User login
U.S. measles cases nearing postelimination-era high
The United States has topped 600 cases of measles for 2019 and is likely to pass the postelimination high set in 2014 “in the coming weeks,” according to the Centers for Disease Control and Prevention.
The 71 new measles cases reported during the week ending April 18 bring the total for the year to 626 in 22 states, the CDC reported April 22. Two states, Iowa and Tennessee, reported their first cases last week.
Outbreaks continue in five states: one in California (Butte County), one in Michigan (Oakland County/Wayne County/Detroit), one in New Jersey (Ocean County/Monmouth County), two in New York (New York City and Rockland County), and one in Washington (Clark County/King County), the CDC said.
The most active outbreak since mid-February has been the one occurring in New York City, mainly in Brooklyn, and last week was no exception as 50 of the 71 new U.S. cases were reported in the borough.
On April 18, a judge in Brooklyn “ruled against a group of parents who challenged New York City’s recently imposed mandatory measles vaccination order,” Reuters reported. That same day, the city issued a summons, subject to a fine of $1,000 each, to three people in Brooklyn who were still unvaccinated, according to NYC Health, which also said that four additional schools would be closed for not complying with an order to exclude unvaccinated students.
On April 15, the Iowa Department of Public Health confirmed the state’s first case of measles since 2011. The individual from Northeastern Iowa had not been vaccinated and had recently returned from Israel. The state’s second case of the year, a household contact of the first individual, was confirmed on April 18.
Also on April 18, the Tennessee Department of Health confirmed its first case of the year in a resident of the eastern part of the state. Meanwhile, media are reporting that state health officials in Mississippi are investigating possible exposures on April 9 and 10 in the Hattiesburg area by the infected Tennessee man.
Outside the United States, “many countries are in the midst of sizeable measles outbreaks, with all regions of the world experiencing sustained rises in cases,” the World Health Organization said. Current outbreaks include the Democratic Republic of the Congo, Ethiopia, Georgia, Kazakhstan, Kyrgyzstan, Madagascar, Myanmar, Philippines, Sudan, Thailand, and Ukraine.
Preliminary data for the first 3 months of 2019 show that cases worldwide were up by 300% over the first 3 months of 2018: 112,163 cases vs. 28,124. The actual numbers for 2019 are expected to be considerably higher than those reported so far, and WHO estimates that, globally, less than 1 in 10 cases are actually reported.
The United States has topped 600 cases of measles for 2019 and is likely to pass the postelimination high set in 2014 “in the coming weeks,” according to the Centers for Disease Control and Prevention.
The 71 new measles cases reported during the week ending April 18 bring the total for the year to 626 in 22 states, the CDC reported April 22. Two states, Iowa and Tennessee, reported their first cases last week.
Outbreaks continue in five states: one in California (Butte County), one in Michigan (Oakland County/Wayne County/Detroit), one in New Jersey (Ocean County/Monmouth County), two in New York (New York City and Rockland County), and one in Washington (Clark County/King County), the CDC said.
The most active outbreak since mid-February has been the one occurring in New York City, mainly in Brooklyn, and last week was no exception as 50 of the 71 new U.S. cases were reported in the borough.
On April 18, a judge in Brooklyn “ruled against a group of parents who challenged New York City’s recently imposed mandatory measles vaccination order,” Reuters reported. That same day, the city issued a summons, subject to a fine of $1,000 each, to three people in Brooklyn who were still unvaccinated, according to NYC Health, which also said that four additional schools would be closed for not complying with an order to exclude unvaccinated students.
On April 15, the Iowa Department of Public Health confirmed the state’s first case of measles since 2011. The individual from Northeastern Iowa had not been vaccinated and had recently returned from Israel. The state’s second case of the year, a household contact of the first individual, was confirmed on April 18.
Also on April 18, the Tennessee Department of Health confirmed its first case of the year in a resident of the eastern part of the state. Meanwhile, media are reporting that state health officials in Mississippi are investigating possible exposures on April 9 and 10 in the Hattiesburg area by the infected Tennessee man.
Outside the United States, “many countries are in the midst of sizeable measles outbreaks, with all regions of the world experiencing sustained rises in cases,” the World Health Organization said. Current outbreaks include the Democratic Republic of the Congo, Ethiopia, Georgia, Kazakhstan, Kyrgyzstan, Madagascar, Myanmar, Philippines, Sudan, Thailand, and Ukraine.
Preliminary data for the first 3 months of 2019 show that cases worldwide were up by 300% over the first 3 months of 2018: 112,163 cases vs. 28,124. The actual numbers for 2019 are expected to be considerably higher than those reported so far, and WHO estimates that, globally, less than 1 in 10 cases are actually reported.
The United States has topped 600 cases of measles for 2019 and is likely to pass the postelimination high set in 2014 “in the coming weeks,” according to the Centers for Disease Control and Prevention.
The 71 new measles cases reported during the week ending April 18 bring the total for the year to 626 in 22 states, the CDC reported April 22. Two states, Iowa and Tennessee, reported their first cases last week.
Outbreaks continue in five states: one in California (Butte County), one in Michigan (Oakland County/Wayne County/Detroit), one in New Jersey (Ocean County/Monmouth County), two in New York (New York City and Rockland County), and one in Washington (Clark County/King County), the CDC said.
The most active outbreak since mid-February has been the one occurring in New York City, mainly in Brooklyn, and last week was no exception as 50 of the 71 new U.S. cases were reported in the borough.
On April 18, a judge in Brooklyn “ruled against a group of parents who challenged New York City’s recently imposed mandatory measles vaccination order,” Reuters reported. That same day, the city issued a summons, subject to a fine of $1,000 each, to three people in Brooklyn who were still unvaccinated, according to NYC Health, which also said that four additional schools would be closed for not complying with an order to exclude unvaccinated students.
On April 15, the Iowa Department of Public Health confirmed the state’s first case of measles since 2011. The individual from Northeastern Iowa had not been vaccinated and had recently returned from Israel. The state’s second case of the year, a household contact of the first individual, was confirmed on April 18.
Also on April 18, the Tennessee Department of Health confirmed its first case of the year in a resident of the eastern part of the state. Meanwhile, media are reporting that state health officials in Mississippi are investigating possible exposures on April 9 and 10 in the Hattiesburg area by the infected Tennessee man.
Outside the United States, “many countries are in the midst of sizeable measles outbreaks, with all regions of the world experiencing sustained rises in cases,” the World Health Organization said. Current outbreaks include the Democratic Republic of the Congo, Ethiopia, Georgia, Kazakhstan, Kyrgyzstan, Madagascar, Myanmar, Philippines, Sudan, Thailand, and Ukraine.
Preliminary data for the first 3 months of 2019 show that cases worldwide were up by 300% over the first 3 months of 2018: 112,163 cases vs. 28,124. The actual numbers for 2019 are expected to be considerably higher than those reported so far, and WHO estimates that, globally, less than 1 in 10 cases are actually reported.
Gut bacterium R. gnavus linked to lupus flares
SAN FRANCISCO –
Not only that, but those patients also had highly elevated antibodies to an endotoxin-like antigen released by one particular R. gnavus strain.
That antigen is “very proinflammatory, very immunogenic. We are wondering if this is actually [what drives] the immune activation that results in immune complexes in the glomeruli” of patients with lupus nephritis, said investigator Gregg Silverman, MD, a professor of medicine and pathology and head of the laboratory of B-cell immunobiology at New York University.
R. gnavus is an obligate anaerobe found in the guts of most people, but in lupus, it might be a problem.
“We are finding a very specific relationship with lupus patients and this bacteria – and this particular antibody,” Dr. Silverman explained in an interview at an international congress on systemic lupus erythematosus. “There’s an expansion of this particular bug, but also a contraction of others” as disease activity progresses.
“It speaks to an imbalance,” he added, and it suggests a role for probiotics or even fecal transplants to restore order.
“What if instead of killing the immune system” in lupus treatment, “we should be reducing or removing a single bacterium or a single molecule?” he asked.
Dr. Silverman is one of many researchers working to unravel the role of the human microbiome in both disease and health. His findings are preliminary, and, as he cautioned, correlation is not causation. But the implications are remarkable, Dr. Silverman noted.
SAN FRANCISCO –
Not only that, but those patients also had highly elevated antibodies to an endotoxin-like antigen released by one particular R. gnavus strain.
That antigen is “very proinflammatory, very immunogenic. We are wondering if this is actually [what drives] the immune activation that results in immune complexes in the glomeruli” of patients with lupus nephritis, said investigator Gregg Silverman, MD, a professor of medicine and pathology and head of the laboratory of B-cell immunobiology at New York University.
R. gnavus is an obligate anaerobe found in the guts of most people, but in lupus, it might be a problem.
“We are finding a very specific relationship with lupus patients and this bacteria – and this particular antibody,” Dr. Silverman explained in an interview at an international congress on systemic lupus erythematosus. “There’s an expansion of this particular bug, but also a contraction of others” as disease activity progresses.
“It speaks to an imbalance,” he added, and it suggests a role for probiotics or even fecal transplants to restore order.
“What if instead of killing the immune system” in lupus treatment, “we should be reducing or removing a single bacterium or a single molecule?” he asked.
Dr. Silverman is one of many researchers working to unravel the role of the human microbiome in both disease and health. His findings are preliminary, and, as he cautioned, correlation is not causation. But the implications are remarkable, Dr. Silverman noted.
SAN FRANCISCO –
Not only that, but those patients also had highly elevated antibodies to an endotoxin-like antigen released by one particular R. gnavus strain.
That antigen is “very proinflammatory, very immunogenic. We are wondering if this is actually [what drives] the immune activation that results in immune complexes in the glomeruli” of patients with lupus nephritis, said investigator Gregg Silverman, MD, a professor of medicine and pathology and head of the laboratory of B-cell immunobiology at New York University.
R. gnavus is an obligate anaerobe found in the guts of most people, but in lupus, it might be a problem.
“We are finding a very specific relationship with lupus patients and this bacteria – and this particular antibody,” Dr. Silverman explained in an interview at an international congress on systemic lupus erythematosus. “There’s an expansion of this particular bug, but also a contraction of others” as disease activity progresses.
“It speaks to an imbalance,” he added, and it suggests a role for probiotics or even fecal transplants to restore order.
“What if instead of killing the immune system” in lupus treatment, “we should be reducing or removing a single bacterium or a single molecule?” he asked.
Dr. Silverman is one of many researchers working to unravel the role of the human microbiome in both disease and health. His findings are preliminary, and, as he cautioned, correlation is not causation. But the implications are remarkable, Dr. Silverman noted.
REPORTING FROM LUPUS 2019
Decline in CIN2+ in younger women after HPV vaccine introduced
The introduction of human papillomavirus vaccination in the United States in 2006 was associated with a significant decrease in the rates of cervical intraepithelial neoplasia grades 2 and above (CIN2+) in younger women.
The overall rate of CIN2+ declined from an estimated 216,000 cases in 2008 – 55% of which were in women aged 18-29 years – to 196,000 cases in 2016, of which 36% were in women aged 18-29 years, according to analysis of data from the Human Papillomavirus Vaccine Impact Monitoring Program (MMWR. 2019 Apr 19;68:337-43.
In 2008, the highest rates of CIN2+ were seen in women aged 20-24 years and decreased with age, but in 2016, the highest rates were in women aged 25-29 years. The rates of CIN2+ declined significantly in women aged 18-19 years from 2008-2016, but increased in women aged 40-64 years.
In 2008 and 2016, around three-quarters of all CIN2+ cases were attributable to HPV types that are targeted by the HPV vaccine. However the rates of vaccine-preventable CIN2+ declined among women aged 18-24 years, from 52% in 2008 to 30% in 2016.
“Both the estimated number and rates of U.S. CIN2+ cases in this report must be interpreted in the context of cervical cancer prevention strategies, including HPV vaccination and cervical cancer screening,” wrote Nancy M. McClung, PhD, of the Epidemic Intelligence Service at the Centers for Disease Control and Prevention and coauthors.
Notably, the screening interval for cervical cancer was increased from yearly in 2008 to once in 3 years with cytology alone or once in 5 years with cytology plus HPV testing for women aged 30 or above in 2016.
