with a rash on the face that had been present for a few months. She denied any treatment or prior occurrence. Her medical history was remarkable for non-Hodgkin lymphoma that had been successfully treated with chemotherapy 4 years prior. Additionally, she recently had been diagnosed with stage IV colon cancer. She reported that surgery had been scheduled and she would start adjuvant chemotherapy soon after.

On physical examination she exhibited perioral and perinasal erythematous papules with sparing of the vermilion border. A diagnosis of perioral dermatitis was made, and she was started on topical metronidazole. At 1-month follow-up, her condition had slightly worsened and she was subsequently started on doxycycline. When she returned to the clinic again the following month, physical examination revealed agminated folliculocentric papules with central spicules on the face, nose, ears, upper extremities (Figure 1), and trunk. The differential diagnosis included multiple minute digitate hyperkeratosis, spiculosis of multiple myeloma, and trichodysplasia spinulosa (TS).

Comment

History and Presentation
Trichodysplasia spinulosa was first recognized as hairlike hyperkeratosis.¹ The name by which it is currently known was later championed by Haycox et al.² They reported a case of a 44-year-old man who underwent a combined renal-pancreas transplant and while taking immunosuppressive medication developed erythematous papules with follicular spinous processes and progressive alopecia.² Other synonymous terms used for this condition include pilomatrix dysplasia, cyclosporine-induced folliculodystrophy, virus-associated trichodysplasia,³ and follicular dystrophy of immunosuppression.⁴ Trichodysplasia spinulosa can affect both adult and pediatric immunocompromised patients, including organ transplant recipients on immunosuppressants and cancer patients on chemotherapy.³ The condition also has been reported to precede the recurrence of lymphoma.⁵

Etiology
The connection of TS with a viral etiology was first demonstrated in 1999, and subsequently it was confirmed to be a polyomavirus.² The family name of Polyomaviridae possesses a Greek derivation with poly- meaning many and -oma meaning cancer.³ This name was given after the polyomavirus induced multiple tumors in mice.^3,6 This viral family consists of multiple naked viruses with a surrounding icosahedral capsid containing 3 structural proteins known as VP1, VP2, and VP3. Their life cycle is characterized by early and late phases with respective early and late protein formation.³

Polyomavirus infections maintain an asymptomatic and latent course in immunocompetent patients.⁷ The prevalence and manifestation of these viruses change when the host’s immune system is altered. The first identified JC virus and BK virus of the same family have been found at increased frequencies in blood and lymphoid tissue during host immunosuppression.⁶ Moreover, the Merkel cell polyomavirus detected in Merkel cell carcinoma is well documented in the dermatologic literature.^6,8

A specific polyomavirus has been implicated in the majority of TS cases and has subsequently received the name of TS polyomavirus.⁹ As a polyomavirus, it similarly produces capsid antigens and large/small T antigens. Among the viral protein antigens produced, the large tumor or LT antigen represents one of the most potent viral proteins. It has been postulated to inhibit the retinoblastoma family of proteins, leading to increased inner root sheath cells that allow for further viral replication.^9,10

The disease presents with folliculocentric papules localized mainly on the central face and ears, which grow central keratin spines or spicules that can become 1 to 3 mm in length. Coinciding alopecia and madarosis also may be present.⁹

Diagnosis

Histologic examination reveals abnormal follicular maturation and distension. Additionally, increased proliferation and amount of trichohyalin is seen within the inner root sheath cells. Further testing via viral culture, polymerase chain reaction, electron microscopy, or immunohistochemical stains can confirm the diagnosis. Such testing may not be warranted in all cases given that classic clinical findings coupled with routine histopathology staining can provide enough evidence.^10,11

Management

Currently, a universal successful treatment for TS does not exist. There have been anecdotal successes reported with topical medications such as cidofovir ointment 1%, acyclovir combined with 2-deoxy-D-glucose and epigallocatechin, corticosteroids, topical tacrolimus, topical retinoids, and imiquimod. Additionally, success has been seen with oral minocycline, oral retinoids, valacyclovir, and valganciclovir, with the latter showing the best results. Patients also have shown improvement after modifying their immunosuppressive treatment regimen.^10,12

Conclusion

Given the previously published case of TS preceding the recurrence of lymphoma,⁵ we notified our patient’s oncologist of this potential risk. Her history of lymphoma and immunosuppressive treatment 4 years prior may represent the etiology of the cutaneous presentation; however, the TS with concurrent colon cancer presented prior to starting immunosuppressive therapy, suggesting that it also may have been a paraneoplastic process and not just a sign of immunosuppression. Therefore, we recommend that patients who present with TS should be evaluated for underlying malignancy if not already diagnosed.

Case Report

An 82-year-old woman presented to the clinic with a rash on the face that had been present for a few months. She denied any treatment or prior occurrence. Her medical history was remarkable for non-Hodgkin lymphoma that had been successfully treated with chemotherapy 4 years prior. Additionally, she recently had been diagnosed with stage IV colon cancer. She reported that surgery had been scheduled and she would start adjuvant chemotherapy soon after.

On physical examination she exhibited perioral and perinasal erythematous papules with sparing of the vermilion border. A diagnosis of perioral dermatitis was made, and she was started on topical metronidazole. At 1-month follow-up, her condition had slightly worsened and she was subsequently started on doxycycline. When she returned to the clinic again the following month, physical examination revealed agminated folliculocentric papules with central spicules on the face, nose, ears, upper extremities (Figure 1), and trunk. The differential diagnosis included multiple minute digitate hyperkeratosis, spiculosis of multiple myeloma, and trichodysplasia spinulosa (TS).

Comment

History and Presentation
Trichodysplasia spinulosa was first recognized as hairlike hyperkeratosis.¹ The name by which it is currently known was later championed by Haycox et al.² They reported a case of a 44-year-old man who underwent a combined renal-pancreas transplant and while taking immunosuppressive medication developed erythematous papules with follicular spinous processes and progressive alopecia.² Other synonymous terms used for this condition include pilomatrix dysplasia, cyclosporine-induced folliculodystrophy, virus-associated trichodysplasia,³ and follicular dystrophy of immunosuppression.⁴ Trichodysplasia spinulosa can affect both adult and pediatric immunocompromised patients, including organ transplant recipients on immunosuppressants and cancer patients on chemotherapy.³ The condition also has been reported to precede the recurrence of lymphoma.⁵

Etiology
The connection of TS with a viral etiology was first demonstrated in 1999, and subsequently it was confirmed to be a polyomavirus.² The family name of Polyomaviridae possesses a Greek derivation with poly- meaning many and -oma meaning cancer.³ This name was given after the polyomavirus induced multiple tumors in mice.^3,6 This viral family consists of multiple naked viruses with a surrounding icosahedral capsid containing 3 structural proteins known as VP1, VP2, and VP3. Their life cycle is characterized by early and late phases with respective early and late protein formation.³

Polyomavirus infections maintain an asymptomatic and latent course in immunocompetent patients.⁷ The prevalence and manifestation of these viruses change when the host’s immune system is altered. The first identified JC virus and BK virus of the same family have been found at increased frequencies in blood and lymphoid tissue during host immunosuppression.⁶ Moreover, the Merkel cell polyomavirus detected in Merkel cell carcinoma is well documented in the dermatologic literature.^6,8

A specific polyomavirus has been implicated in the majority of TS cases and has subsequently received the name of TS polyomavirus.⁹ As a polyomavirus, it similarly produces capsid antigens and large/small T antigens. Among the viral protein antigens produced, the large tumor or LT antigen represents one of the most potent viral proteins. It has been postulated to inhibit the retinoblastoma family of proteins, leading to increased inner root sheath cells that allow for further viral replication.^9,10

The disease presents with folliculocentric papules localized mainly on the central face and ears, which grow central keratin spines or spicules that can become 1 to 3 mm in length. Coinciding alopecia and madarosis also may be present.⁹

Diagnosis

Histologic examination reveals abnormal follicular maturation and distension. Additionally, increased proliferation and amount of trichohyalin is seen within the inner root sheath cells. Further testing via viral culture, polymerase chain reaction, electron microscopy, or immunohistochemical stains can confirm the diagnosis. Such testing may not be warranted in all cases given that classic clinical findings coupled with routine histopathology staining can provide enough evidence.^10,11

Management

Currently, a universal successful treatment for TS does not exist. There have been anecdotal successes reported with topical medications such as cidofovir ointment 1%, acyclovir combined with 2-deoxy-D-glucose and epigallocatechin, corticosteroids, topical tacrolimus, topical retinoids, and imiquimod. Additionally, success has been seen with oral minocycline, oral retinoids, valacyclovir, and valganciclovir, with the latter showing the best results. Patients also have shown improvement after modifying their immunosuppressive treatment regimen.^10,12

Conclusion

Given the previously published case of TS preceding the recurrence of lymphoma,⁵ we notified our patient’s oncologist of this potential risk. Her history of lymphoma and immunosuppressive treatment 4 years prior may represent the etiology of the cutaneous presentation; however, the TS with concurrent colon cancer presented prior to starting immunosuppressive therapy, suggesting that it also may have been a paraneoplastic process and not just a sign of immunosuppression. Therefore, we recommend that patients who present with TS should be evaluated for underlying malignancy if not already diagnosed.

Case Report

An 82-year-old woman presented to the clinic with a rash on the face that had been present for a few months. She denied any treatment or prior occurrence. Her medical history was remarkable for non-Hodgkin lymphoma that had been successfully treated with chemotherapy 4 years prior. Additionally, she recently had been diagnosed with stage IV colon cancer. She reported that surgery had been scheduled and she would start adjuvant chemotherapy soon after.

On physical examination she exhibited perioral and perinasal erythematous papules with sparing of the vermilion border. A diagnosis of perioral dermatitis was made, and she was started on topical metronidazole. At 1-month follow-up, her condition had slightly worsened and she was subsequently started on doxycycline. When she returned to the clinic again the following month, physical examination revealed agminated folliculocentric papules with central spicules on the face, nose, ears, upper extremities (Figure 1), and trunk. The differential diagnosis included multiple minute digitate hyperkeratosis, spiculosis of multiple myeloma, and trichodysplasia spinulosa (TS).

Comment

History and Presentation
Trichodysplasia spinulosa was first recognized as hairlike hyperkeratosis.¹ The name by which it is currently known was later championed by Haycox et al.² They reported a case of a 44-year-old man who underwent a combined renal-pancreas transplant and while taking immunosuppressive medication developed erythematous papules with follicular spinous processes and progressive alopecia.² Other synonymous terms used for this condition include pilomatrix dysplasia, cyclosporine-induced folliculodystrophy, virus-associated trichodysplasia,³ and follicular dystrophy of immunosuppression.⁴ Trichodysplasia spinulosa can affect both adult and pediatric immunocompromised patients, including organ transplant recipients on immunosuppressants and cancer patients on chemotherapy.³ The condition also has been reported to precede the recurrence of lymphoma.⁵

Etiology
The connection of TS with a viral etiology was first demonstrated in 1999, and subsequently it was confirmed to be a polyomavirus.² The family name of Polyomaviridae possesses a Greek derivation with poly- meaning many and -oma meaning cancer.³ This name was given after the polyomavirus induced multiple tumors in mice.^3,6 This viral family consists of multiple naked viruses with a surrounding icosahedral capsid containing 3 structural proteins known as VP1, VP2, and VP3. Their life cycle is characterized by early and late phases with respective early and late protein formation.³

Polyomavirus infections maintain an asymptomatic and latent course in immunocompetent patients.⁷ The prevalence and manifestation of these viruses change when the host’s immune system is altered. The first identified JC virus and BK virus of the same family have been found at increased frequencies in blood and lymphoid tissue during host immunosuppression.⁶ Moreover, the Merkel cell polyomavirus detected in Merkel cell carcinoma is well documented in the dermatologic literature.^6,8

A specific polyomavirus has been implicated in the majority of TS cases and has subsequently received the name of TS polyomavirus.⁹ As a polyomavirus, it similarly produces capsid antigens and large/small T antigens. Among the viral protein antigens produced, the large tumor or LT antigen represents one of the most potent viral proteins. It has been postulated to inhibit the retinoblastoma family of proteins, leading to increased inner root sheath cells that allow for further viral replication.^9,10

The disease presents with folliculocentric papules localized mainly on the central face and ears, which grow central keratin spines or spicules that can become 1 to 3 mm in length. Coinciding alopecia and madarosis also may be present.⁹

Diagnosis

Histologic examination reveals abnormal follicular maturation and distension. Additionally, increased proliferation and amount of trichohyalin is seen within the inner root sheath cells. Further testing via viral culture, polymerase chain reaction, electron microscopy, or immunohistochemical stains can confirm the diagnosis. Such testing may not be warranted in all cases given that classic clinical findings coupled with routine histopathology staining can provide enough evidence.^10,11

Management

Currently, a universal successful treatment for TS does not exist. There have been anecdotal successes reported with topical medications such as cidofovir ointment 1%, acyclovir combined with 2-deoxy-D-glucose and epigallocatechin, corticosteroids, topical tacrolimus, topical retinoids, and imiquimod. Additionally, success has been seen with oral minocycline, oral retinoids, valacyclovir, and valganciclovir, with the latter showing the best results. Patients also have shown improvement after modifying their immunosuppressive treatment regimen.^10,12

Conclusion

Given the previously published case of TS preceding the recurrence of lymphoma,⁵ we notified our patient’s oncologist of this potential risk. Her history of lymphoma and immunosuppressive treatment 4 years prior may represent the etiology of the cutaneous presentation; however, the TS with concurrent colon cancer presented prior to starting immunosuppressive therapy, suggesting that it also may have been a paraneoplastic process and not just a sign of immunosuppression. Therefore, we recommend that patients who present with TS should be evaluated for underlying malignancy if not already diagnosed.

ATLANTA – Postlicensure surveillance of a trivalent adjuvanted influenza vaccine approved in 2015 for adults aged 65 years and older revealed no new or unexpected patterns of adverse events, according to an analysis of reports to the Vaccine Adverse Event Reporting System (VAERS) during July 2016 through March 2018.