“Older age at screening initiation, longer screening intervals, and more conservative management in young women might be expected to reduce the number of CIN2+ cases detected in younger age groups in whom lesions are most likely to regress and shift detection of some CIN2+ to older age groups, resulting in a transient increase in rates,” Dr. McClung and colleagues wrote.
However they noted that the decrease in HPV 16/18–attributable CIN2+ rates among younger age groups was likely a reflection of the impact of the introduction of the quadrivalent vaccine immunization program.
One author declared personal fees from Merck during the course of the study. No other conflicts of interest were declared.
SOURCE: McClung N et al. MMWR. 2019 Apr 19;68:337-43.
The introduction of human papillomavirus vaccination in the United States in 2006 was associated with a significant decrease in the rates of cervical intraepithelial neoplasia grades 2 and above (CIN2+) in younger women.
The overall rate of CIN2+ declined from an estimated 216,000 cases in 2008 – 55% of which were in women aged 18-29 years – to 196,000 cases in 2016, of which 36% were in women aged 18-29 years, according to analysis of data from the Human Papillomavirus Vaccine Impact Monitoring Program (MMWR. 2019 Apr 19;68:337-43.
In 2008, the highest rates of CIN2+ were seen in women aged 20-24 years and decreased with age, but in 2016, the highest rates were in women aged 25-29 years. The rates of CIN2+ declined significantly in women aged 18-19 years from 2008-2016, but increased in women aged 40-64 years.
In 2008 and 2016, around three-quarters of all CIN2+ cases were attributable to HPV types that are targeted by the HPV vaccine. However the rates of vaccine-preventable CIN2+ declined among women aged 18-24 years, from 52% in 2008 to 30% in 2016.
“Both the estimated number and rates of U.S. CIN2+ cases in this report must be interpreted in the context of cervical cancer prevention strategies, including HPV vaccination and cervical cancer screening,” wrote Nancy M. McClung, PhD, of the Epidemic Intelligence Service at the Centers for Disease Control and Prevention and coauthors.
Notably, the screening interval for cervical cancer was increased from yearly in 2008 to once in 3 years with cytology alone or once in 5 years with cytology plus HPV testing for women aged 30 or above in 2016.
“Older age at screening initiation, longer screening intervals, and more conservative management in young women might be expected to reduce the number of CIN2+ cases detected in younger age groups in whom lesions are most likely to regress and shift detection of some CIN2+ to older age groups, resulting in a transient increase in rates,” Dr. McClung and colleagues wrote.
However they noted that the decrease in HPV 16/18–attributable CIN2+ rates among younger age groups was likely a reflection of the impact of the introduction of the quadrivalent vaccine immunization program.
One author declared personal fees from Merck during the course of the study. No other conflicts of interest were declared.
SOURCE: McClung N et al. MMWR. 2019 Apr 19;68:337-43.
The introduction of human papillomavirus vaccination in the United States in 2006 was associated with a significant decrease in the rates of cervical intraepithelial neoplasia grades 2 and above (CIN2+) in younger women.
The overall rate of CIN2+ declined from an estimated 216,000 cases in 2008 – 55% of which were in women aged 18-29 years – to 196,000 cases in 2016, of which 36% were in women aged 18-29 years, according to analysis of data from the Human Papillomavirus Vaccine Impact Monitoring Program (MMWR. 2019 Apr 19;68:337-43.
In 2008, the highest rates of CIN2+ were seen in women aged 20-24 years and decreased with age, but in 2016, the highest rates were in women aged 25-29 years. The rates of CIN2+ declined significantly in women aged 18-19 years from 2008-2016, but increased in women aged 40-64 years.
In 2008 and 2016, around three-quarters of all CIN2+ cases were attributable to HPV types that are targeted by the HPV vaccine. However the rates of vaccine-preventable CIN2+ declined among women aged 18-24 years, from 52% in 2008 to 30% in 2016.
“Both the estimated number and rates of U.S. CIN2+ cases in this report must be interpreted in the context of cervical cancer prevention strategies, including HPV vaccination and cervical cancer screening,” wrote Nancy M. McClung, PhD, of the Epidemic Intelligence Service at the Centers for Disease Control and Prevention and coauthors.
Notably, the screening interval for cervical cancer was increased from yearly in 2008 to once in 3 years with cytology alone or once in 5 years with cytology plus HPV testing for women aged 30 or above in 2016.
“Older age at screening initiation, longer screening intervals, and more conservative management in young women might be expected to reduce the number of CIN2+ cases detected in younger age groups in whom lesions are most likely to regress and shift detection of some CIN2+ to older age groups, resulting in a transient increase in rates,” Dr. McClung and colleagues wrote.
However they noted that the decrease in HPV 16/18–attributable CIN2+ rates among younger age groups was likely a reflection of the impact of the introduction of the quadrivalent vaccine immunization program.
One author declared personal fees from Merck during the course of the study. No other conflicts of interest were declared.
SOURCE: McClung N et al. MMWR. 2019 Apr 19;68:337-43.
FROM MMWR
Ibrexafungerp effective against C. auris in two early case reports
A novel antifungal successfully eradicated Candida auris in two critically ill patients with fungemia, according to data presented in a poster session at the European Congress of Clinical Microbiology & Infectious Diseases.
The case reports, drawn from the phase 3 CARES study of the oral formulation of ibrexafungerp, demonstrated complete response to the glucan synthase inhibitor, according to Deven Juneja, MD, and his coauthors of the Max Super Specialty Hospital, New Delhi.
The first patient was an Asian male, aged 58 years, who had a previous history of diabetes and experienced a protracted ICU stay after acute ischemic stroke. He developed septic shock after aspiration pneumonia, and also experienced a popliteal thrombosis and liver, spleen, and kidney infarcts.
The patient had received empiric antibiotics with the addition of fluconazole; the antifungal was later switched to micafungin after C. auris was identified from blood cultures. Despite clinical improvement on micafungin, blood cultures remained positive for C. auris, so ibrexafungerp was started and continued for 17 days. Blood cultures became negative by day 3 of ibrexafungerp and remained negative for the follow-up period. The patient later developed Klebsiella pneumonia and died.
The second patient, an Asian female, aged 64 years, presented with a lower respiratory tract infection accompanied by fever and hypotension. She had a previous history of diabetes, hypertension, and chronic kidney disease with maintenance hemodialysis. Her fever also persisted despite antibiotics, and C. auris was isolated from her blood cultures with the subsequent initiation of ibrexafungerp. Her blood cultures were still positive at day 3 of ibrexafungerp, but negative at day 9 and 21. She completed 22 days of ibrexafungerp therapy and was asymptomatic with no evidence of C. auris recurrence at a 6-week follow-up visit.
The male patient experienced 2 days of loose stools soon after initiating ibrexafungerp; the female patient had no adverse events.
“These cases provide initial evidence of efficacy and safety of ibrexafungerp in the treatment of candidemia caused by C. auris, including in patients who failed previous therapies,” wrote Dr. Juneja and his coauthors in the late-breaking poster.
Ibrexafungerp belongs to a novel class of glucan synthase inhibitors called triterpenoids. Scynexis funded the CARES study and also is evaluating it alone or in combination with other antifungals for treatment of vulvovaginal candidiasis, invasive pulmonary aspergillosis, and refractory invasive and/or severe fungal disease.
SOURCE: Juneja D et al. ECCMID 2019, Poster L0028.
A novel antifungal successfully eradicated Candida auris in two critically ill patients with fungemia, according to data presented in a poster session at the European Congress of Clinical Microbiology & Infectious Diseases.
The case reports, drawn from the phase 3 CARES study of the oral formulation of ibrexafungerp, demonstrated complete response to the glucan synthase inhibitor, according to Deven Juneja, MD, and his coauthors of the Max Super Specialty Hospital, New Delhi.
The first patient was an Asian male, aged 58 years, who had a previous history of diabetes and experienced a protracted ICU stay after acute ischemic stroke. He developed septic shock after aspiration pneumonia, and also experienced a popliteal thrombosis and liver, spleen, and kidney infarcts.
The patient had received empiric antibiotics with the addition of fluconazole; the antifungal was later switched to micafungin after C. auris was identified from blood cultures. Despite clinical improvement on micafungin, blood cultures remained positive for C. auris, so ibrexafungerp was started and continued for 17 days. Blood cultures became negative by day 3 of ibrexafungerp and remained negative for the follow-up period. The patient later developed Klebsiella pneumonia and died.
The second patient, an Asian female, aged 64 years, presented with a lower respiratory tract infection accompanied by fever and hypotension. She had a previous history of diabetes, hypertension, and chronic kidney disease with maintenance hemodialysis. Her fever also persisted despite antibiotics, and C. auris was isolated from her blood cultures with the subsequent initiation of ibrexafungerp. Her blood cultures were still positive at day 3 of ibrexafungerp, but negative at day 9 and 21. She completed 22 days of ibrexafungerp therapy and was asymptomatic with no evidence of C. auris recurrence at a 6-week follow-up visit.
The male patient experienced 2 days of loose stools soon after initiating ibrexafungerp; the female patient had no adverse events.
“These cases provide initial evidence of efficacy and safety of ibrexafungerp in the treatment of candidemia caused by C. auris, including in patients who failed previous therapies,” wrote Dr. Juneja and his coauthors in the late-breaking poster.
Ibrexafungerp belongs to a novel class of glucan synthase inhibitors called triterpenoids. Scynexis funded the CARES study and also is evaluating it alone or in combination with other antifungals for treatment of vulvovaginal candidiasis, invasive pulmonary aspergillosis, and refractory invasive and/or severe fungal disease.
SOURCE: Juneja D et al. ECCMID 2019, Poster L0028.
A novel antifungal successfully eradicated Candida auris in two critically ill patients with fungemia, according to data presented in a poster session at the European Congress of Clinical Microbiology & Infectious Diseases.
The case reports, drawn from the phase 3 CARES study of the oral formulation of ibrexafungerp, demonstrated complete response to the glucan synthase inhibitor, according to Deven Juneja, MD, and his coauthors of the Max Super Specialty Hospital, New Delhi.
The first patient was an Asian male, aged 58 years, who had a previous history of diabetes and experienced a protracted ICU stay after acute ischemic stroke. He developed septic shock after aspiration pneumonia, and also experienced a popliteal thrombosis and liver, spleen, and kidney infarcts.
The patient had received empiric antibiotics with the addition of fluconazole; the antifungal was later switched to micafungin after C. auris was identified from blood cultures. Despite clinical improvement on micafungin, blood cultures remained positive for C. auris, so ibrexafungerp was started and continued for 17 days. Blood cultures became negative by day 3 of ibrexafungerp and remained negative for the follow-up period. The patient later developed Klebsiella pneumonia and died.
The second patient, an Asian female, aged 64 years, presented with a lower respiratory tract infection accompanied by fever and hypotension. She had a previous history of diabetes, hypertension, and chronic kidney disease with maintenance hemodialysis. Her fever also persisted despite antibiotics, and C. auris was isolated from her blood cultures with the subsequent initiation of ibrexafungerp. Her blood cultures were still positive at day 3 of ibrexafungerp, but negative at day 9 and 21. She completed 22 days of ibrexafungerp therapy and was asymptomatic with no evidence of C. auris recurrence at a 6-week follow-up visit.
The male patient experienced 2 days of loose stools soon after initiating ibrexafungerp; the female patient had no adverse events.
“These cases provide initial evidence of efficacy and safety of ibrexafungerp in the treatment of candidemia caused by C. auris, including in patients who failed previous therapies,” wrote Dr. Juneja and his coauthors in the late-breaking poster.
Ibrexafungerp belongs to a novel class of glucan synthase inhibitors called triterpenoids. Scynexis funded the CARES study and also is evaluating it alone or in combination with other antifungals for treatment of vulvovaginal candidiasis, invasive pulmonary aspergillosis, and refractory invasive and/or severe fungal disease.
SOURCE: Juneja D et al. ECCMID 2019, Poster L0028.
FROM ECCMID 2019
Candida auris: Dangerous and here to stay
Critical care units and long-term care facilities are on alert for cases of Candida auris, a novel fungal infection that is both dangerous to vulnerable patients and difficult to eradicate. The increased profile of C. auris is not a welcome development but is no surprise to critical care physicians.
This pathogen was first identified in 2009 and has since been found in increasing numbers of patients all over the world. As expected, cases of C. auris are on the rise in the United States.