Wavebreakmedia/Thinkstock

VAERS received 630 reports related to the vaccine (aIIV3; FLUAD) during the study period, of which 521 involved adults aged 65 years and older.

“Eighteen (3%) were serious reports, including two death reports (0.4%), all in adults aged [at least] 65 years,” Penina Haber and her colleagues at the Immunization Safety Office at the Centers for Disease Control and Prevention reported in a poster at the International Conference on Emerging Infectious Diseases.

The deaths included a 75-year-old man who died from Sjögren’s syndrome and a 65-year-old man who died from a myocardial infarction. The other serious events included five neurologic disorders (two cases of Guillain-Barré syndrome and one each of Bell’s palsy, Bickerstaff encephalitis, and lower-extremity weakness), five musculoskeletal and connective tissue disorders (three with shoulder pain and two with arm pain), three general disorders and administration site conditions (two cases of fever/chills and one case of cellulitis/bursitis), and one case each of a gastrointestinal disorder (acute diarrhea/gastroenteritis), an injury (a fall), and a skin/subcutaneous tissue disorder (keratosis pilaris rubra), according to the investigators.

There were no reports of anaphylaxis.

For the sake of comparison, the investigators also looked at reports associated with IIV3-HD and IIV3/IIV4 vaccines in adults aged 65 years and older during the same time period; they found that patient characteristics and reported events were similar for all the vaccines. For example, the percentages of reports involving patients aged 65 years and older were 65% or 66% for each, and those involving patients aged 75-84 years were 27%-29%. Further, 0.2%-0.6% of reports for each vaccine involved death.

The most frequently reported events for aIIV3, IIV3-HD, and IIV3/IIV4, respectively, were extremity pain (21%, 17%, and 15%, respectively), injection site erythema (18%, 19%, and 15%), and injection site pain (15%, 16%, and 16%), they said.

The aIIV3 vaccine – the first seasonal inactivated trivalent influenza vaccine produced from three influenza virus strains (two subtype A strains and one type B strain) – was approved by the Food and Drug Administration in 2015 for adults aged 65 years and older. It was the first influenza vaccine containing the adjuvant MF59 – a purified oil-in-water emulsion of squalene oil added to boost immune response in that population. Its safety was assessed in 15 randomized, controlled clinical studies, and several trials in older adults supported its efficacy and safety over nonadjuvanted influenza vaccines, the investigators reported. They noted that the Advisory Committee on Immunization Practices (ACIP) recommended the vaccine as an option for routine use in adults aged 65 years and older during the 2016-2017 flu seasons.

For the 2018-2019 flu season, ACIP determined that “For persons aged ≥65 years, any age-appropriate IIV formulation (standard-dose or high-dose, trivalent or quadrivalent, unadjuvanted or adjuvanted) or RIV4 are acceptable options.”

The findings of the analysis of the 2017-2018 flu season data are consistent with prelicensure studies, Ms. Haber and her colleagues concluded, noting that data mining did not detect disproportional reporting of any unexpected adverse event.

“[There were] no safety concerns following aIIV3 when compared to the nonadjuvanted influenza vaccines (IIV3-HD or IIV3/IIV4),” they wrote, adding that the “CDC and FDA will continue to monitor and ensure the safety of aIIV3.”

Ms. Haber reported having no disclosures

[email protected]

SOURCE: Haber P et al. ICEID 2018, Board 320.

ATLANTA – Postlicensure surveillance of a trivalent adjuvanted influenza vaccine approved in 2015 for adults aged 65 years and older revealed no new or unexpected patterns of adverse events, according to an analysis of reports to the Vaccine Adverse Event Reporting System (VAERS) during July 2016 through March 2018.

Wavebreakmedia/Thinkstock

VAERS received 630 reports related to the vaccine (aIIV3; FLUAD) during the study period, of which 521 involved adults aged 65 years and older.

“Eighteen (3%) were serious reports, including two death reports (0.4%), all in adults aged [at least] 65 years,” Penina Haber and her colleagues at the Immunization Safety Office at the Centers for Disease Control and Prevention reported in a poster at the International Conference on Emerging Infectious Diseases.

The deaths included a 75-year-old man who died from Sjögren’s syndrome and a 65-year-old man who died from a myocardial infarction. The other serious events included five neurologic disorders (two cases of Guillain-Barré syndrome and one each of Bell’s palsy, Bickerstaff encephalitis, and lower-extremity weakness), five musculoskeletal and connective tissue disorders (three with shoulder pain and two with arm pain), three general disorders and administration site conditions (two cases of fever/chills and one case of cellulitis/bursitis), and one case each of a gastrointestinal disorder (acute diarrhea/gastroenteritis), an injury (a fall), and a skin/subcutaneous tissue disorder (keratosis pilaris rubra), according to the investigators.

There were no reports of anaphylaxis.

For the sake of comparison, the investigators also looked at reports associated with IIV3-HD and IIV3/IIV4 vaccines in adults aged 65 years and older during the same time period; they found that patient characteristics and reported events were similar for all the vaccines. For example, the percentages of reports involving patients aged 65 years and older were 65% or 66% for each, and those involving patients aged 75-84 years were 27%-29%. Further, 0.2%-0.6% of reports for each vaccine involved death.

The most frequently reported events for aIIV3, IIV3-HD, and IIV3/IIV4, respectively, were extremity pain (21%, 17%, and 15%, respectively), injection site erythema (18%, 19%, and 15%), and injection site pain (15%, 16%, and 16%), they said.

The aIIV3 vaccine – the first seasonal inactivated trivalent influenza vaccine produced from three influenza virus strains (two subtype A strains and one type B strain) – was approved by the Food and Drug Administration in 2015 for adults aged 65 years and older. It was the first influenza vaccine containing the adjuvant MF59 – a purified oil-in-water emulsion of squalene oil added to boost immune response in that population. Its safety was assessed in 15 randomized, controlled clinical studies, and several trials in older adults supported its efficacy and safety over nonadjuvanted influenza vaccines, the investigators reported. They noted that the Advisory Committee on Immunization Practices (ACIP) recommended the vaccine as an option for routine use in adults aged 65 years and older during the 2016-2017 flu seasons.

For the 2018-2019 flu season, ACIP determined that “For persons aged ≥65 years, any age-appropriate IIV formulation (standard-dose or high-dose, trivalent or quadrivalent, unadjuvanted or adjuvanted) or RIV4 are acceptable options.”

The findings of the analysis of the 2017-2018 flu season data are consistent with prelicensure studies, Ms. Haber and her colleagues concluded, noting that data mining did not detect disproportional reporting of any unexpected adverse event.

“[There were] no safety concerns following aIIV3 when compared to the nonadjuvanted influenza vaccines (IIV3-HD or IIV3/IIV4),” they wrote, adding that the “CDC and FDA will continue to monitor and ensure the safety of aIIV3.”

Ms. Haber reported having no disclosures

[email protected]

SOURCE: Haber P et al. ICEID 2018, Board 320.

ATLANTA – Postlicensure surveillance of a trivalent adjuvanted influenza vaccine approved in 2015 for adults aged 65 years and older revealed no new or unexpected patterns of adverse events, according to an analysis of reports to the Vaccine Adverse Event Reporting System (VAERS) during July 2016 through March 2018.

Wavebreakmedia/Thinkstock

VAERS received 630 reports related to the vaccine (aIIV3; FLUAD) during the study period, of which 521 involved adults aged 65 years and older.

“Eighteen (3%) were serious reports, including two death reports (0.4%), all in adults aged [at least] 65 years,” Penina Haber and her colleagues at the Immunization Safety Office at the Centers for Disease Control and Prevention reported in a poster at the International Conference on Emerging Infectious Diseases.

The deaths included a 75-year-old man who died from Sjögren’s syndrome and a 65-year-old man who died from a myocardial infarction. The other serious events included five neurologic disorders (two cases of Guillain-Barré syndrome and one each of Bell’s palsy, Bickerstaff encephalitis, and lower-extremity weakness), five musculoskeletal and connective tissue disorders (three with shoulder pain and two with arm pain), three general disorders and administration site conditions (two cases of fever/chills and one case of cellulitis/bursitis), and one case each of a gastrointestinal disorder (acute diarrhea/gastroenteritis), an injury (a fall), and a skin/subcutaneous tissue disorder (keratosis pilaris rubra), according to the investigators.

There were no reports of anaphylaxis.

For the sake of comparison, the investigators also looked at reports associated with IIV3-HD and IIV3/IIV4 vaccines in adults aged 65 years and older during the same time period; they found that patient characteristics and reported events were similar for all the vaccines. For example, the percentages of reports involving patients aged 65 years and older were 65% or 66% for each, and those involving patients aged 75-84 years were 27%-29%. Further, 0.2%-0.6% of reports for each vaccine involved death.

The most frequently reported events for aIIV3, IIV3-HD, and IIV3/IIV4, respectively, were extremity pain (21%, 17%, and 15%, respectively), injection site erythema (18%, 19%, and 15%), and injection site pain (15%, 16%, and 16%), they said.

The aIIV3 vaccine – the first seasonal inactivated trivalent influenza vaccine produced from three influenza virus strains (two subtype A strains and one type B strain) – was approved by the Food and Drug Administration in 2015 for adults aged 65 years and older. It was the first influenza vaccine containing the adjuvant MF59 – a purified oil-in-water emulsion of squalene oil added to boost immune response in that population. Its safety was assessed in 15 randomized, controlled clinical studies, and several trials in older adults supported its efficacy and safety over nonadjuvanted influenza vaccines, the investigators reported. They noted that the Advisory Committee on Immunization Practices (ACIP) recommended the vaccine as an option for routine use in adults aged 65 years and older during the 2016-2017 flu seasons.

For the 2018-2019 flu season, ACIP determined that “For persons aged ≥65 years, any age-appropriate IIV formulation (standard-dose or high-dose, trivalent or quadrivalent, unadjuvanted or adjuvanted) or RIV4 are acceptable options.”

The findings of the analysis of the 2017-2018 flu season data are consistent with prelicensure studies, Ms. Haber and her colleagues concluded, noting that data mining did not detect disproportional reporting of any unexpected adverse event.

“[There were] no safety concerns following aIIV3 when compared to the nonadjuvanted influenza vaccines (IIV3-HD or IIV3/IIV4),” they wrote, adding that the “CDC and FDA will continue to monitor and ensure the safety of aIIV3.”

Ms. Haber reported having no disclosures

[email protected]

SOURCE: Haber P et al. ICEID 2018, Board 320.

ATLANTA – The 13-valent pneumococcal conjugate vaccine (PCV13) shows moderate overall effectiveness for preventing invasive pneumococcal disease (IPD) caused by PCV13 vaccine serotypes in adults aged 65 years and older, according to a case-control study involving Medicare beneficiaries.

Sharon Worcester/MDedge News

Conversely, the 23-valent pneumococcal polysaccharide vaccine (PPSV23) showed limited effectiveness against serotypes unique to that vaccine in the study, which included 699 cases and more than 10,000 controls, Olivia Almendares, an epidemiologist at the Centers for Disease Control and Prevention, Atlanta, and her colleagues reported in a poster at the International Conference on Emerging Infectious Diseases.

“Vaccine efficacy against PCV13 [plus 6C type, which has cross-reactivity with serotype 6A] was 47% in those who received PCV13 vaccine only,” Ms. Almendares said in an interview, noting that efficacy was 26% against serotype 3 and 67% against other PCV13 serotypes (plus 6C). “Vaccine efficacy against PPSV23-unique types was 36% for those who received only PPSV23.”

Neither vaccine showed effectiveness against serotypes not included in the respective vaccines, she said.

The findings are timely given that the Advisory Committee on Immunization Practices (ACIP) is reevaluating its PCV13 recommendation for adults aged 65 years and older, she added.

“Specifically, ACIP is addressing whether PCV13 should be recommended routinely for all immunocompetent adults aged 65 and older given sustained indirect effects,” she said, explaining that, in 2014 when ACIP recommended routine use of the vaccine in series with PPSV23 for adults aged 65 years and older, the committee recognized that herd immunity effects from PCV13 use in children might eventually limit the utility of this recommendation, and therefore it proposed reevaluation and revision as needed after 4 years.

For the current study, she and her colleagues linked IPD cases in persons aged 65 years and older, which were identified through Active Bacterial Core surveillance during 2015-2016, to records for Centers for Medicare & Medicaid Services (CMS) beneficiaries. Vaccination and medical histories were obtained through medical records, and vaccine effectiveness was estimated as one minus the odds ratio for vaccination with PCV13 only or PPSV23 only versus neither vaccine using conditional logistic regression, with adjustment for sex and underlying medical conditions.

Of 2,246 IPD cases, 1,017 (45%) were matched to Medicare beneficiaries, and 699 were included in the analysis after those with noncontinuous enrollment in Medicare, long-term care residence, and missing census tract data were excluded. The cases were matched based on age, census tract of residence, and length of Medicare enrollment to 10,152 matched controls identified through CMS.

IPD associated with PCV13 (plus type 6C) accounted for 164 (23% of cases), of which 88 (12% of cases) involved serotype 3, and invasive pneumococcal disease associated with PPSV23 accounted for 350 cases (50%), she said.

PCV13 vaccine was given alone in 14% and 18% of cases and controls, respectively; PPSV23 alone was given in 22% and 21% of case patients and controls, respectively; and both vaccines were given in 8% of cases and controls.

Compared with controls, case patients were more likely to be of nonwhite race (16% vs. 11%), to have more than one chronic medical condition (88% vs. 58%), and to have one or more immunocompromising conditions (54% vs. 32%), she and her colleagues reported.

“PCV13 showed moderate overall effectiveness in preventing IPD caused by PCV13 (including 6C), but effectiveness may be lower for serotype 3 than for other PCV13 types,” she said.

“These results are in agreement with those from CAPiTA – a large clinical trial conducted in the Netherlands, which showed PCV13 to be effective against IPD caused by vaccine serotypes among community-dwelling adults aged 65 and older,” she noted. “Additionally, data from CDC surveillance suggest that PCV13-serotype [invasive pneumococcal disease] among children and adults aged 65 and older has declined dramatically following PCV13 introduction for children in 2010, as predicted.”

In fact, among adults aged 65 years and older, PCV13-serotype invasive pneumococcal disease declined by 40% after the vaccine was introduced in children. This corresponds to a change in the annual PCV13-serotype incidence from 14 cases per 100,000 population in 2010 to five cases per 100,000 population in 2014, she said; she added that IPD incidence plateaued in 2014-2016 with vaccine serotypes contributing to a small proportion of overall IPD burden among adults aged 65 years and older.

ACIP’s reevaluation of the PCV13 recommendation is ongoing and will be addressed at upcoming meetings.

“As part of the review process, we look at changes in disease incidence focusing primarily on invasive pneumococcal disease and noninvasive pneumonia, vaccine efficacy and effectiveness, and vaccine safety,” she said. She noted that ACIP currently has no plans to consider revising PCV13 recommendations for adults who have immunocompromising conditions, for whom PCV13 has been recommended since 2012.

Ms. Almendares reported having no disclosures.

[email protected]

SOURCE: Almendares O et al. ICEID 2018, Board 376.

ATLANTA – The 13-valent pneumococcal conjugate vaccine (PCV13) shows moderate overall effectiveness for preventing invasive pneumococcal disease (IPD) caused by PCV13 vaccine serotypes in adults aged 65 years and older, according to a case-control study involving Medicare beneficiaries.

Sharon Worcester/MDedge News

Conversely, the 23-valent pneumococcal polysaccharide vaccine (PPSV23) showed limited effectiveness against serotypes unique to that vaccine in the study, which included 699 cases and more than 10,000 controls, Olivia Almendares, an epidemiologist at the Centers for Disease Control and Prevention, Atlanta, and her colleagues reported in a poster at the International Conference on Emerging Infectious Diseases.

“Vaccine efficacy against PCV13 [plus 6C type, which has cross-reactivity with serotype 6A] was 47% in those who received PCV13 vaccine only,” Ms. Almendares said in an interview, noting that efficacy was 26% against serotype 3 and 67% against other PCV13 serotypes (plus 6C). “Vaccine efficacy against PPSV23-unique types was 36% for those who received only PPSV23.”

Neither vaccine showed effectiveness against serotypes not included in the respective vaccines, she said.

The findings are timely given that the Advisory Committee on Immunization Practices (ACIP) is reevaluating its PCV13 recommendation for adults aged 65 years and older, she added.

“Specifically, ACIP is addressing whether PCV13 should be recommended routinely for all immunocompetent adults aged 65 and older given sustained indirect effects,” she said, explaining that, in 2014 when ACIP recommended routine use of the vaccine in series with PPSV23 for adults aged 65 years and older, the committee recognized that herd immunity effects from PCV13 use in children might eventually limit the utility of this recommendation, and therefore it proposed reevaluation and revision as needed after 4 years.

For the current study, she and her colleagues linked IPD cases in persons aged 65 years and older, which were identified through Active Bacterial Core surveillance during 2015-2016, to records for Centers for Medicare & Medicaid Services (CMS) beneficiaries. Vaccination and medical histories were obtained through medical records, and vaccine effectiveness was estimated as one minus the odds ratio for vaccination with PCV13 only or PPSV23 only versus neither vaccine using conditional logistic regression, with adjustment for sex and underlying medical conditions.

Of 2,246 IPD cases, 1,017 (45%) were matched to Medicare beneficiaries, and 699 were included in the analysis after those with noncontinuous enrollment in Medicare, long-term care residence, and missing census tract data were excluded. The cases were matched based on age, census tract of residence, and length of Medicare enrollment to 10,152 matched controls identified through CMS.

IPD associated with PCV13 (plus type 6C) accounted for 164 (23% of cases), of which 88 (12% of cases) involved serotype 3, and invasive pneumococcal disease associated with PPSV23 accounted for 350 cases (50%), she said.

PCV13 vaccine was given alone in 14% and 18% of cases and controls, respectively; PPSV23 alone was given in 22% and 21% of case patients and controls, respectively; and both vaccines were given in 8% of cases and controls.

Compared with controls, case patients were more likely to be of nonwhite race (16% vs. 11%), to have more than one chronic medical condition (88% vs. 58%), and to have one or more immunocompromising conditions (54% vs. 32%), she and her colleagues reported.

“PCV13 showed moderate overall effectiveness in preventing IPD caused by PCV13 (including 6C), but effectiveness may be lower for serotype 3 than for other PCV13 types,” she said.

“These results are in agreement with those from CAPiTA – a large clinical trial conducted in the Netherlands, which showed PCV13 to be effective against IPD caused by vaccine serotypes among community-dwelling adults aged 65 and older,” she noted. “Additionally, data from CDC surveillance suggest that PCV13-serotype [invasive pneumococcal disease] among children and adults aged 65 and older has declined dramatically following PCV13 introduction for children in 2010, as predicted.”

In fact, among adults aged 65 years and older, PCV13-serotype invasive pneumococcal disease declined by 40% after the vaccine was introduced in children. This corresponds to a change in the annual PCV13-serotype incidence from 14 cases per 100,000 population in 2010 to five cases per 100,000 population in 2014, she said; she added that IPD incidence plateaued in 2014-2016 with vaccine serotypes contributing to a small proportion of overall IPD burden among adults aged 65 years and older.

ACIP’s reevaluation of the PCV13 recommendation is ongoing and will be addressed at upcoming meetings.

“As part of the review process, we look at changes in disease incidence focusing primarily on invasive pneumococcal disease and noninvasive pneumonia, vaccine efficacy and effectiveness, and vaccine safety,” she said. She noted that ACIP currently has no plans to consider revising PCV13 recommendations for adults who have immunocompromising conditions, for whom PCV13 has been recommended since 2012.

Ms. Almendares reported having no disclosures.

[email protected]

SOURCE: Almendares O et al. ICEID 2018, Board 376.

ATLANTA – The 13-valent pneumococcal conjugate vaccine (PCV13) shows moderate overall effectiveness for preventing invasive pneumococcal disease (IPD) caused by PCV13 vaccine serotypes in adults aged 65 years and older, according to a case-control study involving Medicare beneficiaries.

Sharon Worcester/MDedge News

Conversely, the 23-valent pneumococcal polysaccharide vaccine (PPSV23) showed limited effectiveness against serotypes unique to that vaccine in the study, which included 699 cases and more than 10,000 controls, Olivia Almendares, an epidemiologist at the Centers for Disease Control and Prevention, Atlanta, and her colleagues reported in a poster at the International Conference on Emerging Infectious Diseases.

“Vaccine efficacy against PCV13 [plus 6C type, which has cross-reactivity with serotype 6A] was 47% in those who received PCV13 vaccine only,” Ms. Almendares said in an interview, noting that efficacy was 26% against serotype 3 and 67% against other PCV13 serotypes (plus 6C). “Vaccine efficacy against PPSV23-unique types was 36% for those who received only PPSV23.”

Neither vaccine showed effectiveness against serotypes not included in the respective vaccines, she said.

The findings are timely given that the Advisory Committee on Immunization Practices (ACIP) is reevaluating its PCV13 recommendation for adults aged 65 years and older, she added.

“Specifically, ACIP is addressing whether PCV13 should be recommended routinely for all immunocompetent adults aged 65 and older given sustained indirect effects,” she said, explaining that, in 2014 when ACIP recommended routine use of the vaccine in series with PPSV23 for adults aged 65 years and older, the committee recognized that herd immunity effects from PCV13 use in children might eventually limit the utility of this recommendation, and therefore it proposed reevaluation and revision as needed after 4 years.

For the current study, she and her colleagues linked IPD cases in persons aged 65 years and older, which were identified through Active Bacterial Core surveillance during 2015-2016, to records for Centers for Medicare & Medicaid Services (CMS) beneficiaries. Vaccination and medical histories were obtained through medical records, and vaccine effectiveness was estimated as one minus the odds ratio for vaccination with PCV13 only or PPSV23 only versus neither vaccine using conditional logistic regression, with adjustment for sex and underlying medical conditions.

Of 2,246 IPD cases, 1,017 (45%) were matched to Medicare beneficiaries, and 699 were included in the analysis after those with noncontinuous enrollment in Medicare, long-term care residence, and missing census tract data were excluded. The cases were matched based on age, census tract of residence, and length of Medicare enrollment to 10,152 matched controls identified through CMS.

IPD associated with PCV13 (plus type 6C) accounted for 164 (23% of cases), of which 88 (12% of cases) involved serotype 3, and invasive pneumococcal disease associated with PPSV23 accounted for 350 cases (50%), she said.

PCV13 vaccine was given alone in 14% and 18% of cases and controls, respectively; PPSV23 alone was given in 22% and 21% of case patients and controls, respectively; and both vaccines were given in 8% of cases and controls.

Compared with controls, case patients were more likely to be of nonwhite race (16% vs. 11%), to have more than one chronic medical condition (88% vs. 58%), and to have one or more immunocompromising conditions (54% vs. 32%), she and her colleagues reported.

“PCV13 showed moderate overall effectiveness in preventing IPD caused by PCV13 (including 6C), but effectiveness may be lower for serotype 3 than for other PCV13 types,” she said.

“These results are in agreement with those from CAPiTA – a large clinical trial conducted in the Netherlands, which showed PCV13 to be effective against IPD caused by vaccine serotypes among community-dwelling adults aged 65 and older,” she noted. “Additionally, data from CDC surveillance suggest that PCV13-serotype [invasive pneumococcal disease] among children and adults aged 65 and older has declined dramatically following PCV13 introduction for children in 2010, as predicted.”

In fact, among adults aged 65 years and older, PCV13-serotype invasive pneumococcal disease declined by 40% after the vaccine was introduced in children. This corresponds to a change in the annual PCV13-serotype incidence from 14 cases per 100,000 population in 2010 to five cases per 100,000 population in 2014, she said; she added that IPD incidence plateaued in 2014-2016 with vaccine serotypes contributing to a small proportion of overall IPD burden among adults aged 65 years and older.

ACIP’s reevaluation of the PCV13 recommendation is ongoing and will be addressed at upcoming meetings.

“As part of the review process, we look at changes in disease incidence focusing primarily on invasive pneumococcal disease and noninvasive pneumonia, vaccine efficacy and effectiveness, and vaccine safety,” she said. She noted that ACIP currently has no plans to consider revising PCV13 recommendations for adults who have immunocompromising conditions, for whom PCV13 has been recommended since 2012.

Ms. Almendares reported having no disclosures.

[email protected]

SOURCE: Almendares O et al. ICEID 2018, Board 376.

Last year’s influenza season was severe enough that hospitals around the United States set up special evaluation areas beyond their emergency departments, at times spilling over to tents or other temporary structures in what otherwise would be parking lots. The scale and potential severity of the annual epidemic can be difficult to convey to our patients, who sometimes say “just the flu” to refer to an illness responsible for more than 170 pediatric deaths in the United States this past year.¹ The Centers for Disease Control and Prevention (CDC) recently updated its 5-year estimates of influenza-related deaths in the United States; influenza mortality ranges from about 12,000 deaths in a mild season (such as 2011-2012) to 56,000 in a more severe season (eg, 2012-2013).²

Although influenza cannot be completely prevented, the following strategies can help reduce the risk for the illness and limit its severity if contracted.

Prevention

Strategy 1: Vaccinate against influenza

While the efficacy of vaccines varies from year to year, vaccination remains the core of influenza prevention efforts. In this decade, vaccine effectiveness has ranged from 19% to 60%.³ However, models suggest that even when the vaccine is only 20% effective, vaccinating 140 million people (the average number of doses delivered annually in the United States over the past 5 seasons) prevents 21 million infections, 130,000 hospitalizations, and more than 61,000 deaths.⁴ In a case-control study, Flannery et al found that vaccination was 65% effective in preventing laboratory-confirmed influenza-associated death in children over 4 seasons (July 2010 through June 2014).⁵

Deciding who should be vaccinated is simpler than in prior years: Rather than targeting people who are at higher risk (those ages 65 and older, or those with comorbidities), the current CDC recommendation is to vaccinate nearly everyone ages 6 months or older, with limited exceptions.^6,7 (See Table 1⁸).

Formulations. Many types of influenza vaccine are approved for use in the United States; these differ in the number of strains included (3 or 4), the amount of antigen present for each strain, the presence of an adjuvant, the growth medium used for the virus, and the route of administration (see Table 2⁹). The relative merits of each type are a matter of some debate. There is ongoing research into the comparative efficacy of vaccines comprised of egg- vs cell-based cultures, as well as studies comparing high-dose or adjuvant vaccines to standard-dose inactivated vaccines.

Previously, the CDC has recommended preferential use (or avoidance) of some vaccine types, based on their efficacy. For the 2018-2019 flu season, however, the CDC has rescinded its recommendation against vaccine containing live attenuated virus (LAIV; FluMist brand) and expresses no preference for any vaccine formulation for patients of appropriate age and health status.¹⁰ The American Academy of Pediatrics (AAP), however, is recommends that LAIV be used only if patients and their families decline injectable vaccines.¹¹

Timing. Influenza vaccines are now distributed as early as July to some locations, raising concerns about waning immunity from early vaccination (July/August) if the influenza season does not peak until February or March.^8,12,13 Currently, the CDC recommends balancing the possible benefit of delayed vaccination against the risks of missed opportunities to vaccinate, a possible early season, and logistical problems related to vaccinating the same number of people in a smaller time interval. Offering vaccination by the end of October, if possible, is recommended in order for immunity to develop by mid-November.⁸ Note: Children ages 6 months to 8 years will need to receive their initial vaccination in 2 half-doses administered at least 28 days apart; completing their vaccination by the end of October would require starting the process weeks earlier.