The Centers for Disease Control and Prevention stated “Candida auris is an emerging fungus that presents a serious global health threat.” This is an opportunistic pathogen that hits critically ill patients and those with compromised immunity.
On March 29, 2019, CDC reported that confirmed clinical cases of C. auris in the United States have more than doubled over the past year, from 257 cases in 2018 to 587 cases with an additional 1,056 colonized patients identified as of February 2019. “Most C. auris cases in the United States have been detected in the New York City area, New Jersey, and the Chicago area. Strains of C. auris in the United States have been linked to other parts of the world. U.S. C. auris cases are a result of inadvertent introduction into the United States from a patient who recently received health care in a country where C. auris has been reported or a result of local spread after such an introduction.”
Case reports have found a mortality rate of up to 50% in patients with C. auris candidemia. The total number of cases is still small, but the trajectory is clear. The hunt is on in labs all over the world for optimal treatments and processes to handle outbreaks.
Jeniel Nett, MD, an infectious disease specialist, and a team of investigators at the University of Wisconsin, Madison, have focused their research on the characteristics of C. auris and its progression in patients and in medical facilities.
According to Dr. Nett, it’s not clear why this emerging threat has cropped up in multiple locations globally. “Candida auris was first recognized in 2009, in Japan, and relatively quickly we saw emergence of this species in relatively distant locations,” she said, adding that independent clades in these locations ruled out transmission as the source of the multiple outbreaks. Antifungal resistance is an epidemiologic area of concern and increased antifungal use may be a contributor, she said.
Once established, the organism is persistent: “It is found on mattresses, on bedsheets, IV poles, and a lot of reusable equipment,” said Dr. Nett in an interview. “It appears to persist in the environment for weeks – maybe longer.” In addition, “it seems to behave differently than a lot of the Candida species that we see; it readily colonizes the skin” to a much greater extent than does other Candida species, she said. “This allows it to be transmitted readily person to person, particularly in the hospitalized setting.” However, it can also colonize both the urinary and respiratory tracts, she said.
Which patients are susceptible to C. auris candidemia? “Many of these patients have undergone multiple procedures; they may have undergone mechanical ventilation as well as different surgical procedures,” said Dr. Nett. Affected patients often have received many rounds of antibiotic and antifungal treatment as well, she said, and may have an underlying illness like diabetes or malignancy.
Studies of C. auris outbreaks have begun to appear in the literature and give clinicians some perspective on the progression of an outbreak and potential strategies for containment. A prospective cohort study of a large outbreak of C. auris was conducted by Alba Ruiz-Gaitán, MD, and her colleagues at La Fe University and Polytechnic Hospital, Valencia, Spain (Expert Rev Anti Infect Ther. 2019 Apr;17[4]:295-305). The researchers followed 114 patients who were colonized with C. auris or had C. auris candidemia. The patients were compared with 114 case-matched controls within the hospital’s adult surgical and medical intensive care units over an 11-month period during the hospital’s protracted outbreak.
The investigators found a crude mortality rate of 58.5% at 30 days for patients with C. auris candidemia. All isolates in the study were completely resistant to fluconazole and had reduced susceptibility to voriconazole.
In critical care units at Hospital La Fe, investigators found C. auris on 25% of blood pressure cuffs, 10% of patient tables and keyboards, and 8% of infusion pumps.
Among the patients at Hospital La Fe, multivariable analysis revealed that those most likely to develop C. auris colonization or candidemia were individuals with polytrauma, cardiovascular disease, and cancer.
Patients receiving parenteral nutrition (odds ratio, 3.49), mechanical ventilation (OR, 2.43), and especially those having indwelling central venous catheters (OR, 13.48) were more likely to be colonized or have candidemia as well, according to Dr. Ruiz-Gaitán and her coauthors.
Once identified, how should C. auris be treated? “The majority of strains – upward of 90% – are resistant to fluconazole,” said Dr. Nett. “Moreover, 30%-50% of them are resistant to another antifungal, often amphotericin B. The isolates that we see in the United States are most often susceptible to an echinocandin, and echinocandins remain the choice for treatment of Candida auris pending susceptibility tests.”
However, in Valencia, “The susceptibility to echinocandins presented interesting features. These antifungals were not fungicidal against C. auris,” wrote Dr. Ruiz-Gaitán and her colleagues. They found that for caspofungin, “most isolates presented a clear paradoxical growth after 24 hours of incubation.” Additionally, fungal growth was inhibited at lower caspofungin concentrations, but rebounded at higher levels. Similar patterns were seen for anidulafungin and micafungin, they said.
These findings meant that Hospital La Fe patients received initial treatment with echinocandins, with the addition of liposomal amphotericin B or isavuconazole if candidemia persisted or clinical response was not seen, wrote the investigators.
Patient presentation is similar to other forms of candidiasis, said Dr. Nett. “Patients often have fever, chills, leukocytosis, and this persists despite antibacterial therapy… If Candida auris is suspected, the first course of action would be to place the patient in isolation, and laboratory staff should be alerted regarding the diagnosis.”
Most large clinical laboratories, she said, can now detect C. auris. Matrix-assisted laser desorption/ionization–time of flight is the identification technique of choice, provided that the databases are updated.
Smaller laboratories that use phenotypic tests may misidentify C. auris as another Candida species, or even as Saccharomyces cerevisiae – common beer yeast. Facilities without matrix-assisted laser desorption/ionization can find guidance for interpretation of phenotypic testing on the CDC website as well, said Dr. Nett.
After experiencing what they believe to be the largest C. auris outbreak at a single European hospital, Dr. Ruiz-Gaitán and her colleagues offered best-practice tips for treatment of patients with C. auris candidemia. These include removing mechanical devices as early as is safely practical; performing ophthalmologic examinations for endophthalmitis, a known C. auris complication; obtaining blood cultures every other day to track antimicrobial therapy to the point of sterilization; and searching for metastatic foci if blood cultures remain positive.
All instances of C. auris laboratory identification should be reported to the CDC at [email protected], and to local and state health agencies. The CDC recommends strict isolation and cleaning protocols, similar to those used for the spore-forming Clostridium difficile.
Dr. Nett reported funding support from the National Institutes of Health, the Burroughs Wellcome Fund, and the Doris Duke Charitable Foundation. She reported no conflicts of interest. Dr. Ruiz-Gaitán and her collaborators reported funding from Instituto de Salud Carlos III, Spain, and the Spanish Ministry of Science and University. They reported no conflicts of interest.
Critical care units and long-term care facilities are on alert for cases of Candida auris, a novel fungal infection that is both dangerous to vulnerable patients and difficult to eradicate. The increased profile of C. auris is not a welcome development but is no surprise to critical care physicians.
This pathogen was first identified in 2009 and has since been found in increasing numbers of patients all over the world. As expected, cases of C. auris are on the rise in the United States.
The Centers for Disease Control and Prevention stated “Candida auris is an emerging fungus that presents a serious global health threat.” This is an opportunistic pathogen that hits critically ill patients and those with compromised immunity.
On March 29, 2019, CDC reported that confirmed clinical cases of C. auris in the United States have more than doubled over the past year, from 257 cases in 2018 to 587 cases with an additional 1,056 colonized patients identified as of February 2019. “Most C. auris cases in the United States have been detected in the New York City area, New Jersey, and the Chicago area. Strains of C. auris in the United States have been linked to other parts of the world. U.S. C. auris cases are a result of inadvertent introduction into the United States from a patient who recently received health care in a country where C. auris has been reported or a result of local spread after such an introduction.”
Case reports have found a mortality rate of up to 50% in patients with C. auris candidemia. The total number of cases is still small, but the trajectory is clear. The hunt is on in labs all over the world for optimal treatments and processes to handle outbreaks.
Jeniel Nett, MD, an infectious disease specialist, and a team of investigators at the University of Wisconsin, Madison, have focused their research on the characteristics of C. auris and its progression in patients and in medical facilities.
According to Dr. Nett, it’s not clear why this emerging threat has cropped up in multiple locations globally. “Candida auris was first recognized in 2009, in Japan, and relatively quickly we saw emergence of this species in relatively distant locations,” she said, adding that independent clades in these locations ruled out transmission as the source of the multiple outbreaks. Antifungal resistance is an epidemiologic area of concern and increased antifungal use may be a contributor, she said.
Once established, the organism is persistent: “It is found on mattresses, on bedsheets, IV poles, and a lot of reusable equipment,” said Dr. Nett in an interview. “It appears to persist in the environment for weeks – maybe longer.” In addition, “it seems to behave differently than a lot of the Candida species that we see; it readily colonizes the skin” to a much greater extent than does other Candida species, she said. “This allows it to be transmitted readily person to person, particularly in the hospitalized setting.” However, it can also colonize both the urinary and respiratory tracts, she said.
Which patients are susceptible to C. auris candidemia? “Many of these patients have undergone multiple procedures; they may have undergone mechanical ventilation as well as different surgical procedures,” said Dr. Nett. Affected patients often have received many rounds of antibiotic and antifungal treatment as well, she said, and may have an underlying illness like diabetes or malignancy.
Studies of C. auris outbreaks have begun to appear in the literature and give clinicians some perspective on the progression of an outbreak and potential strategies for containment. A prospective cohort study of a large outbreak of C. auris was conducted by Alba Ruiz-Gaitán, MD, and her colleagues at La Fe University and Polytechnic Hospital, Valencia, Spain (Expert Rev Anti Infect Ther. 2019 Apr;17[4]:295-305). The researchers followed 114 patients who were colonized with C. auris or had C. auris candidemia. The patients were compared with 114 case-matched controls within the hospital’s adult surgical and medical intensive care units over an 11-month period during the hospital’s protracted outbreak.
The investigators found a crude mortality rate of 58.5% at 30 days for patients with C. auris candidemia. All isolates in the study were completely resistant to fluconazole and had reduced susceptibility to voriconazole.
In critical care units at Hospital La Fe, investigators found C. auris on 25% of blood pressure cuffs, 10% of patient tables and keyboards, and 8% of infusion pumps.
Among the patients at Hospital La Fe, multivariable analysis revealed that those most likely to develop C. auris colonization or candidemia were individuals with polytrauma, cardiovascular disease, and cancer.
Patients receiving parenteral nutrition (odds ratio, 3.49), mechanical ventilation (OR, 2.43), and especially those having indwelling central venous catheters (OR, 13.48) were more likely to be colonized or have candidemia as well, according to Dr. Ruiz-Gaitán and her coauthors.
Once identified, how should C. auris be treated? “The majority of strains – upward of 90% – are resistant to fluconazole,” said Dr. Nett. “Moreover, 30%-50% of them are resistant to another antifungal, often amphotericin B. The isolates that we see in the United States are most often susceptible to an echinocandin, and echinocandins remain the choice for treatment of Candida auris pending susceptibility tests.”
However, in Valencia, “The susceptibility to echinocandins presented interesting features. These antifungals were not fungicidal against C. auris,” wrote Dr. Ruiz-Gaitán and her colleagues. They found that for caspofungin, “most isolates presented a clear paradoxical growth after 24 hours of incubation.” Additionally, fungal growth was inhibited at lower caspofungin concentrations, but rebounded at higher levels. Similar patterns were seen for anidulafungin and micafungin, they said.
These findings meant that Hospital La Fe patients received initial treatment with echinocandins, with the addition of liposomal amphotericin B or isavuconazole if candidemia persisted or clinical response was not seen, wrote the investigators.
Patient presentation is similar to other forms of candidiasis, said Dr. Nett. “Patients often have fever, chills, leukocytosis, and this persists despite antibacterial therapy… If Candida auris is suspected, the first course of action would be to place the patient in isolation, and laboratory staff should be alerted regarding the diagnosis.”
Most large clinical laboratories, she said, can now detect C. auris. Matrix-assisted laser desorption/ionization–time of flight is the identification technique of choice, provided that the databases are updated.
Smaller laboratories that use phenotypic tests may misidentify C. auris as another Candida species, or even as Saccharomyces cerevisiae – common beer yeast. Facilities without matrix-assisted laser desorption/ionization can find guidance for interpretation of phenotypic testing on the CDC website as well, said Dr. Nett.