[polldaddy:10124269]

Continue to: Strategy 2

Strategy 2: Make use of chemoprophylaxis

Preventive use of antiviral medication (chemoprophylaxis) may be a useful adjunct or alternative to vaccination in certain circumstances: if the patient is at high risk for complications, has been exposed to someone with influenza, has contraindications to vaccination, or received the vaccine within the past 2 weeks. The CDC also suggests that chemoprophylaxis be considered for those with immune deficiencies or who are otherwise immunosuppressed after exposure.¹⁴ Antivirals can also be used to control outbreaks in long-term care facilities; in these cases, the recommendedregimen is daily administration for at least 2 weeks, continuing until at least 7 days after the identification of the last case.¹⁴ Oseltamivir (Tamiflu) and zanamivir (Relenza) are the recommended prophylactic agents; a related intravenous medication, peramivir (Rapivab), is recommend for treatment only (see Table 3¹⁴).

Strategy 3: Prevent comorbidities and opportunistic infections

Morbidity associated with influenza often comes from secondary infection. Pneumonia is among the most common complications, so influenza season is a good time to ensure that patients are appropriately vaccinated against pneumococcus, as well. Pneumococcal conjugate vaccine (Prevnar or PCV13) is recommended for children younger than 2 years of age, to be administered in a series of 4 doses: at 2, 4, 6, and 12-15 months. Vaccination with PCV13 is also recommended for those ages 65 or older, to be followed at least one year later with pneumococcal polysaccharide vaccine (Pneumovax or PPSV23).¹⁵ Additional doses of PCV13, PPSV23, or both may be indicated, depending on health status.

Strategy 4: Encourage good hygiene

The availability of immunizations and anti­virals does not replace good hygiene. Frequent handwashing reduces the transmission of respiratory viruses, including influenza.¹⁶ Few studies have evaluated the use of alcohol-based hand sanitizers, but available evidence suggests they are effective in lowering viral transmission.¹⁶

Barriers, such as masks, gloves, and gowns, are helpful for health care workers.¹⁶ Surgical masks are often considered more comfortable to wear than N95 respirators. It may therefore be welcome news that when a 2009 randomized study assessed their use by hospital-based nurses, masks were non-inferior in protecting these health care workers against influenza.¹⁷

Presenteeism, the practice of going to work while sick, should be discouraged. People at risk for influenza may wish to avoid crowds during flu season; those with symptoms should be encouraged to stay home and limit contact with others.

Continue to: Treatment

Strategy 1: Make prompt use of antivirals

Despite available preventive measures, tens of millions of people in the United States develop influenza every year. Use of antiviral medication, begun early in the course of illness, can reduce the duration of symptoms and may reduce the risk for complications.

The neuraminidase inhibitor (NI) group of antivirals—oseltamivir, zanamivir, and peramivir—is effective against influenza types A and B and current resistance rates are low.

The adamantine family of antivirals, amantadine and rimantadine, treat type A only. Since the circulating influenza strains in the past several seasons have demonstrated resistance >99%, these medications are not currently recommended.¹⁴

NIs reduce the duration of influenza symptoms by 10% to 20%, shortening the illness by 6 to 24 hours.^18,19 In otherwise healthy patients, this benefit must be balanced against the increased risk for nausea and vomiting (oseltamivir), bronchospasm and sinusitis (zanamivir), and diarrhea (peramivir). In adults, NIs reduce the risk for lower respiratory tract complications and hospitalization. A 2015 meta-analysis by Dobson et al found a relative risk for hospitalization among those prescribed oseltamivir vs placebo of 37%.¹⁸

In the past, antivirals were used only in high-risk patients, such as children younger than 2 years, adults older than 65 years, and those with chronic health conditions.¹⁴ Now, antivirals are recommended for those who are at higher risk for complications (see Table 4), those with “severe, complicated, or progressive illness,” and hospitalized patients.¹⁴

Continue to: Antiviral treatment may have some value...

Antiviral treatment may have some value for hospitalized patients when started even 5 days after symptom onset. Treatment may be extended beyond the usual recommendations (5 days for oseltamivir or zanamivir) in immunosuppressed patients or the critically ill. Additionally, recent guidelines include consideration of antiviral treatment in outpatients who are at normal risk if treatment can be started within 48 hours of symptom onset.¹⁴

The CDC currently recommends use of oseltamivir rather than other antivirals for most hospitalized patients, based on the availability of data on its use in this setting.¹⁴ Intravenous peramivir is recommended for patients who cannot tolerate or absorb oral medication; inhaled zanamivir or IV peramivir are preferred for patients with end-stage renal disease who are not undergoing dialysis (see Table 3).¹⁴

Strategy 2: Exercise caution when it comes to supportive care

There are other medications that may offer symptom relief or prevent complications, especially when antivirals are contraindicated or unavailable.

Corticosteroids are recommended as part of the treatment of community-acquired pneumonia,²⁰ but their role in influenza is controversial. A 2016 Cochrane review²¹ found no randomized controlled trials on the topic. Although the balance of available data from observational studies indicated that use of corticosteroids was associated with increased mortality, the authors also noted that all the studies included in their meta-analysis were of “very low quality.” They concluded that “the use of steroids in influenza remains a clinical judgement call.”

Offering vaccination by the end of October, if possible, is recommended in order for immunity to develop by mid-November.

Statins may be associated with improved outcomes in influenza and pneumonia. Studies thus far have given contradictory results,^22,23 and a planned Cochrane review of the question has been withdrawn.²⁴

Continue to: Over-the-counter medications...

Over-the-counter medications, such as aspirin, acetaminophen, and ibuprofen are often used to manage the fever and myalgia associated with influenza. Patients should be cautioned against using the same ingredient in multiple different branded medications. Acetaminophen, for example, is not limited to Tylenol-branded products. To avoid Reye’s syndrome, children and teens with febrile illness, such as influenza, should not use aspirin.

CORRESPONDENCE
Jennifer L. Hamilton, MD, PhD, Drexel Family Medicine, 10 Shurs Lane, Suite 301, Philadelphia, PA 19127; [email protected].

Last year’s influenza season was severe enough that hospitals around the United States set up special evaluation areas beyond their emergency departments, at times spilling over to tents or other temporary structures in what otherwise would be parking lots. The scale and potential severity of the annual epidemic can be difficult to convey to our patients, who sometimes say “just the flu” to refer to an illness responsible for more than 170 pediatric deaths in the United States this past year.¹ The Centers for Disease Control and Prevention (CDC) recently updated its 5-year estimates of influenza-related deaths in the United States; influenza mortality ranges from about 12,000 deaths in a mild season (such as 2011-2012) to 56,000 in a more severe season (eg, 2012-2013).²

Although influenza cannot be completely prevented, the following strategies can help reduce the risk for the illness and limit its severity if contracted.

Prevention

Strategy 1: Vaccinate against influenza

While the efficacy of vaccines varies from year to year, vaccination remains the core of influenza prevention efforts. In this decade, vaccine effectiveness has ranged from 19% to 60%.³ However, models suggest that even when the vaccine is only 20% effective, vaccinating 140 million people (the average number of doses delivered annually in the United States over the past 5 seasons) prevents 21 million infections, 130,000 hospitalizations, and more than 61,000 deaths.⁴ In a case-control study, Flannery et al found that vaccination was 65% effective in preventing laboratory-confirmed influenza-associated death in children over 4 seasons (July 2010 through June 2014).⁵

Deciding who should be vaccinated is simpler than in prior years: Rather than targeting people who are at higher risk (those ages 65 and older, or those with comorbidities), the current CDC recommendation is to vaccinate nearly everyone ages 6 months or older, with limited exceptions.^6,7 (See Table 1⁸).

Formulations. Many types of influenza vaccine are approved for use in the United States; these differ in the number of strains included (3 or 4), the amount of antigen present for each strain, the presence of an adjuvant, the growth medium used for the virus, and the route of administration (see Table 2⁹). The relative merits of each type are a matter of some debate. There is ongoing research into the comparative efficacy of vaccines comprised of egg- vs cell-based cultures, as well as studies comparing high-dose or adjuvant vaccines to standard-dose inactivated vaccines.

Previously, the CDC has recommended preferential use (or avoidance) of some vaccine types, based on their efficacy. For the 2018-2019 flu season, however, the CDC has rescinded its recommendation against vaccine containing live attenuated virus (LAIV; FluMist brand) and expresses no preference for any vaccine formulation for patients of appropriate age and health status.¹⁰ The American Academy of Pediatrics (AAP), however, is recommends that LAIV be used only if patients and their families decline injectable vaccines.¹¹

Timing. Influenza vaccines are now distributed as early as July to some locations, raising concerns about waning immunity from early vaccination (July/August) if the influenza season does not peak until February or March.^8,12,13 Currently, the CDC recommends balancing the possible benefit of delayed vaccination against the risks of missed opportunities to vaccinate, a possible early season, and logistical problems related to vaccinating the same number of people in a smaller time interval. Offering vaccination by the end of October, if possible, is recommended in order for immunity to develop by mid-November.⁸ Note: Children ages 6 months to 8 years will need to receive their initial vaccination in 2 half-doses administered at least 28 days apart; completing their vaccination by the end of October would require starting the process weeks earlier.

[polldaddy:10124269]

Continue to: Strategy 2

Strategy 2: Make use of chemoprophylaxis

Preventive use of antiviral medication (chemoprophylaxis) may be a useful adjunct or alternative to vaccination in certain circumstances: if the patient is at high risk for complications, has been exposed to someone with influenza, has contraindications to vaccination, or received the vaccine within the past 2 weeks. The CDC also suggests that chemoprophylaxis be considered for those with immune deficiencies or who are otherwise immunosuppressed after exposure.¹⁴ Antivirals can also be used to control outbreaks in long-term care facilities; in these cases, the recommendedregimen is daily administration for at least 2 weeks, continuing until at least 7 days after the identification of the last case.¹⁴ Oseltamivir (Tamiflu) and zanamivir (Relenza) are the recommended prophylactic agents; a related intravenous medication, peramivir (Rapivab), is recommend for treatment only (see Table 3¹⁴).

Strategy 3: Prevent comorbidities and opportunistic infections

Morbidity associated with influenza often comes from secondary infection. Pneumonia is among the most common complications, so influenza season is a good time to ensure that patients are appropriately vaccinated against pneumococcus, as well. Pneumococcal conjugate vaccine (Prevnar or PCV13) is recommended for children younger than 2 years of age, to be administered in a series of 4 doses: at 2, 4, 6, and 12-15 months. Vaccination with PCV13 is also recommended for those ages 65 or older, to be followed at least one year later with pneumococcal polysaccharide vaccine (Pneumovax or PPSV23).¹⁵ Additional doses of PCV13, PPSV23, or both may be indicated, depending on health status.

Strategy 4: Encourage good hygiene

The availability of immunizations and anti­virals does not replace good hygiene. Frequent handwashing reduces the transmission of respiratory viruses, including influenza.¹⁶ Few studies have evaluated the use of alcohol-based hand sanitizers, but available evidence suggests they are effective in lowering viral transmission.¹⁶

Barriers, such as masks, gloves, and gowns, are helpful for health care workers.¹⁶ Surgical masks are often considered more comfortable to wear than N95 respirators. It may therefore be welcome news that when a 2009 randomized study assessed their use by hospital-based nurses, masks were non-inferior in protecting these health care workers against influenza.¹⁷

Presenteeism, the practice of going to work while sick, should be discouraged. People at risk for influenza may wish to avoid crowds during flu season; those with symptoms should be encouraged to stay home and limit contact with others.

Continue to: Treatment

Strategy 1: Make prompt use of antivirals

Despite available preventive measures, tens of millions of people in the United States develop influenza every year. Use of antiviral medication, begun early in the course of illness, can reduce the duration of symptoms and may reduce the risk for complications.

The neuraminidase inhibitor (NI) group of antivirals—oseltamivir, zanamivir, and peramivir—is effective against influenza types A and B and current resistance rates are low.

The adamantine family of antivirals, amantadine and rimantadine, treat type A only. Since the circulating influenza strains in the past several seasons have demonstrated resistance >99%, these medications are not currently recommended.¹⁴

NIs reduce the duration of influenza symptoms by 10% to 20%, shortening the illness by 6 to 24 hours.^18,19 In otherwise healthy patients, this benefit must be balanced against the increased risk for nausea and vomiting (oseltamivir), bronchospasm and sinusitis (zanamivir), and diarrhea (peramivir). In adults, NIs reduce the risk for lower respiratory tract complications and hospitalization. A 2015 meta-analysis by Dobson et al found a relative risk for hospitalization among those prescribed oseltamivir vs placebo of 37%.¹⁸

In the past, antivirals were used only in high-risk patients, such as children younger than 2 years, adults older than 65 years, and those with chronic health conditions.¹⁴ Now, antivirals are recommended for those who are at higher risk for complications (see Table 4), those with “severe, complicated, or progressive illness,” and hospitalized patients.¹⁴

Continue to: Antiviral treatment may have some value...

Antiviral treatment may have some value for hospitalized patients when started even 5 days after symptom onset. Treatment may be extended beyond the usual recommendations (5 days for oseltamivir or zanamivir) in immunosuppressed patients or the critically ill. Additionally, recent guidelines include consideration of antiviral treatment in outpatients who are at normal risk if treatment can be started within 48 hours of symptom onset.¹⁴

The CDC currently recommends use of oseltamivir rather than other antivirals for most hospitalized patients, based on the availability of data on its use in this setting.¹⁴ Intravenous peramivir is recommended for patients who cannot tolerate or absorb oral medication; inhaled zanamivir or IV peramivir are preferred for patients with end-stage renal disease who are not undergoing dialysis (see Table 3).¹⁴

Strategy 2: Exercise caution when it comes to supportive care

There are other medications that may offer symptom relief or prevent complications, especially when antivirals are contraindicated or unavailable.