After experiencing what they believe to be the largest C. auris outbreak at a single European hospital, Dr. Ruiz-Gaitán and her colleagues offered best-practice tips for treatment of patients with C. auris candidemia. These include removing mechanical devices as early as is safely practical; performing ophthalmologic examinations for endophthalmitis, a known C. auris complication; obtaining blood cultures every other day to track antimicrobial therapy to the point of sterilization; and searching for metastatic foci if blood cultures remain positive.
All instances of C. auris laboratory identification should be reported to the CDC at [email protected], and to local and state health agencies. The CDC recommends strict isolation and cleaning protocols, similar to those used for the spore-forming Clostridium difficile.
Dr. Nett reported funding support from the National Institutes of Health, the Burroughs Wellcome Fund, and the Doris Duke Charitable Foundation. She reported no conflicts of interest. Dr. Ruiz-Gaitán and her collaborators reported funding from Instituto de Salud Carlos III, Spain, and the Spanish Ministry of Science and University. They reported no conflicts of interest.
Critical care units and long-term care facilities are on alert for cases of Candida auris, a novel fungal infection that is both dangerous to vulnerable patients and difficult to eradicate. The increased profile of C. auris is not a welcome development but is no surprise to critical care physicians.
This pathogen was first identified in 2009 and has since been found in increasing numbers of patients all over the world. As expected, cases of C. auris are on the rise in the United States.
The Centers for Disease Control and Prevention stated “Candida auris is an emerging fungus that presents a serious global health threat.” This is an opportunistic pathogen that hits critically ill patients and those with compromised immunity.
On March 29, 2019, CDC reported that confirmed clinical cases of C. auris in the United States have more than doubled over the past year, from 257 cases in 2018 to 587 cases with an additional 1,056 colonized patients identified as of February 2019. “Most C. auris cases in the United States have been detected in the New York City area, New Jersey, and the Chicago area. Strains of C. auris in the United States have been linked to other parts of the world. U.S. C. auris cases are a result of inadvertent introduction into the United States from a patient who recently received health care in a country where C. auris has been reported or a result of local spread after such an introduction.”
Case reports have found a mortality rate of up to 50% in patients with C. auris candidemia. The total number of cases is still small, but the trajectory is clear. The hunt is on in labs all over the world for optimal treatments and processes to handle outbreaks.
Jeniel Nett, MD, an infectious disease specialist, and a team of investigators at the University of Wisconsin, Madison, have focused their research on the characteristics of C. auris and its progression in patients and in medical facilities.
According to Dr. Nett, it’s not clear why this emerging threat has cropped up in multiple locations globally. “Candida auris was first recognized in 2009, in Japan, and relatively quickly we saw emergence of this species in relatively distant locations,” she said, adding that independent clades in these locations ruled out transmission as the source of the multiple outbreaks. Antifungal resistance is an epidemiologic area of concern and increased antifungal use may be a contributor, she said.
Once established, the organism is persistent: “It is found on mattresses, on bedsheets, IV poles, and a lot of reusable equipment,” said Dr. Nett in an interview. “It appears to persist in the environment for weeks – maybe longer.” In addition, “it seems to behave differently than a lot of the Candida species that we see; it readily colonizes the skin” to a much greater extent than does other Candida species, she said. “This allows it to be transmitted readily person to person, particularly in the hospitalized setting.” However, it can also colonize both the urinary and respiratory tracts, she said.
Which patients are susceptible to C. auris candidemia? “Many of these patients have undergone multiple procedures; they may have undergone mechanical ventilation as well as different surgical procedures,” said Dr. Nett. Affected patients often have received many rounds of antibiotic and antifungal treatment as well, she said, and may have an underlying illness like diabetes or malignancy.
Studies of C. auris outbreaks have begun to appear in the literature and give clinicians some perspective on the progression of an outbreak and potential strategies for containment. A prospective cohort study of a large outbreak of C. auris was conducted by Alba Ruiz-Gaitán, MD, and her colleagues at La Fe University and Polytechnic Hospital, Valencia, Spain (Expert Rev Anti Infect Ther. 2019 Apr;17[4]:295-305). The researchers followed 114 patients who were colonized with C. auris or had C. auris candidemia. The patients were compared with 114 case-matched controls within the hospital’s adult surgical and medical intensive care units over an 11-month period during the hospital’s protracted outbreak.
The investigators found a crude mortality rate of 58.5% at 30 days for patients with C. auris candidemia. All isolates in the study were completely resistant to fluconazole and had reduced susceptibility to voriconazole.
In critical care units at Hospital La Fe, investigators found C. auris on 25% of blood pressure cuffs, 10% of patient tables and keyboards, and 8% of infusion pumps.
Among the patients at Hospital La Fe, multivariable analysis revealed that those most likely to develop C. auris colonization or candidemia were individuals with polytrauma, cardiovascular disease, and cancer.
Patients receiving parenteral nutrition (odds ratio, 3.49), mechanical ventilation (OR, 2.43), and especially those having indwelling central venous catheters (OR, 13.48) were more likely to be colonized or have candidemia as well, according to Dr. Ruiz-Gaitán and her coauthors.
Once identified, how should C. auris be treated? “The majority of strains – upward of 90% – are resistant to fluconazole,” said Dr. Nett. “Moreover, 30%-50% of them are resistant to another antifungal, often amphotericin B. The isolates that we see in the United States are most often susceptible to an echinocandin, and echinocandins remain the choice for treatment of Candida auris pending susceptibility tests.”
However, in Valencia, “The susceptibility to echinocandins presented interesting features. These antifungals were not fungicidal against C. auris,” wrote Dr. Ruiz-Gaitán and her colleagues. They found that for caspofungin, “most isolates presented a clear paradoxical growth after 24 hours of incubation.” Additionally, fungal growth was inhibited at lower caspofungin concentrations, but rebounded at higher levels. Similar patterns were seen for anidulafungin and micafungin, they said.
These findings meant that Hospital La Fe patients received initial treatment with echinocandins, with the addition of liposomal amphotericin B or isavuconazole if candidemia persisted or clinical response was not seen, wrote the investigators.
Patient presentation is similar to other forms of candidiasis, said Dr. Nett. “Patients often have fever, chills, leukocytosis, and this persists despite antibacterial therapy… If Candida auris is suspected, the first course of action would be to place the patient in isolation, and laboratory staff should be alerted regarding the diagnosis.”
Most large clinical laboratories, she said, can now detect C. auris. Matrix-assisted laser desorption/ionization–time of flight is the identification technique of choice, provided that the databases are updated.
Smaller laboratories that use phenotypic tests may misidentify C. auris as another Candida species, or even as Saccharomyces cerevisiae – common beer yeast. Facilities without matrix-assisted laser desorption/ionization can find guidance for interpretation of phenotypic testing on the CDC website as well, said Dr. Nett.
After experiencing what they believe to be the largest C. auris outbreak at a single European hospital, Dr. Ruiz-Gaitán and her colleagues offered best-practice tips for treatment of patients with C. auris candidemia. These include removing mechanical devices as early as is safely practical; performing ophthalmologic examinations for endophthalmitis, a known C. auris complication; obtaining blood cultures every other day to track antimicrobial therapy to the point of sterilization; and searching for metastatic foci if blood cultures remain positive.
All instances of C. auris laboratory identification should be reported to the CDC at [email protected], and to local and state health agencies. The CDC recommends strict isolation and cleaning protocols, similar to those used for the spore-forming Clostridium difficile.
Dr. Nett reported funding support from the National Institutes of Health, the Burroughs Wellcome Fund, and the Doris Duke Charitable Foundation. She reported no conflicts of interest. Dr. Ruiz-Gaitán and her collaborators reported funding from Instituto de Salud Carlos III, Spain, and the Spanish Ministry of Science and University. They reported no conflicts of interest.
ICYMI: Anti-CD4 antibody maintains viral suppression in HIV patients post ART
according to results from a small, nonrandomized, open-label, phase 2 trial published in the New England Journal of Medicine (2019 Apr 17. doi: 10.1056/NEJMoa1802264).
We reported on this story at the 2017 Conference on Retroviruses & Opportunistic Infections before it was published in the journal. Find our coverage at the link below.
according to results from a small, nonrandomized, open-label, phase 2 trial published in the New England Journal of Medicine (2019 Apr 17. doi: 10.1056/NEJMoa1802264).
We reported on this story at the 2017 Conference on Retroviruses & Opportunistic Infections before it was published in the journal. Find our coverage at the link below.
according to results from a small, nonrandomized, open-label, phase 2 trial published in the New England Journal of Medicine (2019 Apr 17. doi: 10.1056/NEJMoa1802264).
We reported on this story at the 2017 Conference on Retroviruses & Opportunistic Infections before it was published in the journal. Find our coverage at the link below.
FROM THE NEW ENGLAND JOURNAL OF MEDICINE
Can immune checkpoint inhibitors treat PML?
investigators reported in the New England Journal of Medicine.
Three research teams described 10 cases in which patients with PML received pembrolizumab or nivolumab.
In one study, researchers administered pembrolizumab to eight adults with PML. Five patients had clinical improvement or stabilization, whereas 3 patients did not. Among the patients with clinical improvement, treatment led to reduced JC viral load in cerebrospinal fluid (CSF) and increased CD4+ and CD8+ anti–JC virus activity in vitro. Among patients without clinical improvement, treatment did not meaningfully change viral load or antiviral cellular immune response.
In a separate letter, researchers in Germany described an additional patient with PML who had clinical stabilization and no disease progression on MRI after treatment with pembrolizumab.
In another letter, researchers in France described a patient with PML whose condition improved after treatment with nivolumab.
“Do pembrolizumab and nivolumab fit the bill for treatment of PML? The current reports are encouraging but suggest that the presence of JC virus–specific T cells in the blood is a prerequisite for their use,” said Igor J. Koralnik, MD, of the department of neurological sciences at Rush University Medical Center in Chicago, in an accompanying editorial. “A controlled trial may be needed to determine whether immune checkpoint inhibitors are indeed able to keep JC virus in check in patients with PML.”
Reinvigorating T cells
Both monoclonal antibodies target programmed cell death protein 1 (PD-1), which inhibits T-cell proliferation and cytokine production when it binds its associated ligand, Dr. Koralnik said. Pembrolizumab and nivolumab block this inhibition and have been used to spur T-cell activity against tumors in patients with cancer.
PML, an often fatal brain infection caused by the JC virus in patients with immunosuppression, has no specific treatment. Management hinges on “recovery of the immune system, either by treating the underlying cause of immunosuppression or by discontinuing the use of immunosuppressive medications,” said Dr. Koralnik.
Pembrolizumab
Prior studies have found that PD-1 expression is elevated on T lymphocytes of patients with PML. To determine whether PD-1 blockade with pembrolizumab reinvigorates anti–JC virus immune activity in patients with PML, Irene Cortese, MD, of the National Institutes of Health’s Neuroimmunology Clinic and her research colleagues administered pembrolizumab at a dose of 2 mg/kg of body weight every 4-6 weeks to eight adults with PML. The patients received 1-3 doses, and each patient had a different underlying condition.
In all patients, treatment induced down-regulation of PD-1 expression on lymphocytes in CSF and peripheral blood, and five of the eight patients had clinical stabilization or improvement. Of the other three patients who did not improve, one had stabilized prior to treatment and remained stable. The other two patients died from PML.
Additional reports
Separately, Sebastian Rauer, MD, of Albert Ludwigs University in Freiburg, Germany, and his colleagues reported that a patient with PML whose symptoms culminated in mutism in February 2018 began speaking again after receiving five infusions of pembrolizumab over 10 weeks. “In addition, the size and number of lesions on MRI decreased, and JCV was no longer detectable in CSF,” Dr. Rauer and his colleagues wrote. “The patient has remained stable as of the end of March 2019, with persistent but abating psychomotor slowing, aphasia, and disorientation.”
Finally, Ondine Walter, of Toulouse (France) University Hospital and colleagues described the case of a 60-year-old woman with PML who received nivolumab on a compassionate-use basis. Two weeks after treatment, JC viral load in CSF and blood had decreased. “Starting 8 weeks after the initiation of nivolumab therapy, the patient’s neurologic symptoms and signs stabilized, and subsequently she showed improved alertness, and the ptosis and hemiplegia abated.”