Corticosteroids are recommended as part of the treatment of community-acquired pneumonia,²⁰ but their role in influenza is controversial. A 2016 Cochrane review²¹ found no randomized controlled trials on the topic. Although the balance of available data from observational studies indicated that use of corticosteroids was associated with increased mortality, the authors also noted that all the studies included in their meta-analysis were of “very low quality.” They concluded that “the use of steroids in influenza remains a clinical judgement call.”

Offering vaccination by the end of October, if possible, is recommended in order for immunity to develop by mid-November.

Statins may be associated with improved outcomes in influenza and pneumonia. Studies thus far have given contradictory results,^22,23 and a planned Cochrane review of the question has been withdrawn.²⁴

Continue to: Over-the-counter medications...

Over-the-counter medications, such as aspirin, acetaminophen, and ibuprofen are often used to manage the fever and myalgia associated with influenza. Patients should be cautioned against using the same ingredient in multiple different branded medications. Acetaminophen, for example, is not limited to Tylenol-branded products. To avoid Reye’s syndrome, children and teens with febrile illness, such as influenza, should not use aspirin.

CORRESPONDENCE
Jennifer L. Hamilton, MD, PhD, Drexel Family Medicine, 10 Shurs Lane, Suite 301, Philadelphia, PA 19127; [email protected].

Last year’s influenza season was severe enough that hospitals around the United States set up special evaluation areas beyond their emergency departments, at times spilling over to tents or other temporary structures in what otherwise would be parking lots. The scale and potential severity of the annual epidemic can be difficult to convey to our patients, who sometimes say “just the flu” to refer to an illness responsible for more than 170 pediatric deaths in the United States this past year.¹ The Centers for Disease Control and Prevention (CDC) recently updated its 5-year estimates of influenza-related deaths in the United States; influenza mortality ranges from about 12,000 deaths in a mild season (such as 2011-2012) to 56,000 in a more severe season (eg, 2012-2013).²

Although influenza cannot be completely prevented, the following strategies can help reduce the risk for the illness and limit its severity if contracted.

Prevention

Strategy 1: Vaccinate against influenza

While the efficacy of vaccines varies from year to year, vaccination remains the core of influenza prevention efforts. In this decade, vaccine effectiveness has ranged from 19% to 60%.³ However, models suggest that even when the vaccine is only 20% effective, vaccinating 140 million people (the average number of doses delivered annually in the United States over the past 5 seasons) prevents 21 million infections, 130,000 hospitalizations, and more than 61,000 deaths.⁴ In a case-control study, Flannery et al found that vaccination was 65% effective in preventing laboratory-confirmed influenza-associated death in children over 4 seasons (July 2010 through June 2014).⁵

Deciding who should be vaccinated is simpler than in prior years: Rather than targeting people who are at higher risk (those ages 65 and older, or those with comorbidities), the current CDC recommendation is to vaccinate nearly everyone ages 6 months or older, with limited exceptions.^6,7 (See Table 1⁸).

Formulations. Many types of influenza vaccine are approved for use in the United States; these differ in the number of strains included (3 or 4), the amount of antigen present for each strain, the presence of an adjuvant, the growth medium used for the virus, and the route of administration (see Table 2⁹). The relative merits of each type are a matter of some debate. There is ongoing research into the comparative efficacy of vaccines comprised of egg- vs cell-based cultures, as well as studies comparing high-dose or adjuvant vaccines to standard-dose inactivated vaccines.

Previously, the CDC has recommended preferential use (or avoidance) of some vaccine types, based on their efficacy. For the 2018-2019 flu season, however, the CDC has rescinded its recommendation against vaccine containing live attenuated virus (LAIV; FluMist brand) and expresses no preference for any vaccine formulation for patients of appropriate age and health status.¹⁰ The American Academy of Pediatrics (AAP), however, is recommends that LAIV be used only if patients and their families decline injectable vaccines.¹¹

Timing. Influenza vaccines are now distributed as early as July to some locations, raising concerns about waning immunity from early vaccination (July/August) if the influenza season does not peak until February or March.^8,12,13 Currently, the CDC recommends balancing the possible benefit of delayed vaccination against the risks of missed opportunities to vaccinate, a possible early season, and logistical problems related to vaccinating the same number of people in a smaller time interval. Offering vaccination by the end of October, if possible, is recommended in order for immunity to develop by mid-November.⁸ Note: Children ages 6 months to 8 years will need to receive their initial vaccination in 2 half-doses administered at least 28 days apart; completing their vaccination by the end of October would require starting the process weeks earlier.

[polldaddy:10124269]

Continue to: Strategy 2

Strategy 2: Make use of chemoprophylaxis

Preventive use of antiviral medication (chemoprophylaxis) may be a useful adjunct or alternative to vaccination in certain circumstances: if the patient is at high risk for complications, has been exposed to someone with influenza, has contraindications to vaccination, or received the vaccine within the past 2 weeks. The CDC also suggests that chemoprophylaxis be considered for those with immune deficiencies or who are otherwise immunosuppressed after exposure.¹⁴ Antivirals can also be used to control outbreaks in long-term care facilities; in these cases, the recommendedregimen is daily administration for at least 2 weeks, continuing until at least 7 days after the identification of the last case.¹⁴ Oseltamivir (Tamiflu) and zanamivir (Relenza) are the recommended prophylactic agents; a related intravenous medication, peramivir (Rapivab), is recommend for treatment only (see Table 3¹⁴).

Strategy 3: Prevent comorbidities and opportunistic infections

Morbidity associated with influenza often comes from secondary infection. Pneumonia is among the most common complications, so influenza season is a good time to ensure that patients are appropriately vaccinated against pneumococcus, as well. Pneumococcal conjugate vaccine (Prevnar or PCV13) is recommended for children younger than 2 years of age, to be administered in a series of 4 doses: at 2, 4, 6, and 12-15 months. Vaccination with PCV13 is also recommended for those ages 65 or older, to be followed at least one year later with pneumococcal polysaccharide vaccine (Pneumovax or PPSV23).¹⁵ Additional doses of PCV13, PPSV23, or both may be indicated, depending on health status.

Strategy 4: Encourage good hygiene

The availability of immunizations and anti­virals does not replace good hygiene. Frequent handwashing reduces the transmission of respiratory viruses, including influenza.¹⁶ Few studies have evaluated the use of alcohol-based hand sanitizers, but available evidence suggests they are effective in lowering viral transmission.¹⁶

Barriers, such as masks, gloves, and gowns, are helpful for health care workers.¹⁶ Surgical masks are often considered more comfortable to wear than N95 respirators. It may therefore be welcome news that when a 2009 randomized study assessed their use by hospital-based nurses, masks were non-inferior in protecting these health care workers against influenza.¹⁷

Presenteeism, the practice of going to work while sick, should be discouraged. People at risk for influenza may wish to avoid crowds during flu season; those with symptoms should be encouraged to stay home and limit contact with others.

Continue to: Treatment

Strategy 1: Make prompt use of antivirals

Despite available preventive measures, tens of millions of people in the United States develop influenza every year. Use of antiviral medication, begun early in the course of illness, can reduce the duration of symptoms and may reduce the risk for complications.

The neuraminidase inhibitor (NI) group of antivirals—oseltamivir, zanamivir, and peramivir—is effective against influenza types A and B and current resistance rates are low.

The adamantine family of antivirals, amantadine and rimantadine, treat type A only. Since the circulating influenza strains in the past several seasons have demonstrated resistance >99%, these medications are not currently recommended.¹⁴

NIs reduce the duration of influenza symptoms by 10% to 20%, shortening the illness by 6 to 24 hours.^18,19 In otherwise healthy patients, this benefit must be balanced against the increased risk for nausea and vomiting (oseltamivir), bronchospasm and sinusitis (zanamivir), and diarrhea (peramivir). In adults, NIs reduce the risk for lower respiratory tract complications and hospitalization. A 2015 meta-analysis by Dobson et al found a relative risk for hospitalization among those prescribed oseltamivir vs placebo of 37%.¹⁸

In the past, antivirals were used only in high-risk patients, such as children younger than 2 years, adults older than 65 years, and those with chronic health conditions.¹⁴ Now, antivirals are recommended for those who are at higher risk for complications (see Table 4), those with “severe, complicated, or progressive illness,” and hospitalized patients.¹⁴

Continue to: Antiviral treatment may have some value...

Antiviral treatment may have some value for hospitalized patients when started even 5 days after symptom onset. Treatment may be extended beyond the usual recommendations (5 days for oseltamivir or zanamivir) in immunosuppressed patients or the critically ill. Additionally, recent guidelines include consideration of antiviral treatment in outpatients who are at normal risk if treatment can be started within 48 hours of symptom onset.¹⁴

The CDC currently recommends use of oseltamivir rather than other antivirals for most hospitalized patients, based on the availability of data on its use in this setting.¹⁴ Intravenous peramivir is recommended for patients who cannot tolerate or absorb oral medication; inhaled zanamivir or IV peramivir are preferred for patients with end-stage renal disease who are not undergoing dialysis (see Table 3).¹⁴

Strategy 2: Exercise caution when it comes to supportive care

There are other medications that may offer symptom relief or prevent complications, especially when antivirals are contraindicated or unavailable.

Corticosteroids are recommended as part of the treatment of community-acquired pneumonia,²⁰ but their role in influenza is controversial. A 2016 Cochrane review²¹ found no randomized controlled trials on the topic. Although the balance of available data from observational studies indicated that use of corticosteroids was associated with increased mortality, the authors also noted that all the studies included in their meta-analysis were of “very low quality.” They concluded that “the use of steroids in influenza remains a clinical judgement call.”

Offering vaccination by the end of October, if possible, is recommended in order for immunity to develop by mid-November.

Statins may be associated with improved outcomes in influenza and pneumonia. Studies thus far have given contradictory results,^22,23 and a planned Cochrane review of the question has been withdrawn.²⁴

Continue to: Over-the-counter medications...

Over-the-counter medications, such as aspirin, acetaminophen, and ibuprofen are often used to manage the fever and myalgia associated with influenza. Patients should be cautioned against using the same ingredient in multiple different branded medications. Acetaminophen, for example, is not limited to Tylenol-branded products. To avoid Reye’s syndrome, children and teens with febrile illness, such as influenza, should not use aspirin.

CORRESPONDENCE
Jennifer L. Hamilton, MD, PhD, Drexel Family Medicine, 10 Shurs Lane, Suite 301, Philadelphia, PA 19127; [email protected].

Researchers found a lower rate of pediatric fever after applying a standard definition of fever across three different clinical trials of pediatric patients receiving influenza vaccinations, according to research published in the Pediatric Infectious Disease Journal.

Yangna/Thinkstock

Investigators in future studies must adopt a standardized definition of pediatric fever after an influenza vaccination. “Our study demonstrates the variability in results which occur due to minor differences in the definition of fever, methods of analysis and reporting of results,” Jean Li-Kim-Moy, MBBS, of the University of Sydney, and colleagues wrote.

Dr. Li-Kim-Moy and colleagues analyzed pediatric datasets from three different clinical trials using trivalent influenza vaccine (TIV); the primary trial included 3,317 children aged 6-35 months who were randomized to receive Fluarix at 0.25 mL or 0.5 mL, or receive 0.25 mL of Fluzone. The other two trials studied children receiving TIV between 6 months–17 years and 3-17 years. The researchers also performed a multivariable regression analysis to determine the relationship between immunogenicity, antipyretic use, and postvaccination fever.

The primary study initially reported the fever rate 0 days–3 days after vaccination was between 6% and 7%. After reporting the rate of fever separately for each dose and changing the criteria to “defining fever as greater than or equal to 38.0°C by any route of measurement” for the primary study, the researchers found a rate of any-cause fever was 3%-4% for the first dose and 4%-5% for the second dose. The rate of vaccine-related fever in the primary study was 3% for the first dose and 3%-4% for the second dose, with researchers noting vaccine-related fever occurred significantly earlier compared with any-cause fever (mean 1 days vs. 2 days after vaccination; P equals .04).

Impact of fever, antipyretics

The researchers also performed a pooled immunogenicity analysis of 5,902 children from all three trials and found a strong association between fever after vaccination and increased geometric mean titer (GMT) ratios (1.21-1.39; P less than or equal to .01) and an association between antipyretic use and reduced GMT ratios (0.80-0.87; P less than .0006).

“Our pooled analysis of the three trials demonstrated highly significant associations, for all strains, between postvaccination fever and up to 39% higher GMT; this may suggest a close role between fever and the body’s immunologic response to the influenza antigens within the vaccine. Similarly, strong evidence of associations in the opposite direction was found between postvaccination antipyretic use (days 0-3), adjusting for all other factors including fever, and decreased immunogenicity against all vaccine strains in children,” Dr. Li-Kim-Moy and colleagues said.

Antipyretic use was common in the primary study, occurring in one in six of the children, they said. These findings of “significant associations between fever and increased vaccine immunogenicity, and between antipyretic use and reduced immunogenicity in children after influenza vaccination” suggest the need for further study, especially because parents often give antipyretics if their children are febrile after vaccinations.

“There is uncertainty whether our findings, and those of others, on immunogenicity translate into clinically significant effects,” they wrote. “However, the fact that influenza vaccine, unlike many routine childhood vaccines, is only moderately protective may mean that modest reductions in antibody response are more likely to correlate to less protection.”

Dr. Wood reported receiving a fellowship from the National Health and Medical Research Council (NHMRC) and being an investigator for GlaxoSmithKline trials. Dr. Booy reported being an advisor for influenza vaccine manufacturing, an advisory board member, on the speaker’s bureau, and a researcher of vaccines for several manufacturers. The other authors reported no relevant conflicts of interest.

SOURCE: Li-Kim-Moy J et al. Pediatr Infect Dis J. 2018 Oct;37(10):971-5.

Researchers found a lower rate of pediatric fever after applying a standard definition of fever across three different clinical trials of pediatric patients receiving influenza vaccinations, according to research published in the Pediatric Infectious Disease Journal.

Yangna/Thinkstock

Investigators in future studies must adopt a standardized definition of pediatric fever after an influenza vaccination. “Our study demonstrates the variability in results which occur due to minor differences in the definition of fever, methods of analysis and reporting of results,” Jean Li-Kim-Moy, MBBS, of the University of Sydney, and colleagues wrote.

Dr. Li-Kim-Moy and colleagues analyzed pediatric datasets from three different clinical trials using trivalent influenza vaccine (TIV); the primary trial included 3,317 children aged 6-35 months who were randomized to receive Fluarix at 0.25 mL or 0.5 mL, or receive 0.25 mL of Fluzone. The other two trials studied children receiving TIV between 6 months–17 years and 3-17 years. The researchers also performed a multivariable regression analysis to determine the relationship between immunogenicity, antipyretic use, and postvaccination fever.

The primary study initially reported the fever rate 0 days–3 days after vaccination was between 6% and 7%. After reporting the rate of fever separately for each dose and changing the criteria to “defining fever as greater than or equal to 38.0°C by any route of measurement” for the primary study, the researchers found a rate of any-cause fever was 3%-4% for the first dose and 4%-5% for the second dose. The rate of vaccine-related fever in the primary study was 3% for the first dose and 3%-4% for the second dose, with researchers noting vaccine-related fever occurred significantly earlier compared with any-cause fever (mean 1 days vs. 2 days after vaccination; P equals .04).

Impact of fever, antipyretics

The researchers also performed a pooled immunogenicity analysis of 5,902 children from all three trials and found a strong association between fever after vaccination and increased geometric mean titer (GMT) ratios (1.21-1.39; P less than or equal to .01) and an association between antipyretic use and reduced GMT ratios (0.80-0.87; P less than .0006).

“Our pooled analysis of the three trials demonstrated highly significant associations, for all strains, between postvaccination fever and up to 39% higher GMT; this may suggest a close role between fever and the body’s immunologic response to the influenza antigens within the vaccine. Similarly, strong evidence of associations in the opposite direction was found between postvaccination antipyretic use (days 0-3), adjusting for all other factors including fever, and decreased immunogenicity against all vaccine strains in children,” Dr. Li-Kim-Moy and colleagues said.

Antipyretic use was common in the primary study, occurring in one in six of the children, they said. These findings of “significant associations between fever and increased vaccine immunogenicity, and between antipyretic use and reduced immunogenicity in children after influenza vaccination” suggest the need for further study, especially because parents often give antipyretics if their children are febrile after vaccinations.

“There is uncertainty whether our findings, and those of others, on immunogenicity translate into clinically significant effects,” they wrote. “However, the fact that influenza vaccine, unlike many routine childhood vaccines, is only moderately protective may mean that modest reductions in antibody response are more likely to correlate to less protection.”

Dr. Wood reported receiving a fellowship from the National Health and Medical Research Council (NHMRC) and being an investigator for GlaxoSmithKline trials. Dr. Booy reported being an advisor for influenza vaccine manufacturing, an advisory board member, on the speaker’s bureau, and a researcher of vaccines for several manufacturers. The other authors reported no relevant conflicts of interest.

SOURCE: Li-Kim-Moy J et al. Pediatr Infect Dis J. 2018 Oct;37(10):971-5.

Researchers found a lower rate of pediatric fever after applying a standard definition of fever across three different clinical trials of pediatric patients receiving influenza vaccinations, according to research published in the Pediatric Infectious Disease Journal.

Yangna/Thinkstock

Investigators in future studies must adopt a standardized definition of pediatric fever after an influenza vaccination. “Our study demonstrates the variability in results which occur due to minor differences in the definition of fever, methods of analysis and reporting of results,” Jean Li-Kim-Moy, MBBS, of the University of Sydney, and colleagues wrote.

Dr. Li-Kim-Moy and colleagues analyzed pediatric datasets from three different clinical trials using trivalent influenza vaccine (TIV); the primary trial included 3,317 children aged 6-35 months who were randomized to receive Fluarix at 0.25 mL or 0.5 mL, or receive 0.25 mL of Fluzone. The other two trials studied children receiving TIV between 6 months–17 years and 3-17 years. The researchers also performed a multivariable regression analysis to determine the relationship between immunogenicity, antipyretic use, and postvaccination fever.

The primary study initially reported the fever rate 0 days–3 days after vaccination was between 6% and 7%. After reporting the rate of fever separately for each dose and changing the criteria to “defining fever as greater than or equal to 38.0°C by any route of measurement” for the primary study, the researchers found a rate of any-cause fever was 3%-4% for the first dose and 4%-5% for the second dose. The rate of vaccine-related fever in the primary study was 3% for the first dose and 3%-4% for the second dose, with researchers noting vaccine-related fever occurred significantly earlier compared with any-cause fever (mean 1 days vs. 2 days after vaccination; P equals .04).

Impact of fever, antipyretics

The researchers also performed a pooled immunogenicity analysis of 5,902 children from all three trials and found a strong association between fever after vaccination and increased geometric mean titer (GMT) ratios (1.21-1.39; P less than or equal to .01) and an association between antipyretic use and reduced GMT ratios (0.80-0.87; P less than .0006).

“Our pooled analysis of the three trials demonstrated highly significant associations, for all strains, between postvaccination fever and up to 39% higher GMT; this may suggest a close role between fever and the body’s immunologic response to the influenza antigens within the vaccine. Similarly, strong evidence of associations in the opposite direction was found between postvaccination antipyretic use (days 0-3), adjusting for all other factors including fever, and decreased immunogenicity against all vaccine strains in children,” Dr. Li-Kim-Moy and colleagues said.

Antipyretic use was common in the primary study, occurring in one in six of the children, they said. These findings of “significant associations between fever and increased vaccine immunogenicity, and between antipyretic use and reduced immunogenicity in children after influenza vaccination” suggest the need for further study, especially because parents often give antipyretics if their children are febrile after vaccinations.

“There is uncertainty whether our findings, and those of others, on immunogenicity translate into clinically significant effects,” they wrote. “However, the fact that influenza vaccine, unlike many routine childhood vaccines, is only moderately protective may mean that modest reductions in antibody response are more likely to correlate to less protection.”

Dr. Wood reported receiving a fellowship from the National Health and Medical Research Council (NHMRC) and being an investigator for GlaxoSmithKline trials. Dr. Booy reported being an advisor for influenza vaccine manufacturing, an advisory board member, on the speaker’s bureau, and a researcher of vaccines for several manufacturers. The other authors reported no relevant conflicts of interest.

SOURCE: Li-Kim-Moy J et al. Pediatr Infect Dis J. 2018 Oct;37(10):971-5.

For patients with Clostridium difficile infections, undetectable peripheral eosinophils at admission were a significant predictor of severe outcomes, even in the absence of hypotension and tachycardia, researchers wrote in JAMA Surgery.

CDC/Jennifer Hulsey

“In animal models, peripheral eosinopenia is a biologically plausible predictive factor for adverse outcomes, and human data from this study indicate that this frequent addition to an admission complete blood cell count is an inexpensive, widely available risk index in the treatment of C. difficile infection,” wrote Audrey S. Kulaylat, MD, of Penn State University, Hershey, and her associates.

In their cohort study of 2,065 patients admitted to two tertiary referral centers with C. difficile infection, undetectable eosinophil counts at hospital admission were associated with significantly increased odds of in-hospital mortality in both a training dataset (odds ratio, 2.01; 95% confidence interval, 1.08-3.73; P = .03) and a validation dataset (OR, 2.26; 95% CI, 1.33-3.83; P = .002). Undetectable eosinophil counts also were associated with elevated odds of severe disease requiring intensive care, vasopressor use, and emergency total colectomy. Besides eosinopenia, significant predictors of mortality included having more comorbidities and lower systolic blood pressure at admission. Strikingly, when patients had no initial hypotension or tachycardia, an undetectable eosinophil count was the only identifiable predictor of in-hospital death (OR, 5.76; 95% CI, 1.99-16.64). An elevated white blood cell count was not a significant predictor of mortality in this subgroup.

Dr. Kulaylat and her associates are studying the microbiome in C. difficile infection. Their work has identified a host immune reaction marked by an “exaggerated inflammasome response” and peripheral eosinopenia, they explained. Two recent murine models have produced similar results.

Admission eosinophil counts “allow for an immediate assessment of mortality risk at admission that is inexpensive and part of a differential for a standard complete blood count available at any hospital,” they concluded. They are now prospectively evaluating a prognostic score for C. difficile infection that includes eosinopenia and other easily discernible admission factors. The National Institutes of Health supported the work. The researchers reported having no conflicts of interest.
 

SOURCE: Kulaylat AS et al. JAMA Surg. 2018 Sep 12. doi: 10.1001/jamasurg.2018.3174.
 

For patients with Clostridium difficile infections, undetectable peripheral eosinophils at admission were a significant predictor of severe outcomes, even in the absence of hypotension and tachycardia, researchers wrote in JAMA Surgery.

CDC/Jennifer Hulsey

“In animal models, peripheral eosinopenia is a biologically plausible predictive factor for adverse outcomes, and human data from this study indicate that this frequent addition to an admission complete blood cell count is an inexpensive, widely available risk index in the treatment of C. difficile infection,” wrote Audrey S. Kulaylat, MD, of Penn State University, Hershey, and her associates.

In their cohort study of 2,065 patients admitted to two tertiary referral centers with C. difficile infection, undetectable eosinophil counts at hospital admission were associated with significantly increased odds of in-hospital mortality in both a training dataset (odds ratio, 2.01; 95% confidence interval, 1.08-3.73; P = .03) and a validation dataset (OR, 2.26; 95% CI, 1.33-3.83; P = .002). Undetectable eosinophil counts also were associated with elevated odds of severe disease requiring intensive care, vasopressor use, and emergency total colectomy. Besides eosinopenia, significant predictors of mortality included having more comorbidities and lower systolic blood pressure at admission. Strikingly, when patients had no initial hypotension or tachycardia, an undetectable eosinophil count was the only identifiable predictor of in-hospital death (OR, 5.76; 95% CI, 1.99-16.64). An elevated white blood cell count was not a significant predictor of mortality in this subgroup.

Dr. Kulaylat and her associates are studying the microbiome in C. difficile infection. Their work has identified a host immune reaction marked by an “exaggerated inflammasome response” and peripheral eosinopenia, they explained. Two recent murine models have produced similar results.

Admission eosinophil counts “allow for an immediate assessment of mortality risk at admission that is inexpensive and part of a differential for a standard complete blood count available at any hospital,” they concluded. They are now prospectively evaluating a prognostic score for C. difficile infection that includes eosinopenia and other easily discernible admission factors. The National Institutes of Health supported the work. The researchers reported having no conflicts of interest.
 

SOURCE: Kulaylat AS et al. JAMA Surg. 2018 Sep 12. doi: 10.1001/jamasurg.2018.3174.
 

For patients with Clostridium difficile infections, undetectable peripheral eosinophils at admission were a significant predictor of severe outcomes, even in the absence of hypotension and tachycardia, researchers wrote in JAMA Surgery.

CDC/Jennifer Hulsey

“In animal models, peripheral eosinopenia is a biologically plausible predictive factor for adverse outcomes, and human data from this study indicate that this frequent addition to an admission complete blood cell count is an inexpensive, widely available risk index in the treatment of C. difficile infection,” wrote Audrey S. Kulaylat, MD, of Penn State University, Hershey, and her associates.

In their cohort study of 2,065 patients admitted to two tertiary referral centers with C. difficile infection, undetectable eosinophil counts at hospital admission were associated with significantly increased odds of in-hospital mortality in both a training dataset (odds ratio, 2.01; 95% confidence interval, 1.08-3.73; P = .03) and a validation dataset (OR, 2.26; 95% CI, 1.33-3.83; P = .002). Undetectable eosinophil counts also were associated with elevated odds of severe disease requiring intensive care, vasopressor use, and emergency total colectomy. Besides eosinopenia, significant predictors of mortality included having more comorbidities and lower systolic blood pressure at admission. Strikingly, when patients had no initial hypotension or tachycardia, an undetectable eosinophil count was the only identifiable predictor of in-hospital death (OR, 5.76; 95% CI, 1.99-16.64). An elevated white blood cell count was not a significant predictor of mortality in this subgroup.

Dr. Kulaylat and her associates are studying the microbiome in C. difficile infection. Their work has identified a host immune reaction marked by an “exaggerated inflammasome response” and peripheral eosinopenia, they explained. Two recent murine models have produced similar results.

Admission eosinophil counts “allow for an immediate assessment of mortality risk at admission that is inexpensive and part of a differential for a standard complete blood count available at any hospital,” they concluded. They are now prospectively evaluating a prognostic score for C. difficile infection that includes eosinopenia and other easily discernible admission factors. The National Institutes of Health supported the work. The researchers reported having no conflicts of interest.
 

SOURCE: Kulaylat AS et al. JAMA Surg. 2018 Sep 12. doi: 10.1001/jamasurg.2018.3174.
 

The Diagnosis: Chromomycosis

Skin scrapings revealed brownish sclerotic bodies. A review of the skin biopsy performed 4 years prior showed florid pseudoepitheliomatous hyperplasia overlying dense mixed inflammatory infiltrates of predominantly granulomatous microabscesses in the dermis. Numerous sclerotic bodies were evident within multinucleated giant cells and scattered among epidermal and dermal microabscesses (Figure). Few atypical basal keratinocytes were noted, but frank pleomorphism and aberrant mitosis was absent.