Reason for caution
Prior studies, however, give reasons for caution when considering the potential use of immune checkpoint inhibitors to treat PML, Dr. Koralnik noted. In one case, a patient developed an inflammatory form of PML known as immune reconstitution inflammatory syndrome after receiving nivolumab (J Neurovirol. 2019 March 12. doi: 10.1007/s13365-019-00738-x). In addition, researchers have reported a case of PML that occurred after 1 year of nivolumab treatment, and four cases of PML related to nivolumab have been reported in pharmacovigilance databases (Emerg Infect Dis. 2018;24:1594-6). The cost and safety profiles of the medications also may be considerations, Dr. Koralnik said.
The study by Dr. Cortese and colleagues was funded by the National Institutes of Health, and the authors had no relevant disclosures. Some of the research letter authors disclosed grants and personal fees from pharmaceutical companies.
SOURCES: Cortese I et al. N Engl J Med. 2019 Apr 10. doi: 10.1056/NEJMoa1815039; Rauer S et al. N Engl J Med. 2019 Apr 10. doi: 10.1056/NEJMc1817193; Walter O et al. N Engl J Med. 2019 Apr 10. doi: 10.1056/NEJMc1816198; Koralnik IJ. N Engl J Med. 2019 Apr 10. doi: 10.1056/NEJMe1904140.
investigators reported in the New England Journal of Medicine.
Three research teams described 10 cases in which patients with PML received pembrolizumab or nivolumab.
In one study, researchers administered pembrolizumab to eight adults with PML. Five patients had clinical improvement or stabilization, whereas 3 patients did not. Among the patients with clinical improvement, treatment led to reduced JC viral load in cerebrospinal fluid (CSF) and increased CD4+ and CD8+ anti–JC virus activity in vitro. Among patients without clinical improvement, treatment did not meaningfully change viral load or antiviral cellular immune response.
In a separate letter, researchers in Germany described an additional patient with PML who had clinical stabilization and no disease progression on MRI after treatment with pembrolizumab.
In another letter, researchers in France described a patient with PML whose condition improved after treatment with nivolumab.
“Do pembrolizumab and nivolumab fit the bill for treatment of PML? The current reports are encouraging but suggest that the presence of JC virus–specific T cells in the blood is a prerequisite for their use,” said Igor J. Koralnik, MD, of the department of neurological sciences at Rush University Medical Center in Chicago, in an accompanying editorial. “A controlled trial may be needed to determine whether immune checkpoint inhibitors are indeed able to keep JC virus in check in patients with PML.”
Reinvigorating T cells
Both monoclonal antibodies target programmed cell death protein 1 (PD-1), which inhibits T-cell proliferation and cytokine production when it binds its associated ligand, Dr. Koralnik said. Pembrolizumab and nivolumab block this inhibition and have been used to spur T-cell activity against tumors in patients with cancer.
PML, an often fatal brain infection caused by the JC virus in patients with immunosuppression, has no specific treatment. Management hinges on “recovery of the immune system, either by treating the underlying cause of immunosuppression or by discontinuing the use of immunosuppressive medications,” said Dr. Koralnik.
Pembrolizumab
Prior studies have found that PD-1 expression is elevated on T lymphocytes of patients with PML. To determine whether PD-1 blockade with pembrolizumab reinvigorates anti–JC virus immune activity in patients with PML, Irene Cortese, MD, of the National Institutes of Health’s Neuroimmunology Clinic and her research colleagues administered pembrolizumab at a dose of 2 mg/kg of body weight every 4-6 weeks to eight adults with PML. The patients received 1-3 doses, and each patient had a different underlying condition.
In all patients, treatment induced down-regulation of PD-1 expression on lymphocytes in CSF and peripheral blood, and five of the eight patients had clinical stabilization or improvement. Of the other three patients who did not improve, one had stabilized prior to treatment and remained stable. The other two patients died from PML.
Additional reports
Separately, Sebastian Rauer, MD, of Albert Ludwigs University in Freiburg, Germany, and his colleagues reported that a patient with PML whose symptoms culminated in mutism in February 2018 began speaking again after receiving five infusions of pembrolizumab over 10 weeks. “In addition, the size and number of lesions on MRI decreased, and JCV was no longer detectable in CSF,” Dr. Rauer and his colleagues wrote. “The patient has remained stable as of the end of March 2019, with persistent but abating psychomotor slowing, aphasia, and disorientation.”
Finally, Ondine Walter, of Toulouse (France) University Hospital and colleagues described the case of a 60-year-old woman with PML who received nivolumab on a compassionate-use basis. Two weeks after treatment, JC viral load in CSF and blood had decreased. “Starting 8 weeks after the initiation of nivolumab therapy, the patient’s neurologic symptoms and signs stabilized, and subsequently she showed improved alertness, and the ptosis and hemiplegia abated.”
Reason for caution
Prior studies, however, give reasons for caution when considering the potential use of immune checkpoint inhibitors to treat PML, Dr. Koralnik noted. In one case, a patient developed an inflammatory form of PML known as immune reconstitution inflammatory syndrome after receiving nivolumab (J Neurovirol. 2019 March 12. doi: 10.1007/s13365-019-00738-x). In addition, researchers have reported a case of PML that occurred after 1 year of nivolumab treatment, and four cases of PML related to nivolumab have been reported in pharmacovigilance databases (Emerg Infect Dis. 2018;24:1594-6). The cost and safety profiles of the medications also may be considerations, Dr. Koralnik said.
The study by Dr. Cortese and colleagues was funded by the National Institutes of Health, and the authors had no relevant disclosures. Some of the research letter authors disclosed grants and personal fees from pharmaceutical companies.
SOURCES: Cortese I et al. N Engl J Med. 2019 Apr 10. doi: 10.1056/NEJMoa1815039; Rauer S et al. N Engl J Med. 2019 Apr 10. doi: 10.1056/NEJMc1817193; Walter O et al. N Engl J Med. 2019 Apr 10. doi: 10.1056/NEJMc1816198; Koralnik IJ. N Engl J Med. 2019 Apr 10. doi: 10.1056/NEJMe1904140.
investigators reported in the New England Journal of Medicine.
Three research teams described 10 cases in which patients with PML received pembrolizumab or nivolumab.
In one study, researchers administered pembrolizumab to eight adults with PML. Five patients had clinical improvement or stabilization, whereas 3 patients did not. Among the patients with clinical improvement, treatment led to reduced JC viral load in cerebrospinal fluid (CSF) and increased CD4+ and CD8+ anti–JC virus activity in vitro. Among patients without clinical improvement, treatment did not meaningfully change viral load or antiviral cellular immune response.
In a separate letter, researchers in Germany described an additional patient with PML who had clinical stabilization and no disease progression on MRI after treatment with pembrolizumab.
In another letter, researchers in France described a patient with PML whose condition improved after treatment with nivolumab.
“Do pembrolizumab and nivolumab fit the bill for treatment of PML? The current reports are encouraging but suggest that the presence of JC virus–specific T cells in the blood is a prerequisite for their use,” said Igor J. Koralnik, MD, of the department of neurological sciences at Rush University Medical Center in Chicago, in an accompanying editorial. “A controlled trial may be needed to determine whether immune checkpoint inhibitors are indeed able to keep JC virus in check in patients with PML.”
Reinvigorating T cells
Both monoclonal antibodies target programmed cell death protein 1 (PD-1), which inhibits T-cell proliferation and cytokine production when it binds its associated ligand, Dr. Koralnik said. Pembrolizumab and nivolumab block this inhibition and have been used to spur T-cell activity against tumors in patients with cancer.
PML, an often fatal brain infection caused by the JC virus in patients with immunosuppression, has no specific treatment. Management hinges on “recovery of the immune system, either by treating the underlying cause of immunosuppression or by discontinuing the use of immunosuppressive medications,” said Dr. Koralnik.
Pembrolizumab
Prior studies have found that PD-1 expression is elevated on T lymphocytes of patients with PML. To determine whether PD-1 blockade with pembrolizumab reinvigorates anti–JC virus immune activity in patients with PML, Irene Cortese, MD, of the National Institutes of Health’s Neuroimmunology Clinic and her research colleagues administered pembrolizumab at a dose of 2 mg/kg of body weight every 4-6 weeks to eight adults with PML. The patients received 1-3 doses, and each patient had a different underlying condition.
In all patients, treatment induced down-regulation of PD-1 expression on lymphocytes in CSF and peripheral blood, and five of the eight patients had clinical stabilization or improvement. Of the other three patients who did not improve, one had stabilized prior to treatment and remained stable. The other two patients died from PML.
Additional reports
Separately, Sebastian Rauer, MD, of Albert Ludwigs University in Freiburg, Germany, and his colleagues reported that a patient with PML whose symptoms culminated in mutism in February 2018 began speaking again after receiving five infusions of pembrolizumab over 10 weeks. “In addition, the size and number of lesions on MRI decreased, and JCV was no longer detectable in CSF,” Dr. Rauer and his colleagues wrote. “The patient has remained stable as of the end of March 2019, with persistent but abating psychomotor slowing, aphasia, and disorientation.”
Finally, Ondine Walter, of Toulouse (France) University Hospital and colleagues described the case of a 60-year-old woman with PML who received nivolumab on a compassionate-use basis. Two weeks after treatment, JC viral load in CSF and blood had decreased. “Starting 8 weeks after the initiation of nivolumab therapy, the patient’s neurologic symptoms and signs stabilized, and subsequently she showed improved alertness, and the ptosis and hemiplegia abated.”
Reason for caution
Prior studies, however, give reasons for caution when considering the potential use of immune checkpoint inhibitors to treat PML, Dr. Koralnik noted. In one case, a patient developed an inflammatory form of PML known as immune reconstitution inflammatory syndrome after receiving nivolumab (J Neurovirol. 2019 March 12. doi: 10.1007/s13365-019-00738-x). In addition, researchers have reported a case of PML that occurred after 1 year of nivolumab treatment, and four cases of PML related to nivolumab have been reported in pharmacovigilance databases (Emerg Infect Dis. 2018;24:1594-6). The cost and safety profiles of the medications also may be considerations, Dr. Koralnik said.
The study by Dr. Cortese and colleagues was funded by the National Institutes of Health, and the authors had no relevant disclosures. Some of the research letter authors disclosed grants and personal fees from pharmaceutical companies.
SOURCES: Cortese I et al. N Engl J Med. 2019 Apr 10. doi: 10.1056/NEJMoa1815039; Rauer S et al. N Engl J Med. 2019 Apr 10. doi: 10.1056/NEJMc1817193; Walter O et al. N Engl J Med. 2019 Apr 10. doi: 10.1056/NEJMc1816198; Koralnik IJ. N Engl J Med. 2019 Apr 10. doi: 10.1056/NEJMe1904140.
FROM THE NEW ENGLAND JOURNAL OF MEDICINE
Diagnostic test helps clinicians identify IPF with nonsurgical biopsy
, according to recent research published in the Lancet Respiratory Medicine.
The results of the molecular test, called the Envisia Genomic Classifier (Veracyte; San Francisco), had a high positive predictive value of proven usual interstitial pneumonia, and could be used in place of surgical lung biopsy to confirm a diagnosis of idiopathic pulmonary fibrosis (IPF), wrote Ganesh Raghu, MD, director at the Center for Interstitial Lung Diseases and professor of medicine at the University of Washington, Seattle, and his colleagues.* The Envisia Genomic Classifier recently received final Medicare local coverage determination for IPF diagnosis, according to a recent press release by Veracyte.
“IPF is often challenging to distinguish from other [interstitial lung disease], but timely and accurate diagnosis is critical so that patients with IPF can access therapies that may slow progression of the disease, while avoiding potentially harmful treatments,” Dr. Raghu stated in a press release. “Our results with molecular classification through machine learning [the Envisia classifier] are promising and, along with clinical information and radiological features in high-resolution CT imaging, physicians through multidisciplinary discussions, may be able to utilize the molecular classification as a diagnostic tool to make a more informed and confident diagnoses.”
The researchers prospectively recruited 237 patients from 29 centers in the United States and Europe who were evaluated with the Bronchial Sample Collection for a Novel Genomic Test for suspected interstitial lung disease and who underwent surgical biopsy, transbronchial biopsy, or cryobiopsy for sample collection. They used histopathology and RNA sequence data from 90 patients to create a training data set of an unusual interstitial pneumonia pattern for the machine learning algorithm.
The classifier found usual interstitial pneumonia diagnoses in 49 patients; the test had a specificity of 88% (95% confidence interval, 70%-98%) and a sensitivity of 70% (95% CI, 47%-87%). Of 42 patients with inconsistent or possible usual interstitial pneumonia identified from high-resolution CT imaging, there was a positive predictive value of 81% (95% CI, 54%-96%). When multidisciplinary teams made diagnoses with the molecular classifier data, there was a clinical agreement of 86% (95% CI, 78%-92%) with diagnoses made using histopathology data. In 18 cases of IPF, there was an improvement in diagnostic confidence using the molecular classifier data, with 89% of diagnoses designated as high confidence, compared with 56% of cases based on histopathologic data (P = .0339). In 48 patients with nondiagnostic pathology or nonclassifiable fibrosis histopathology, 63% of diagnoses with the molecular classifier data were high confidence, compared with 42% using histopathologic data (P = .0412).
This study was funded by Veracyte, creator of the Envisia Genomic Classifier. Some authors reported relationships with Veracyte and other companies.
SOURCE: Raghu G et al. Lancet Respir Med. 2019 Apr 1. doi: 10.1016/S2213-8587(19)300.
Correction, 4/25/19: An earlier version of this article misstated how the Envisia Genomic Classifier could be used. The Envisia test is not intended to replace high-resolution chest CT (HRCT). It is used when HRCT is inconclusive to help prevent patients from having to undergo invasive diagnostic procedures.
Use of a molecular classifier could be most helpful in situations where patients have atypical radiology results or in cases where multidisciplinary teams disagree on the diagnosis, Simon Hart, PhD, wrote in a related editorial.
According to the 2018 international guidelines for idiopathic pulmonary fibrosis, usual interstitial pneumonia certainty is defined as honeycombing seen on high-resolution CT (HRCT), probable if there is presence of traction bronchiectasis but not honeycombing, and indeterminate if there is no presence of usual interstitial pneumonia or another diagnosis. As radiologists “often disagree on HRCT patterns,” IPF sometimes becomes a working diagnosis based on progression of disease, Dr. Hart wrote. In these cases, molecular classifier samples could help identify IPF in patients who have undergone less invasive transbronchial lung biopsy.
Among patients for whom diagnoses using identical clinical features have different results, HRCT and pathology data, particularly in cases of nonspecific interstitial pneumonia and chronic hypersensitivity pneumonitis that follow a similar disease course to idiopathic pulmonary fibrosis, molecular classifier testing could help identify patients with these diseases so treatments such as to avoid treating these patients with anti-inflammatory or immunosuppressive therapy.
“It seems conceivable that in future interstitial lung diseases could be classified by a simple dichotomy: primarily scarring diseases characterized by molecular usual interstitial pneumonia to be treated with antifibrotics versus immune-driven conditions without usual interstitial pneumonia that need an anti-inflammatory approach,” he wrote.
Dr. Hart is from the respiratory research group at Castle Hill Hospital in Cottingham, England. These comments summarize his editorial in response to Raghu et al. (Lancet Respir Med. 2019 Apr 1. doi 10.1016/S2213-2600[19]30058-X). He reported receiving grants and support to attend conferences, and consultancy fees from Boehringer Ingelheim.
Use of a molecular classifier could be most helpful in situations where patients have atypical radiology results or in cases where multidisciplinary teams disagree on the diagnosis, Simon Hart, PhD, wrote in a related editorial.
According to the 2018 international guidelines for idiopathic pulmonary fibrosis, usual interstitial pneumonia certainty is defined as honeycombing seen on high-resolution CT (HRCT), probable if there is presence of traction bronchiectasis but not honeycombing, and indeterminate if there is no presence of usual interstitial pneumonia or another diagnosis. As radiologists “often disagree on HRCT patterns,” IPF sometimes becomes a working diagnosis based on progression of disease, Dr. Hart wrote. In these cases, molecular classifier samples could help identify IPF in patients who have undergone less invasive transbronchial lung biopsy.
Among patients for whom diagnoses using identical clinical features have different results, HRCT and pathology data, particularly in cases of nonspecific interstitial pneumonia and chronic hypersensitivity pneumonitis that follow a similar disease course to idiopathic pulmonary fibrosis, molecular classifier testing could help identify patients with these diseases so treatments such as to avoid treating these patients with anti-inflammatory or immunosuppressive therapy.
“It seems conceivable that in future interstitial lung diseases could be classified by a simple dichotomy: primarily scarring diseases characterized by molecular usual interstitial pneumonia to be treated with antifibrotics versus immune-driven conditions without usual interstitial pneumonia that need an anti-inflammatory approach,” he wrote.
Dr. Hart is from the respiratory research group at Castle Hill Hospital in Cottingham, England. These comments summarize his editorial in response to Raghu et al. (Lancet Respir Med. 2019 Apr 1. doi 10.1016/S2213-2600[19]30058-X). He reported receiving grants and support to attend conferences, and consultancy fees from Boehringer Ingelheim.
Use of a molecular classifier could be most helpful in situations where patients have atypical radiology results or in cases where multidisciplinary teams disagree on the diagnosis, Simon Hart, PhD, wrote in a related editorial.
According to the 2018 international guidelines for idiopathic pulmonary fibrosis, usual interstitial pneumonia certainty is defined as honeycombing seen on high-resolution CT (HRCT), probable if there is presence of traction bronchiectasis but not honeycombing, and indeterminate if there is no presence of usual interstitial pneumonia or another diagnosis. As radiologists “often disagree on HRCT patterns,” IPF sometimes becomes a working diagnosis based on progression of disease, Dr. Hart wrote. In these cases, molecular classifier samples could help identify IPF in patients who have undergone less invasive transbronchial lung biopsy.
Among patients for whom diagnoses using identical clinical features have different results, HRCT and pathology data, particularly in cases of nonspecific interstitial pneumonia and chronic hypersensitivity pneumonitis that follow a similar disease course to idiopathic pulmonary fibrosis, molecular classifier testing could help identify patients with these diseases so treatments such as to avoid treating these patients with anti-inflammatory or immunosuppressive therapy.
“It seems conceivable that in future interstitial lung diseases could be classified by a simple dichotomy: primarily scarring diseases characterized by molecular usual interstitial pneumonia to be treated with antifibrotics versus immune-driven conditions without usual interstitial pneumonia that need an anti-inflammatory approach,” he wrote.
Dr. Hart is from the respiratory research group at Castle Hill Hospital in Cottingham, England. These comments summarize his editorial in response to Raghu et al. (Lancet Respir Med. 2019 Apr 1. doi 10.1016/S2213-2600[19]30058-X). He reported receiving grants and support to attend conferences, and consultancy fees from Boehringer Ingelheim.
, according to recent research published in the Lancet Respiratory Medicine.
The results of the molecular test, called the Envisia Genomic Classifier (Veracyte; San Francisco), had a high positive predictive value of proven usual interstitial pneumonia, and could be used in place of surgical lung biopsy to confirm a diagnosis of idiopathic pulmonary fibrosis (IPF), wrote Ganesh Raghu, MD, director at the Center for Interstitial Lung Diseases and professor of medicine at the University of Washington, Seattle, and his colleagues.* The Envisia Genomic Classifier recently received final Medicare local coverage determination for IPF diagnosis, according to a recent press release by Veracyte.
“IPF is often challenging to distinguish from other [interstitial lung disease], but timely and accurate diagnosis is critical so that patients with IPF can access therapies that may slow progression of the disease, while avoiding potentially harmful treatments,” Dr. Raghu stated in a press release. “Our results with molecular classification through machine learning [the Envisia classifier] are promising and, along with clinical information and radiological features in high-resolution CT imaging, physicians through multidisciplinary discussions, may be able to utilize the molecular classification as a diagnostic tool to make a more informed and confident diagnoses.”
The researchers prospectively recruited 237 patients from 29 centers in the United States and Europe who were evaluated with the Bronchial Sample Collection for a Novel Genomic Test for suspected interstitial lung disease and who underwent surgical biopsy, transbronchial biopsy, or cryobiopsy for sample collection. They used histopathology and RNA sequence data from 90 patients to create a training data set of an unusual interstitial pneumonia pattern for the machine learning algorithm.
The classifier found usual interstitial pneumonia diagnoses in 49 patients; the test had a specificity of 88% (95% confidence interval, 70%-98%) and a sensitivity of 70% (95% CI, 47%-87%). Of 42 patients with inconsistent or possible usual interstitial pneumonia identified from high-resolution CT imaging, there was a positive predictive value of 81% (95% CI, 54%-96%). When multidisciplinary teams made diagnoses with the molecular classifier data, there was a clinical agreement of 86% (95% CI, 78%-92%) with diagnoses made using histopathology data. In 18 cases of IPF, there was an improvement in diagnostic confidence using the molecular classifier data, with 89% of diagnoses designated as high confidence, compared with 56% of cases based on histopathologic data (P = .0339). In 48 patients with nondiagnostic pathology or nonclassifiable fibrosis histopathology, 63% of diagnoses with the molecular classifier data were high confidence, compared with 42% using histopathologic data (P = .0412).
This study was funded by Veracyte, creator of the Envisia Genomic Classifier. Some authors reported relationships with Veracyte and other companies.
SOURCE: Raghu G et al. Lancet Respir Med. 2019 Apr 1. doi: 10.1016/S2213-8587(19)300.
Correction, 4/25/19: An earlier version of this article misstated how the Envisia Genomic Classifier could be used. The Envisia test is not intended to replace high-resolution chest CT (HRCT). It is used when HRCT is inconclusive to help prevent patients from having to undergo invasive diagnostic procedures.
, according to recent research published in the Lancet Respiratory Medicine.
The results of the molecular test, called the Envisia Genomic Classifier (Veracyte; San Francisco), had a high positive predictive value of proven usual interstitial pneumonia, and could be used in place of surgical lung biopsy to confirm a diagnosis of idiopathic pulmonary fibrosis (IPF), wrote Ganesh Raghu, MD, director at the Center for Interstitial Lung Diseases and professor of medicine at the University of Washington, Seattle, and his colleagues.* The Envisia Genomic Classifier recently received final Medicare local coverage determination for IPF diagnosis, according to a recent press release by Veracyte.
“IPF is often challenging to distinguish from other [interstitial lung disease], but timely and accurate diagnosis is critical so that patients with IPF can access therapies that may slow progression of the disease, while avoiding potentially harmful treatments,” Dr. Raghu stated in a press release. “Our results with molecular classification through machine learning [the Envisia classifier] are promising and, along with clinical information and radiological features in high-resolution CT imaging, physicians through multidisciplinary discussions, may be able to utilize the molecular classification as a diagnostic tool to make a more informed and confident diagnoses.”
The researchers prospectively recruited 237 patients from 29 centers in the United States and Europe who were evaluated with the Bronchial Sample Collection for a Novel Genomic Test for suspected interstitial lung disease and who underwent surgical biopsy, transbronchial biopsy, or cryobiopsy for sample collection. They used histopathology and RNA sequence data from 90 patients to create a training data set of an unusual interstitial pneumonia pattern for the machine learning algorithm.
The classifier found usual interstitial pneumonia diagnoses in 49 patients; the test had a specificity of 88% (95% confidence interval, 70%-98%) and a sensitivity of 70% (95% CI, 47%-87%). Of 42 patients with inconsistent or possible usual interstitial pneumonia identified from high-resolution CT imaging, there was a positive predictive value of 81% (95% CI, 54%-96%). When multidisciplinary teams made diagnoses with the molecular classifier data, there was a clinical agreement of 86% (95% CI, 78%-92%) with diagnoses made using histopathology data. In 18 cases of IPF, there was an improvement in diagnostic confidence using the molecular classifier data, with 89% of diagnoses designated as high confidence, compared with 56% of cases based on histopathologic data (P = .0339). In 48 patients with nondiagnostic pathology or nonclassifiable fibrosis histopathology, 63% of diagnoses with the molecular classifier data were high confidence, compared with 42% using histopathologic data (P = .0412).
This study was funded by Veracyte, creator of the Envisia Genomic Classifier. Some authors reported relationships with Veracyte and other companies.