Chromomycosis is a chronic subcutaneous fungal infection caused by pigmented (dematiaceous) fungi growing in soil, decaying vegetables, and rotting wood. Infection usually occurs via traumatic inoculation from splinters and thorns. Some of the agents responsible include Fonsecaea pedrosoi, Cladophialophora carrionii, and Phialophora verrucosa.¹

Diverse cutaneous manifestations have been observed with 5 different clinical forms: nodules, verrucous hyperkeratotic plaques, cicatricial lesions with central sparing, scaly plaques, and tumoral (cauliflowerlike) lesions.² Of these clinical presentations, verrucous hyperkeratotic plaques are the most common, as seen in our patient. However, this presentation is not exclusive to chromomycosis because many conditions appear similarly, including sporotrichosis, nontuberculous mycobacterial infection, tuberculosis verrucosa cutis, and squamous cell carcinoma (SCC). The presence of small ulcerations may appear as the black dots seen on the plaques of chromomycosis, distinguishing chromomycosis from other conditions. Although this feature may be a fundamental clue for diagnosis, it should be emphasized that in many occasions, clinical differences between chromomycosis and its differentials are subtle. A study involving 9 patients with chromomycosis reported that only 1 was given the initial diagnosis of mycosis. Six patients initially were diagnosed with cutaneous malignancies, 1 patient with viral warts, and another patient with ganglion.³ Therefore, unless there is a high index of suspicion, these conditions may easily be mistaken for others by clinicians who are unfamiliar with their presentations, particularly in the setting of a busy clinic.

Chromomycosis routinely is diagnosed based on histologic examination and culture. Apart from sclerotic bodies, other histopathologic features include an inflammatory infiltrate characterized by neutrophilic microabscesses, multinucleated cells, fibrosis, acanthosis, papillomatosis, hyperkeratosis, and pseudoepitheliomatous hyperplasia (PEH).² Pseudoepitheliomatous hyperplasia is an exaggerated proliferation of the epidermis, usually secondary to chronic inflammatory skin conditions.⁴ Because most verrucous lesions are thought to be neoplastic and carcinomas more commonly are seen and expected in dermatopathology, PEH can sometimes be mistaken for SCC. At times, the squamous epithelium of PEH can appear infiltrative, giving the illusion of well-differentiated SCC.⁵ However, absence of marked cellular atypia and abnormal mitotic activity should suggest otherwise. Thorough scrutiny for a concomitant infective process is necessary to avoid the overdiagnosis of SCC. Special stains for infectious agents such as periodic acid-Schiff and Grocott-Gomori methenamine-silver for fungal spores and Ziehl-Neelsen for acid-fast bacilli may reveal infectious organisms. Multilevel sections of deeper levels also may be essential to uncover sparse organisms.⁶

There is no standard treatment of chromomycosis. Some treatment options are available based on few open clinical studies and expert opinions. Systemic antifungals such as itraconazole or terbinafine most commonly are used with 15% to 80% cure rates.⁷ In invasive refractory cases, a combination of itraconazole and terbinafine has been employed as salvage therapy. Recently, the use of newer azoles such as posaconazole is favored due to its expanded-spectrum profile along with better pharmacodynamics and pharmacokinetic profile versus itraconazole. Physical methods such as cryotherapy, heat therapy, laser therapy, and photodynamic therapy frequently are practiced in conjunction with systemic antifungal therapy.⁸ Surgical procedures such as photocoagulation, Mohs micrographic surgery, and curettage sometimes are recommended for smaller well-defined lesions. Amputation, however, is rarely ever indicated, as there rarely is deep tissue involvement.²

Our case highlights the importance of clinicopathologic correlation in diagnosing squamous epithelial lesions. A high index of clinical suspicion and a wider list of differential diagnoses of verrucous plaques are necessary to minimize pitfalls in diagnosing lesions with squamous proliferation and therefore reduces the need for unnecessary interventions.

The Diagnosis: Chromomycosis

Skin scrapings revealed brownish sclerotic bodies. A review of the skin biopsy performed 4 years prior showed florid pseudoepitheliomatous hyperplasia overlying dense mixed inflammatory infiltrates of predominantly granulomatous microabscesses in the dermis. Numerous sclerotic bodies were evident within multinucleated giant cells and scattered among epidermal and dermal microabscesses (Figure). Few atypical basal keratinocytes were noted, but frank pleomorphism and aberrant mitosis was absent.

Chromomycosis is a chronic subcutaneous fungal infection caused by pigmented (dematiaceous) fungi growing in soil, decaying vegetables, and rotting wood. Infection usually occurs via traumatic inoculation from splinters and thorns. Some of the agents responsible include Fonsecaea pedrosoi, Cladophialophora carrionii, and Phialophora verrucosa.¹

Diverse cutaneous manifestations have been observed with 5 different clinical forms: nodules, verrucous hyperkeratotic plaques, cicatricial lesions with central sparing, scaly plaques, and tumoral (cauliflowerlike) lesions.² Of these clinical presentations, verrucous hyperkeratotic plaques are the most common, as seen in our patient. However, this presentation is not exclusive to chromomycosis because many conditions appear similarly, including sporotrichosis, nontuberculous mycobacterial infection, tuberculosis verrucosa cutis, and squamous cell carcinoma (SCC). The presence of small ulcerations may appear as the black dots seen on the plaques of chromomycosis, distinguishing chromomycosis from other conditions. Although this feature may be a fundamental clue for diagnosis, it should be emphasized that in many occasions, clinical differences between chromomycosis and its differentials are subtle. A study involving 9 patients with chromomycosis reported that only 1 was given the initial diagnosis of mycosis. Six patients initially were diagnosed with cutaneous malignancies, 1 patient with viral warts, and another patient with ganglion.³ Therefore, unless there is a high index of suspicion, these conditions may easily be mistaken for others by clinicians who are unfamiliar with their presentations, particularly in the setting of a busy clinic.

Chromomycosis routinely is diagnosed based on histologic examination and culture. Apart from sclerotic bodies, other histopathologic features include an inflammatory infiltrate characterized by neutrophilic microabscesses, multinucleated cells, fibrosis, acanthosis, papillomatosis, hyperkeratosis, and pseudoepitheliomatous hyperplasia (PEH).² Pseudoepitheliomatous hyperplasia is an exaggerated proliferation of the epidermis, usually secondary to chronic inflammatory skin conditions.⁴ Because most verrucous lesions are thought to be neoplastic and carcinomas more commonly are seen and expected in dermatopathology, PEH can sometimes be mistaken for SCC. At times, the squamous epithelium of PEH can appear infiltrative, giving the illusion of well-differentiated SCC.⁵ However, absence of marked cellular atypia and abnormal mitotic activity should suggest otherwise. Thorough scrutiny for a concomitant infective process is necessary to avoid the overdiagnosis of SCC. Special stains for infectious agents such as periodic acid-Schiff and Grocott-Gomori methenamine-silver for fungal spores and Ziehl-Neelsen for acid-fast bacilli may reveal infectious organisms. Multilevel sections of deeper levels also may be essential to uncover sparse organisms.⁶

There is no standard treatment of chromomycosis. Some treatment options are available based on few open clinical studies and expert opinions. Systemic antifungals such as itraconazole or terbinafine most commonly are used with 15% to 80% cure rates.⁷ In invasive refractory cases, a combination of itraconazole and terbinafine has been employed as salvage therapy. Recently, the use of newer azoles such as posaconazole is favored due to its expanded-spectrum profile along with better pharmacodynamics and pharmacokinetic profile versus itraconazole. Physical methods such as cryotherapy, heat therapy, laser therapy, and photodynamic therapy frequently are practiced in conjunction with systemic antifungal therapy.⁸ Surgical procedures such as photocoagulation, Mohs micrographic surgery, and curettage sometimes are recommended for smaller well-defined lesions. Amputation, however, is rarely ever indicated, as there rarely is deep tissue involvement.²

Our case highlights the importance of clinicopathologic correlation in diagnosing squamous epithelial lesions. A high index of clinical suspicion and a wider list of differential diagnoses of verrucous plaques are necessary to minimize pitfalls in diagnosing lesions with squamous proliferation and therefore reduces the need for unnecessary interventions.

The Diagnosis: Chromomycosis

Skin scrapings revealed brownish sclerotic bodies. A review of the skin biopsy performed 4 years prior showed florid pseudoepitheliomatous hyperplasia overlying dense mixed inflammatory infiltrates of predominantly granulomatous microabscesses in the dermis. Numerous sclerotic bodies were evident within multinucleated giant cells and scattered among epidermal and dermal microabscesses (Figure). Few atypical basal keratinocytes were noted, but frank pleomorphism and aberrant mitosis was absent.

Chromomycosis is a chronic subcutaneous fungal infection caused by pigmented (dematiaceous) fungi growing in soil, decaying vegetables, and rotting wood. Infection usually occurs via traumatic inoculation from splinters and thorns. Some of the agents responsible include Fonsecaea pedrosoi, Cladophialophora carrionii, and Phialophora verrucosa.¹

Diverse cutaneous manifestations have been observed with 5 different clinical forms: nodules, verrucous hyperkeratotic plaques, cicatricial lesions with central sparing, scaly plaques, and tumoral (cauliflowerlike) lesions.² Of these clinical presentations, verrucous hyperkeratotic plaques are the most common, as seen in our patient. However, this presentation is not exclusive to chromomycosis because many conditions appear similarly, including sporotrichosis, nontuberculous mycobacterial infection, tuberculosis verrucosa cutis, and squamous cell carcinoma (SCC). The presence of small ulcerations may appear as the black dots seen on the plaques of chromomycosis, distinguishing chromomycosis from other conditions. Although this feature may be a fundamental clue for diagnosis, it should be emphasized that in many occasions, clinical differences between chromomycosis and its differentials are subtle. A study involving 9 patients with chromomycosis reported that only 1 was given the initial diagnosis of mycosis. Six patients initially were diagnosed with cutaneous malignancies, 1 patient with viral warts, and another patient with ganglion.³ Therefore, unless there is a high index of suspicion, these conditions may easily be mistaken for others by clinicians who are unfamiliar with their presentations, particularly in the setting of a busy clinic.

Chromomycosis routinely is diagnosed based on histologic examination and culture. Apart from sclerotic bodies, other histopathologic features include an inflammatory infiltrate characterized by neutrophilic microabscesses, multinucleated cells, fibrosis, acanthosis, papillomatosis, hyperkeratosis, and pseudoepitheliomatous hyperplasia (PEH).² Pseudoepitheliomatous hyperplasia is an exaggerated proliferation of the epidermis, usually secondary to chronic inflammatory skin conditions.⁴ Because most verrucous lesions are thought to be neoplastic and carcinomas more commonly are seen and expected in dermatopathology, PEH can sometimes be mistaken for SCC. At times, the squamous epithelium of PEH can appear infiltrative, giving the illusion of well-differentiated SCC.⁵ However, absence of marked cellular atypia and abnormal mitotic activity should suggest otherwise. Thorough scrutiny for a concomitant infective process is necessary to avoid the overdiagnosis of SCC. Special stains for infectious agents such as periodic acid-Schiff and Grocott-Gomori methenamine-silver for fungal spores and Ziehl-Neelsen for acid-fast bacilli may reveal infectious organisms. Multilevel sections of deeper levels also may be essential to uncover sparse organisms.⁶

There is no standard treatment of chromomycosis. Some treatment options are available based on few open clinical studies and expert opinions. Systemic antifungals such as itraconazole or terbinafine most commonly are used with 15% to 80% cure rates.⁷ In invasive refractory cases, a combination of itraconazole and terbinafine has been employed as salvage therapy. Recently, the use of newer azoles such as posaconazole is favored due to its expanded-spectrum profile along with better pharmacodynamics and pharmacokinetic profile versus itraconazole. Physical methods such as cryotherapy, heat therapy, laser therapy, and photodynamic therapy frequently are practiced in conjunction with systemic antifungal therapy.⁸ Surgical procedures such as photocoagulation, Mohs micrographic surgery, and curettage sometimes are recommended for smaller well-defined lesions. Amputation, however, is rarely ever indicated, as there rarely is deep tissue involvement.²

Our case highlights the importance of clinicopathologic correlation in diagnosing squamous epithelial lesions. A high index of clinical suspicion and a wider list of differential diagnoses of verrucous plaques are necessary to minimize pitfalls in diagnosing lesions with squamous proliferation and therefore reduces the need for unnecessary interventions.

WASHINGTON – The flu vaccine may not be perfect, but it can reduce the severity of illness and curb the risk of spreading the disease to others, William Schaffner, MD, emphasized at a press conference held by the National Foundation for Infectious Diseases.

“Give the vaccine credit for softening the blow,” said Dr. Schaffner, medical director of NFID and a professor at Vanderbilt University in Nashville.

Dr. Schaffner and a panel of experts including U.S. Surgeon General Jerome M. Adams, MD, encouraged the public and the health care community to follow recommendation from the Centers for Disease Control & Prevention that everyone aged 6 months and older receive an influenza vaccine.

Dr. Schaffner shared recent data showing that complications from the flu don’t stop when the acute illness resolves. Acute influenza causes a whole-body inflammatory reaction, and consequently “there is an increased risk of heart attack and stroke during the 2-4 weeks of recovery from acute influenza,” he said. In addition, older adults who experience acute flu and are already frail may never regain their pre-flu level of function, as the flu can start a “domino effect of decline and disability.”

Despite last year’s severe flu season that included 180 deaths in children, vaccination remains the most effective protection against the flu, Dr. Adams said.

This year, between 163 million and 168 million doses of vaccine will be available in the United States. The vaccine is available in a range of settings including doctors’ offices, pharmacies, grocery stores, and workplaces, said Dr. Adams.

Flu vaccine choices this year include a return of the live-attenuated influenza vaccine (LAIV) given via nasal spray, along with the standard influenza vaccine that includes either three influenza viruses (trivalent, with two influenza A and one influenza B) or four influenza viruses (quadrivalent, with two influenza A and two influenza B). Other options are adjuvanted vaccine and high-dose vaccine for adults aged 65 years and older, and a cell-based and recombinant vaccine as alternatives to egg-based vaccines.

Dr. Adams emphasized the importance of healthy people getting vaccinated to protect the community. “All the people who died from the flu caught it from someone else,” he said.