SOURCE: Raghu G et al. Lancet Respir Med. 2019 Apr 1. doi: 10.1016/S2213-8587(19)300.
Correction, 4/25/19: An earlier version of this article misstated how the Envisia Genomic Classifier could be used. The Envisia test is not intended to replace high-resolution chest CT (HRCT). It is used when HRCT is inconclusive to help prevent patients from having to undergo invasive diagnostic procedures.
FROM THE LANCET RESPIRATORY MEDICINE
Identifying CMV infection in asymptomatic newborns – one step closer?
Cytomegalovirus (CMV) infection is the most common congenital viral infection in U.S. children, with a frequency between 0.5% and 1% of newborn infants resulting in approximately 30,000 infected children annually. A small minority (approximately 10%) can be identified in the neonatal period as symptomatic with jaundice (from direct hyperbilirubinemia), petechiae (from thrombocytopenia), hepatosplenomegaly, microcephaly, or other manifestations. The vast majority are asymptomatic at birth, yet 15% will have or develop sensorineural hearing loss (SNHL) during the first few years of life; others (1%-2%) will develop vision loss associated with retinal scars. Congenital CMV accounts for 20% of those with SNHL detected at birth and 25% of children with SNHL at 4 years of age.
Screening for congenital CMV has been an ongoing subject of debate. The challenges of implementing screening programs are related both to the diagnostics (collecting urine samples on newborns) as well as with the question of whether we have treatment and interventions to offer babies diagnosed with congenital CMV across the complete spectrum of clinical presentations.
Current screening programs implemented in some hospitals, called “targeted screening,” in which babies who fail newborn screening programs are tested for CMV, are not sufficient to achieve the goal of identifying babies who will need follow-up for early detection of SNHL or vision abnormalities, or possibly early antiviral therapy (Valcyte; valganciclovir), because only a small portion of those who eventually develop SNHL are currently identified by the targeted screening programs.1
However, its availability only has added to the debate as to whether the time has arrived for universal screening.
Vertical transmission of CMV occurs in utero (during any of the trimesters), at birth by passage through the birth canal, or postnatally by ingestion of breast milk. Neonatal infection (in utero and postnatal) occurs in both mothers with primary CMV infection during gestation and in those with recurrent infection (from a different viral strain) or reactivation of infection. Severe clinically symptomatic disease and sequelae is associated with primary maternal infection and early transmission to the fetus. However, it is estimated that nonprimary maternal infection accounts for 75% of neonatal infections. Transmission by breast milk to full-term, healthy infants does not appear to be associated with clinical illness or sequelae; however, preterm infants or those with birth weights less than 1,500 g have a small risk of developing clinical disease.
The polymerase chain reaction–based saliva CMV test (Alethia CMV Assay Test System) was licensed by the Food and Drug Administration in November 2018 after studies demonstrated high sensitivity and specificity, compared with viral culture (the gold standard). In one study, 17,327 infants were screened with the liquid-saliva PCR assay, and 0.5% tested positive for CMV on both the saliva test and culture. Sensitivity and specificity of the liquid-saliva PCR assay were 100% and 99.9%, respectively.2 The availability of an approved saliva-based assay that is both highly sensitive and specific overcomes the challenge of collecting urine, which has been a limiting factor in development of pragmatic universal screening programs. To date, most of the focus in identification of congenital CMV infection has been linking newborn hearing testing programs with CMV testing. For some, these have been labeled “targeted screening programs for CMV.” To us, these appear to be best practice for medical evaluations of an infant with identified SNHL. The availability of saliva-based CMV testing should enable virtually all children who fail newborn screening to be tested for CMV. In multiple studies,3,4 6% of infants with confirmed hearing screen failure tested positive for CMV. A recent study5 identified only 1 infant among the 171 infants who failed newborn screening, however only approximately 15% of the infants were eventually confirmed as hearing impaired at audiology follow-up, suggesting that programmatically testing for CMV might be limited to those with confirmed hearing loss if such can be accomplished within a narrow window of time.
The major challenge with linking CMV testing with newborn hearing screening is whether treatment with valganciclovir would be of value in congenital CMV infection and isolated hearing loss. Studies of children with symptomatic central nervous system congenital CMV disease provide evidence of improvement (or lack of progression) in hearing loss in those treated with valganciclovir. Few, if any of these children had isolated hearing loss in this pivotal study.6 An observational study reported improved outcomes in 55 of 59 (93%) children with congenital CMV and isolated SNHL treated with valganciclovir between birth to 12 weeks of life.7 Hearing improved in nearly 70% of ears, 27% showed no change, and only 3% demonstrated progression of hearing loss; most of the improved ears returned to normal hearing. Currently, a National Institutes of Health study (ValEAR) is recruiting CMV-infected infants with isolated SNHL and randomizing them to treatment with valganciclovir or placebo. The goal is to determine if infants treated with valganciclovir will have better hearing and language outcomes.
Linking CMV testing to those who fail newborn hearing screening programs is an important step, as it appears such children are at least five times more likely to be infected with CMV than is the overall birth cohort. However, such strategies fall short of identifying the majority of newborns with congenital CMV infection, who are completely asymptomatic yet are at risk for development of complications that potentially have substantial impact on their quality of life. Although the availability of sensitive and specific PCR testing in saliva provides a pragmatic approach to identify infected children, many questions remain. First, would a confirmatory test be necessary, such as urine PCR (now considered the gold standard by many CMV experts)? Second, once identified, what regimen for follow-up testing would be indicated to identify those with early SNHL or retinopathy, and until what age? Third, is there a role for treatment in asymptomatic infection? Would that treatment be prophylactic, prior to the development of clinical signs, or implemented once early evidence of SNHL or retinopathy is present?
The Valgan Toddler study – sponsored by NIH and the University of Alabama as part of the Collaborative Antiviral Study Group – will enroll children who are aged 1 month through 3 years and who had a recent diagnosis of hearing loss (within the prior 12 weeks) and evidence of congenital CMV infection. The purpose of this study is to compare the effect on hearing and neurologic outcomes in infants aged 1 month through 4 years with recent onset SNHL who receive 6 weeks of valganciclovir versus children who do not receive this drug. The results of such studies will be critical for the development of best practices.
In summary, the licensure of a rapid PCR-based tool for diagnosis of CMV infection from saliva adds to our ability to develop screening programs to detect asymptomatic infants with congenital CMV infection. The ability to link newborns who fail hearing screening programs with CMV testing will lead to more detection of CMV-infected neonates, both with isolated hearing loss, and subsequently with no signs or symptoms of infection. There is an urgent need for evidence from randomized clinical trials to enable the development of best practices for such infants.
Dr. Pelton is professor of pediatrics and epidemiology at Boston University and senior attending physician at Boston Medical Center. Dr. Lapidot is a senior fellow in pediatric infectious diseases, Boston Medical Center. Neither Dr. Pelton nor Dr. Lapidot have any relevant financial disclosures. Email them at [email protected].
References
1. J Pediatric Infect Dis Soc. 2019 Mar 28;8(1):55-9.
2. N Engl J Med 2011 Jun 2; 364:2111-8.
3. Pediatrics. 2008 May;121(5):970-5
4. J Clin Virol. 2018 May;102:110-5.
5. J Pediatric Infect Dis Soc. 2019 Mar;8(1):55-9.
6. J Pediatr. 2003 Jul;143(1):16-25.
7. J Pediatr. 2018 Aug;199:166-70.
Cytomegalovirus (CMV) infection is the most common congenital viral infection in U.S. children, with a frequency between 0.5% and 1% of newborn infants resulting in approximately 30,000 infected children annually. A small minority (approximately 10%) can be identified in the neonatal period as symptomatic with jaundice (from direct hyperbilirubinemia), petechiae (from thrombocytopenia), hepatosplenomegaly, microcephaly, or other manifestations. The vast majority are asymptomatic at birth, yet 15% will have or develop sensorineural hearing loss (SNHL) during the first few years of life; others (1%-2%) will develop vision loss associated with retinal scars. Congenital CMV accounts for 20% of those with SNHL detected at birth and 25% of children with SNHL at 4 years of age.
Screening for congenital CMV has been an ongoing subject of debate. The challenges of implementing screening programs are related both to the diagnostics (collecting urine samples on newborns) as well as with the question of whether we have treatment and interventions to offer babies diagnosed with congenital CMV across the complete spectrum of clinical presentations.
Current screening programs implemented in some hospitals, called “targeted screening,” in which babies who fail newborn screening programs are tested for CMV, are not sufficient to achieve the goal of identifying babies who will need follow-up for early detection of SNHL or vision abnormalities, or possibly early antiviral therapy (Valcyte; valganciclovir), because only a small portion of those who eventually develop SNHL are currently identified by the targeted screening programs.1
However, its availability only has added to the debate as to whether the time has arrived for universal screening.
Vertical transmission of CMV occurs in utero (during any of the trimesters), at birth by passage through the birth canal, or postnatally by ingestion of breast milk. Neonatal infection (in utero and postnatal) occurs in both mothers with primary CMV infection during gestation and in those with recurrent infection (from a different viral strain) or reactivation of infection. Severe clinically symptomatic disease and sequelae is associated with primary maternal infection and early transmission to the fetus. However, it is estimated that nonprimary maternal infection accounts for 75% of neonatal infections. Transmission by breast milk to full-term, healthy infants does not appear to be associated with clinical illness or sequelae; however, preterm infants or those with birth weights less than 1,500 g have a small risk of developing clinical disease.
The polymerase chain reaction–based saliva CMV test (Alethia CMV Assay Test System) was licensed by the Food and Drug Administration in November 2018 after studies demonstrated high sensitivity and specificity, compared with viral culture (the gold standard). In one study, 17,327 infants were screened with the liquid-saliva PCR assay, and 0.5% tested positive for CMV on both the saliva test and culture. Sensitivity and specificity of the liquid-saliva PCR assay were 100% and 99.9%, respectively.2 The availability of an approved saliva-based assay that is both highly sensitive and specific overcomes the challenge of collecting urine, which has been a limiting factor in development of pragmatic universal screening programs. To date, most of the focus in identification of congenital CMV infection has been linking newborn hearing testing programs with CMV testing. For some, these have been labeled “targeted screening programs for CMV.” To us, these appear to be best practice for medical evaluations of an infant with identified SNHL. The availability of saliva-based CMV testing should enable virtually all children who fail newborn screening to be tested for CMV. In multiple studies,3,4 6% of infants with confirmed hearing screen failure tested positive for CMV. A recent study5 identified only 1 infant among the 171 infants who failed newborn screening, however only approximately 15% of the infants were eventually confirmed as hearing impaired at audiology follow-up, suggesting that programmatically testing for CMV might be limited to those with confirmed hearing loss if such can be accomplished within a narrow window of time.
The major challenge with linking CMV testing with newborn hearing screening is whether treatment with valganciclovir would be of value in congenital CMV infection and isolated hearing loss. Studies of children with symptomatic central nervous system congenital CMV disease provide evidence of improvement (or lack of progression) in hearing loss in those treated with valganciclovir. Few, if any of these children had isolated hearing loss in this pivotal study.6 An observational study reported improved outcomes in 55 of 59 (93%) children with congenital CMV and isolated SNHL treated with valganciclovir between birth to 12 weeks of life.7 Hearing improved in nearly 70% of ears, 27% showed no change, and only 3% demonstrated progression of hearing loss; most of the improved ears returned to normal hearing. Currently, a National Institutes of Health study (ValEAR) is recruiting CMV-infected infants with isolated SNHL and randomizing them to treatment with valganciclovir or placebo. The goal is to determine if infants treated with valganciclovir will have better hearing and language outcomes.
Linking CMV testing to those who fail newborn hearing screening programs is an important step, as it appears such children are at least five times more likely to be infected with CMV than is the overall birth cohort. However, such strategies fall short of identifying the majority of newborns with congenital CMV infection, who are completely asymptomatic yet are at risk for development of complications that potentially have substantial impact on their quality of life. Although the availability of sensitive and specific PCR testing in saliva provides a pragmatic approach to identify infected children, many questions remain. First, would a confirmatory test be necessary, such as urine PCR (now considered the gold standard by many CMV experts)? Second, once identified, what regimen for follow-up testing would be indicated to identify those with early SNHL or retinopathy, and until what age? Third, is there a role for treatment in asymptomatic infection? Would that treatment be prophylactic, prior to the development of clinical signs, or implemented once early evidence of SNHL or retinopathy is present?
The Valgan Toddler study – sponsored by NIH and the University of Alabama as part of the Collaborative Antiviral Study Group – will enroll children who are aged 1 month through 3 years and who had a recent diagnosis of hearing loss (within the prior 12 weeks) and evidence of congenital CMV infection. The purpose of this study is to compare the effect on hearing and neurologic outcomes in infants aged 1 month through 4 years with recent onset SNHL who receive 6 weeks of valganciclovir versus children who do not receive this drug. The results of such studies will be critical for the development of best practices.
In summary, the licensure of a rapid PCR-based tool for diagnosis of CMV infection from saliva adds to our ability to develop screening programs to detect asymptomatic infants with congenital CMV infection. The ability to link newborns who fail hearing screening programs with CMV testing will lead to more detection of CMV-infected neonates, both with isolated hearing loss, and subsequently with no signs or symptoms of infection. There is an urgent need for evidence from randomized clinical trials to enable the development of best practices for such infants.
Dr. Pelton is professor of pediatrics and epidemiology at Boston University and senior attending physician at Boston Medical Center. Dr. Lapidot is a senior fellow in pediatric infectious diseases, Boston Medical Center. Neither Dr. Pelton nor Dr. Lapidot have any relevant financial disclosures. Email them at [email protected].
References
1. J Pediatric Infect Dis Soc. 2019 Mar 28;8(1):55-9.
2. N Engl J Med 2011 Jun 2; 364:2111-8.
3. Pediatrics. 2008 May;121(5):970-5
4. J Clin Virol. 2018 May;102:110-5.
5. J Pediatric Infect Dis Soc. 2019 Mar;8(1):55-9.
6. J Pediatr. 2003 Jul;143(1):16-25.
7. J Pediatr. 2018 Aug;199:166-70.
Cytomegalovirus (CMV) infection is the most common congenital viral infection in U.S. children, with a frequency between 0.5% and 1% of newborn infants resulting in approximately 30,000 infected children annually. A small minority (approximately 10%) can be identified in the neonatal period as symptomatic with jaundice (from direct hyperbilirubinemia), petechiae (from thrombocytopenia), hepatosplenomegaly, microcephaly, or other manifestations. The vast majority are asymptomatic at birth, yet 15% will have or develop sensorineural hearing loss (SNHL) during the first few years of life; others (1%-2%) will develop vision loss associated with retinal scars. Congenital CMV accounts for 20% of those with SNHL detected at birth and 25% of children with SNHL at 4 years of age.
Screening for congenital CMV has been an ongoing subject of debate. The challenges of implementing screening programs are related both to the diagnostics (collecting urine samples on newborns) as well as with the question of whether we have treatment and interventions to offer babies diagnosed with congenital CMV across the complete spectrum of clinical presentations.
Current screening programs implemented in some hospitals, called “targeted screening,” in which babies who fail newborn screening programs are tested for CMV, are not sufficient to achieve the goal of identifying babies who will need follow-up for early detection of SNHL or vision abnormalities, or possibly early antiviral therapy (Valcyte; valganciclovir), because only a small portion of those who eventually develop SNHL are currently identified by the targeted screening programs.1
However, its availability only has added to the debate as to whether the time has arrived for universal screening.
Vertical transmission of CMV occurs in utero (during any of the trimesters), at birth by passage through the birth canal, or postnatally by ingestion of breast milk. Neonatal infection (in utero and postnatal) occurs in both mothers with primary CMV infection during gestation and in those with recurrent infection (from a different viral strain) or reactivation of infection. Severe clinically symptomatic disease and sequelae is associated with primary maternal infection and early transmission to the fetus. However, it is estimated that nonprimary maternal infection accounts for 75% of neonatal infections. Transmission by breast milk to full-term, healthy infants does not appear to be associated with clinical illness or sequelae; however, preterm infants or those with birth weights less than 1,500 g have a small risk of developing clinical disease.
The polymerase chain reaction–based saliva CMV test (Alethia CMV Assay Test System) was licensed by the Food and Drug Administration in November 2018 after studies demonstrated high sensitivity and specificity, compared with viral culture (the gold standard). In one study, 17,327 infants were screened with the liquid-saliva PCR assay, and 0.5% tested positive for CMV on both the saliva test and culture. Sensitivity and specificity of the liquid-saliva PCR assay were 100% and 99.9%, respectively.2 The availability of an approved saliva-based assay that is both highly sensitive and specific overcomes the challenge of collecting urine, which has been a limiting factor in development of pragmatic universal screening programs. To date, most of the focus in identification of congenital CMV infection has been linking newborn hearing testing programs with CMV testing. For some, these have been labeled “targeted screening programs for CMV.” To us, these appear to be best practice for medical evaluations of an infant with identified SNHL. The availability of saliva-based CMV testing should enable virtually all children who fail newborn screening to be tested for CMV. In multiple studies,3,4 6% of infants with confirmed hearing screen failure tested positive for CMV. A recent study5 identified only 1 infant among the 171 infants who failed newborn screening, however only approximately 15% of the infants were eventually confirmed as hearing impaired at audiology follow-up, suggesting that programmatically testing for CMV might be limited to those with confirmed hearing loss if such can be accomplished within a narrow window of time.
The major challenge with linking CMV testing with newborn hearing screening is whether treatment with valganciclovir would be of value in congenital CMV infection and isolated hearing loss. Studies of children with symptomatic central nervous system congenital CMV disease provide evidence of improvement (or lack of progression) in hearing loss in those treated with valganciclovir. Few, if any of these children had isolated hearing loss in this pivotal study.6 An observational study reported improved outcomes in 55 of 59 (93%) children with congenital CMV and isolated SNHL treated with valganciclovir between birth to 12 weeks of life.7 Hearing improved in nearly 70% of ears, 27% showed no change, and only 3% demonstrated progression of hearing loss; most of the improved ears returned to normal hearing. Currently, a National Institutes of Health study (ValEAR) is recruiting CMV-infected infants with isolated SNHL and randomizing them to treatment with valganciclovir or placebo. The goal is to determine if infants treated with valganciclovir will have better hearing and language outcomes.
Linking CMV testing to those who fail newborn hearing screening programs is an important step, as it appears such children are at least five times more likely to be infected with CMV than is the overall birth cohort. However, such strategies fall short of identifying the majority of newborns with congenital CMV infection, who are completely asymptomatic yet are at risk for development of complications that potentially have substantial impact on their quality of life. Although the availability of sensitive and specific PCR testing in saliva provides a pragmatic approach to identify infected children, many questions remain. First, would a confirmatory test be necessary, such as urine PCR (now considered the gold standard by many CMV experts)? Second, once identified, what regimen for follow-up testing would be indicated to identify those with early SNHL or retinopathy, and until what age? Third, is there a role for treatment in asymptomatic infection? Would that treatment be prophylactic, prior to the development of clinical signs, or implemented once early evidence of SNHL or retinopathy is present?
The Valgan Toddler study – sponsored by NIH and the University of Alabama as part of the Collaborative Antiviral Study Group – will enroll children who are aged 1 month through 3 years and who had a recent diagnosis of hearing loss (within the prior 12 weeks) and evidence of congenital CMV infection. The purpose of this study is to compare the effect on hearing and neurologic outcomes in infants aged 1 month through 4 years with recent onset SNHL who receive 6 weeks of valganciclovir versus children who do not receive this drug. The results of such studies will be critical for the development of best practices.
In summary, the licensure of a rapid PCR-based tool for diagnosis of CMV infection from saliva adds to our ability to develop screening programs to detect asymptomatic infants with congenital CMV infection. The ability to link newborns who fail hearing screening programs with CMV testing will lead to more detection of CMV-infected neonates, both with isolated hearing loss, and subsequently with no signs or symptoms of infection. There is an urgent need for evidence from randomized clinical trials to enable the development of best practices for such infants.
Dr. Pelton is professor of pediatrics and epidemiology at Boston University and senior attending physician at Boston Medical Center. Dr. Lapidot is a senior fellow in pediatric infectious diseases, Boston Medical Center. Neither Dr. Pelton nor Dr. Lapidot have any relevant financial disclosures. Email them at [email protected].
References
1. J Pediatric Infect Dis Soc. 2019 Mar 28;8(1):55-9.
2. N Engl J Med 2011 Jun 2; 364:2111-8.
3. Pediatrics. 2008 May;121(5):970-5
4. J Clin Virol. 2018 May;102:110-5.
5. J Pediatric Infect Dis Soc. 2019 Mar;8(1):55-9.
6. J Pediatr. 2003 Jul;143(1):16-25.
7. J Pediatr. 2018 Aug;199:166-70.
Busiest week yet brings 2019 measles total to 555 cases
according to the Centers for Disease Control and Prevention.
The 90 measles cases reported during the week ending April 11 mark the third consecutive weekly high for 2019, topping the 78 recorded during the week of April 4 and the 73 reported during the week of March 28. Meanwhile, this year’s total trails only the 667 cases reported in 2014 for the highest in the postelimination era, the CDC said April 15.
New York reported 26 new cases in Brooklyn’s Williamsburg neighborhood last week, which puts the borough at 227 for the year, with another two occurring in the Flushing section of Queens. A public health emergency declared on April 9 covers several zip codes in Williamsburg and requires unvaccinated individuals who may have been exposed to measles to receive “the measles-mumps-rubella vaccine in order to protect others in the community and help curtail the ongoing outbreak,” the city’s health department said in a written statement.
Maryland became the 20th state to report a measles case this year, and the state’s department of health said it was notifying those in the vicinity of a medical office building in Pikesville about possible exposure on April 2.
The recent outbreak in Michigan’s Oakland County did not result in any new patients over the last week and remains at 38 cases, with the state reporting one additional case in Wayne County. More recent reports of a case in Washtenaw County and another in Oakland County were reversed after additional testing, the state health department reported.
according to the Centers for Disease Control and Prevention.
The 90 measles cases reported during the week ending April 11 mark the third consecutive weekly high for 2019, topping the 78 recorded during the week of April 4 and the 73 reported during the week of March 28. Meanwhile, this year’s total trails only the 667 cases reported in 2014 for the highest in the postelimination era, the CDC said April 15.
New York reported 26 new cases in Brooklyn’s Williamsburg neighborhood last week, which puts the borough at 227 for the year, with another two occurring in the Flushing section of Queens. A public health emergency declared on April 9 covers several zip codes in Williamsburg and requires unvaccinated individuals who may have been exposed to measles to receive “the measles-mumps-rubella vaccine in order to protect others in the community and help curtail the ongoing outbreak,” the city’s health department said in a written statement.
Maryland became the 20th state to report a measles case this year, and the state’s department of health said it was notifying those in the vicinity of a medical office building in Pikesville about possible exposure on April 2.
The recent outbreak in Michigan’s Oakland County did not result in any new patients over the last week and remains at 38 cases, with the state reporting one additional case in Wayne County. More recent reports of a case in Washtenaw County and another in Oakland County were reversed after additional testing, the state health department reported.
according to the Centers for Disease Control and Prevention.
The 90 measles cases reported during the week ending April 11 mark the third consecutive weekly high for 2019, topping the 78 recorded during the week of April 4 and the 73 reported during the week of March 28. Meanwhile, this year’s total trails only the 667 cases reported in 2014 for the highest in the postelimination era, the CDC said April 15.
New York reported 26 new cases in Brooklyn’s Williamsburg neighborhood last week, which puts the borough at 227 for the year, with another two occurring in the Flushing section of Queens. A public health emergency declared on April 9 covers several zip codes in Williamsburg and requires unvaccinated individuals who may have been exposed to measles to receive “the measles-mumps-rubella vaccine in order to protect others in the community and help curtail the ongoing outbreak,” the city’s health department said in a written statement.
Maryland became the 20th state to report a measles case this year, and the state’s department of health said it was notifying those in the vicinity of a medical office building in Pikesville about possible exposure on April 2.
The recent outbreak in Michigan’s Oakland County did not result in any new patients over the last week and remains at 38 cases, with the state reporting one additional case in Wayne County. More recent reports of a case in Washtenaw County and another in Oakland County were reversed after additional testing, the state health department reported.