Courtesy NFID

WASHINGTON – The flu vaccine may not be perfect, but it can reduce the severity of illness and curb the risk of spreading the disease to others, William Schaffner, MD, emphasized at a press conference held by the National Foundation for Infectious Diseases.

“Give the vaccine credit for softening the blow,” said Dr. Schaffner, medical director of NFID and a professor at Vanderbilt University in Nashville.

Dr. Schaffner and a panel of experts including U.S. Surgeon General Jerome M. Adams, MD, encouraged the public and the health care community to follow recommendation from the Centers for Disease Control & Prevention that everyone aged 6 months and older receive an influenza vaccine.

Dr. Schaffner shared recent data showing that complications from the flu don’t stop when the acute illness resolves. Acute influenza causes a whole-body inflammatory reaction, and consequently “there is an increased risk of heart attack and stroke during the 2-4 weeks of recovery from acute influenza,” he said. In addition, older adults who experience acute flu and are already frail may never regain their pre-flu level of function, as the flu can start a “domino effect of decline and disability.”

Despite last year’s severe flu season that included 180 deaths in children, vaccination remains the most effective protection against the flu, Dr. Adams said.

This year, between 163 million and 168 million doses of vaccine will be available in the United States. The vaccine is available in a range of settings including doctors’ offices, pharmacies, grocery stores, and workplaces, said Dr. Adams.

Flu vaccine choices this year include a return of the live-attenuated influenza vaccine (LAIV) given via nasal spray, along with the standard influenza vaccine that includes either three influenza viruses (trivalent, with two influenza A and one influenza B) or four influenza viruses (quadrivalent, with two influenza A and two influenza B). Other options are adjuvanted vaccine and high-dose vaccine for adults aged 65 years and older, and a cell-based and recombinant vaccine as alternatives to egg-based vaccines.

Dr. Adams emphasized the importance of healthy people getting vaccinated to protect the community. “All the people who died from the flu caught it from someone else,” he said.

Courtesy NFID

WASHINGTON – The flu vaccine may not be perfect, but it can reduce the severity of illness and curb the risk of spreading the disease to others, William Schaffner, MD, emphasized at a press conference held by the National Foundation for Infectious Diseases.

“Give the vaccine credit for softening the blow,” said Dr. Schaffner, medical director of NFID and a professor at Vanderbilt University in Nashville.

Dr. Schaffner and a panel of experts including U.S. Surgeon General Jerome M. Adams, MD, encouraged the public and the health care community to follow recommendation from the Centers for Disease Control & Prevention that everyone aged 6 months and older receive an influenza vaccine.

Dr. Schaffner shared recent data showing that complications from the flu don’t stop when the acute illness resolves. Acute influenza causes a whole-body inflammatory reaction, and consequently “there is an increased risk of heart attack and stroke during the 2-4 weeks of recovery from acute influenza,” he said. In addition, older adults who experience acute flu and are already frail may never regain their pre-flu level of function, as the flu can start a “domino effect of decline and disability.”

Despite last year’s severe flu season that included 180 deaths in children, vaccination remains the most effective protection against the flu, Dr. Adams said.

This year, between 163 million and 168 million doses of vaccine will be available in the United States. The vaccine is available in a range of settings including doctors’ offices, pharmacies, grocery stores, and workplaces, said Dr. Adams.

Flu vaccine choices this year include a return of the live-attenuated influenza vaccine (LAIV) given via nasal spray, along with the standard influenza vaccine that includes either three influenza viruses (trivalent, with two influenza A and one influenza B) or four influenza viruses (quadrivalent, with two influenza A and two influenza B). Other options are adjuvanted vaccine and high-dose vaccine for adults aged 65 years and older, and a cell-based and recombinant vaccine as alternatives to egg-based vaccines.

Dr. Adams emphasized the importance of healthy people getting vaccinated to protect the community. “All the people who died from the flu caught it from someone else,” he said.

Courtesy NFID

PARIS – Using a point-of-care test for viral pathogens, hospital admissions were avoided in about a third of emergency department patients with suspected respiratory infection when other clinical signs also suggested a low risk of a bacterial pathogen, according to a single-center experience presented at the annual congress of the European Respiratory Society.

Wikimedia Commons

“We found that when patients had point-of-care respiratory viral testing soon after they were admitted to the emergency department, we were able to reduce unnecessary admission and improve bed flow in our center,” reported Kay Roy, MBBS, consultant physician in respiratory medicine, West Hertfordshire (England) Hospital NHS Trust.

In a protocol that was launched at Dr. Kay’s institution in January 2018, the point-of-care viral test was combined with other clinical factors, particularly chest x-rays and elevated C-reactive protein (CRP), to determine whether patients had a viral pathogen and whether they could be discharged without antibiotics.

“Clinical judgment will always be required in individual patient decisions regarding antibiotic avoidance and early discharge,” Dr. Roy maintained. “But the point-of-care viral assay can be integrated into a strategy that permits more informed and rapid decision-making.”

This assertion is supported by the experience using a protocol anchored with the point-of-care viral test over a 4-month period. During this time, 901 patients with respiratory symptoms suspected of having a viral etiology were evaluated with the proprietary point-of-care device called FilmArray (bioMérieux).

From a sample taken with a nasopharyngeal swab, the test can identify a broad array of viruses using polymerase chain reaction technology in less than 45 minutes. However, the ED protocol for considering discharge without antibiotics requires additional evidence that the pathogen is viral, including a normal chest x-ray and a CRP less than 50 mg/L.

Of the 901 patients tested, a substantial proportion of whom had chronic obstructive pulmonary disease (COPD) or asthma, 507 (56%) tested positive for at least one virus, including influenza, rhinoviruses, coronaviruses, and adenovirus. Of these, 239 had normal chest x-rays and CRPs less than 50 mg/L. Because of the severity of symptoms or other clinical considerations, 154 patients were admitted, but 85 (36% of those meeting protocol criteria) were discharged without an antibiotic prescription.

“Antibiotics were continued in 90% of the patients who had an abnormal chest x-ray and abnormal CRP,” Dr. Roy reported. However, an objective strategy that permits clinicians to discharge patients at very low risk of a bacterial infection has many advantages even if it applies to a relatively modest proportion of those tested, according to Dr. Roy.

“Each respiratory admission can cost around [2,000 pounds] at our center,” reported Dr. Kay, referring to a figure equivalent to more than $2,600. In addition, she said that avoiding hospitalization frees up hospital beds and facilitates improved antimicrobial stewardship, which is vital to stem resistance.

Avoiding antibiotic use in patients with viral respiratory infections also is relevant to improved antibiotic stewardship in the community. For this reason, a randomized trial with a similar protocol involving the point-of-care viral test is planned in the outpatient setting. According to Dr. Roy, this will involve a community hub to which patients can be referred for testing and clinical evaluation.

“We hope that the quality of care can be improved with the point-of-care test for respiratory viruses as well as helping to reduce antibiotic resistance,” Dr. Roy said.

This approach is promising, according to Tobias Welte, MD, of the department of respiratory medicine at Hannover (Germany) Medical School, but he cautioned that it is not a standard approach.

“The protocol described by Dr. Roy will have to be compared to guidelines and recommended best clinical practice to confirm its usefulness,” he said, while conceding that any strategy that reduces unnecessary hospitalizations deserves further evaluation.

PARIS – Using a point-of-care test for viral pathogens, hospital admissions were avoided in about a third of emergency department patients with suspected respiratory infection when other clinical signs also suggested a low risk of a bacterial pathogen, according to a single-center experience presented at the annual congress of the European Respiratory Society.

Wikimedia Commons

“We found that when patients had point-of-care respiratory viral testing soon after they were admitted to the emergency department, we were able to reduce unnecessary admission and improve bed flow in our center,” reported Kay Roy, MBBS, consultant physician in respiratory medicine, West Hertfordshire (England) Hospital NHS Trust.

In a protocol that was launched at Dr. Kay’s institution in January 2018, the point-of-care viral test was combined with other clinical factors, particularly chest x-rays and elevated C-reactive protein (CRP), to determine whether patients had a viral pathogen and whether they could be discharged without antibiotics.

“Clinical judgment will always be required in individual patient decisions regarding antibiotic avoidance and early discharge,” Dr. Roy maintained. “But the point-of-care viral assay can be integrated into a strategy that permits more informed and rapid decision-making.”

This assertion is supported by the experience using a protocol anchored with the point-of-care viral test over a 4-month period. During this time, 901 patients with respiratory symptoms suspected of having a viral etiology were evaluated with the proprietary point-of-care device called FilmArray (bioMérieux).

From a sample taken with a nasopharyngeal swab, the test can identify a broad array of viruses using polymerase chain reaction technology in less than 45 minutes. However, the ED protocol for considering discharge without antibiotics requires additional evidence that the pathogen is viral, including a normal chest x-ray and a CRP less than 50 mg/L.

Of the 901 patients tested, a substantial proportion of whom had chronic obstructive pulmonary disease (COPD) or asthma, 507 (56%) tested positive for at least one virus, including influenza, rhinoviruses, coronaviruses, and adenovirus. Of these, 239 had normal chest x-rays and CRPs less than 50 mg/L. Because of the severity of symptoms or other clinical considerations, 154 patients were admitted, but 85 (36% of those meeting protocol criteria) were discharged without an antibiotic prescription.

“Antibiotics were continued in 90% of the patients who had an abnormal chest x-ray and abnormal CRP,” Dr. Roy reported. However, an objective strategy that permits clinicians to discharge patients at very low risk of a bacterial infection has many advantages even if it applies to a relatively modest proportion of those tested, according to Dr. Roy.

“Each respiratory admission can cost around [2,000 pounds] at our center,” reported Dr. Kay, referring to a figure equivalent to more than $2,600. In addition, she said that avoiding hospitalization frees up hospital beds and facilitates improved antimicrobial stewardship, which is vital to stem resistance.

Avoiding antibiotic use in patients with viral respiratory infections also is relevant to improved antibiotic stewardship in the community. For this reason, a randomized trial with a similar protocol involving the point-of-care viral test is planned in the outpatient setting. According to Dr. Roy, this will involve a community hub to which patients can be referred for testing and clinical evaluation.

“We hope that the quality of care can be improved with the point-of-care test for respiratory viruses as well as helping to reduce antibiotic resistance,” Dr. Roy said.

This approach is promising, according to Tobias Welte, MD, of the department of respiratory medicine at Hannover (Germany) Medical School, but he cautioned that it is not a standard approach.

“The protocol described by Dr. Roy will have to be compared to guidelines and recommended best clinical practice to confirm its usefulness,” he said, while conceding that any strategy that reduces unnecessary hospitalizations deserves further evaluation.

PARIS – Using a point-of-care test for viral pathogens, hospital admissions were avoided in about a third of emergency department patients with suspected respiratory infection when other clinical signs also suggested a low risk of a bacterial pathogen, according to a single-center experience presented at the annual congress of the European Respiratory Society.

Wikimedia Commons

“We found that when patients had point-of-care respiratory viral testing soon after they were admitted to the emergency department, we were able to reduce unnecessary admission and improve bed flow in our center,” reported Kay Roy, MBBS, consultant physician in respiratory medicine, West Hertfordshire (England) Hospital NHS Trust.

In a protocol that was launched at Dr. Kay’s institution in January 2018, the point-of-care viral test was combined with other clinical factors, particularly chest x-rays and elevated C-reactive protein (CRP), to determine whether patients had a viral pathogen and whether they could be discharged without antibiotics.

“Clinical judgment will always be required in individual patient decisions regarding antibiotic avoidance and early discharge,” Dr. Roy maintained. “But the point-of-care viral assay can be integrated into a strategy that permits more informed and rapid decision-making.”

This assertion is supported by the experience using a protocol anchored with the point-of-care viral test over a 4-month period. During this time, 901 patients with respiratory symptoms suspected of having a viral etiology were evaluated with the proprietary point-of-care device called FilmArray (bioMérieux).

From a sample taken with a nasopharyngeal swab, the test can identify a broad array of viruses using polymerase chain reaction technology in less than 45 minutes. However, the ED protocol for considering discharge without antibiotics requires additional evidence that the pathogen is viral, including a normal chest x-ray and a CRP less than 50 mg/L.

Of the 901 patients tested, a substantial proportion of whom had chronic obstructive pulmonary disease (COPD) or asthma, 507 (56%) tested positive for at least one virus, including influenza, rhinoviruses, coronaviruses, and adenovirus. Of these, 239 had normal chest x-rays and CRPs less than 50 mg/L. Because of the severity of symptoms or other clinical considerations, 154 patients were admitted, but 85 (36% of those meeting protocol criteria) were discharged without an antibiotic prescription.

“Antibiotics were continued in 90% of the patients who had an abnormal chest x-ray and abnormal CRP,” Dr. Roy reported. However, an objective strategy that permits clinicians to discharge patients at very low risk of a bacterial infection has many advantages even if it applies to a relatively modest proportion of those tested, according to Dr. Roy.

“Each respiratory admission can cost around [2,000 pounds] at our center,” reported Dr. Kay, referring to a figure equivalent to more than $2,600. In addition, she said that avoiding hospitalization frees up hospital beds and facilitates improved antimicrobial stewardship, which is vital to stem resistance.

Avoiding antibiotic use in patients with viral respiratory infections also is relevant to improved antibiotic stewardship in the community. For this reason, a randomized trial with a similar protocol involving the point-of-care viral test is planned in the outpatient setting. According to Dr. Roy, this will involve a community hub to which patients can be referred for testing and clinical evaluation.

“We hope that the quality of care can be improved with the point-of-care test for respiratory viruses as well as helping to reduce antibiotic resistance,” Dr. Roy said.

This approach is promising, according to Tobias Welte, MD, of the department of respiratory medicine at Hannover (Germany) Medical School, but he cautioned that it is not a standard approach.

“The protocol described by Dr. Roy will have to be compared to guidelines and recommended best clinical practice to confirm its usefulness,” he said, while conceding that any strategy that reduces unnecessary hospitalizations deserves further evaluation.