Carole Ellis

The similarities between the early discovery of congenital rubella syndrome (CRS) and congenital Zika infection (CZI) provide some hope that “successes against rubella will be replicated against Zika virus, including the rapid development of an effective vaccine,” reported a team of researchers at the 2017 Annual Pediatric Academic Societies (PAS) meeting in San Francisco, California, on May 6-9.

The group, led by J.B. Cantey, MD, a physician in the department of pediatrics at Texas A&M Health Science Center in Temple, Texas, reviewed the history of CRS starting with the literature describing a 1940-1941 rubella epidemic in Australia, which ultimately led to the first description of the infection as a congenital issue. “An ophthalmologist named N. McAllister Gregg described 78 infants with congenital cataracts whose mothers had rubella during pregnancy,” Dr. Cantey explained during a “historic” poster session at PAS. He added that subsequent studies revealed that other symptoms of CRS, such as sensorineural hearing loss and patent ductus arteriosus, decreased in severity when the mothers became infected closer to their due dates. By 1969, a vaccine for rubella had been developed, and, a decade later, “CRS incidence had declined by more than 75%.” He concluded saying that CRS was considered “eradicated” in the United States in 2009.

“The history of CRS is similar to the early timeline of the CZI epidemic, including abrupt onset, rapidly accumulating literature, and efforts to fast-track a vaccine,” said Dr. Cantey. He said that, although it “remains to be seen” whether a successful 

 will eventually eradicate CZI, the parallels between the two epidemics give cause for hope. In addition, the group also cited the “long lag between initial discovery and identification as a congenital pathogen” to be another parallel between the two congenital syndromes. CRS was initially discovered in 1814, but it was not identified as a congenital disease until more than a century later, in 1941. Zika’s lag time is shorter, at about 63 years; the infection was discovered in 1952 and the congenital disease was identified in 2015 and confirmed in 2016 due, in large part, to a 

 between 2014 and 2015. With CRS, once the congenital infection was confirmed, doctors began identifying mild and asymptomatic infants less than a year later and developed a vaccine within 5 years.

Should that pattern hold for Zika, an effective vaccine could be on the horizon. Given that Zika now has an animal model —on a similar timeline, again, to CRS – hopefully that vaccine is already underway. According to the National Institutes of Health (NIH)’s NIAID, multiple 

 are currently in testing, with vaccines in trials between phases 1 and 2. One vaccine recently made headlines for a March phase 2 launch aiming to enroll around 2500 adults and adolescents in North and South America.

Another similarity between CZI and CRS is the “gradual recognition of other symptoms beyond the initial primary association,” Dr. Cantey said. With CZI, that “primary association” is microcephaly in infants, while with CRS it was congenital cataracts. Secondary associations for Zika account for a number of 

, according to the Centers for Disease Control and Prevention (CDC), including “decreased brain tissue with a specific pattern of brain damage, damage to the back of the eye, congenital contractures, and hypertonia restricting body movement soon after birth.” The CDC also reports a link between CZI and several neurologic abnormalities, issues with neurologic function, and “excessive and redundant scalp skin.”

As the list of symptoms becomes more well-known, hopefully the next benchmark, the identification of “mild and asymptomatic infants,” will be in close reach, Dr. Cantey and his team hope. Soon thereafter, “the development of an effective vaccine that confers lifelong immunity to women of childbearing age and subsequent reduction in (and hopefully elimination of) CZI” will be developed, according to the presentation.

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Research presented at the 2017 Annual Pediatric Academic Societies (PAS) meeting examines the similarities between Congenital Rubella Syndrome and Congenital Zika Infection.

The Parallels Between Congenital Rubella Syndrome & Congenital Zika Infection

Pre-exposure prophylaxis (PrEP) may cause a loss of bone density in the young men who take them. However, there are alternative treatments including behavioral modification that could also provide protection from HIV infection to high-risk individuals.

 is, according to the Centers for Disease Control and Prevention (CDC), “a way for people who do not have HIV but who are at a substantial risk of getting it to prevent HIV infection by taking a pill every day.” PrEP pills contain the tenovir disoproxil fumarate (TDF) and emtricitabine (FTC) combination that is also used to treat HIV after infection. In addition, according to 

, “gay and bisexual men are more severely affected by HIV than any other group in the United States.” This is why many PrEP studies focus on young men who are more likely to engage in risky sexual behaviors. The CDC estimates that PrEP may reduce the risk of infection in high-risk individuals by up to 92% if the treatment is taken consistently.

Craig Wilson, MD, a professor of epidemiology at the University of Alabama Birmingham School of Public Health, presented his findings on bone density loss due to PrEP at the 2017 Pediatric Academic Societies Meeting (PASM) in San Francisco, California, May 6-9. These findings were initially presented at the 2016 AIDS Conference in Durban, South Africa. Dr. Wilson and his team conducted the study on 18-to-22-year-old males. This is an ongoing extension of a study in the Adolescent Trials Network (ATN) that involved a larger group of adolescent males ages 15 to 22.

“There is evidence of impact on bone density caused by exposure to tenovir disoproxil fumarate (TDF) and emtricitabine (FTC) used as PrEP over 48 weeks in the 18-to-22 male population,” said Dr. Wilson during a panel at PASM titled “Adolescent HIV and Other Sexually Transmitted Infections: Epidemiology, Prevention, and Treatment Updates.” However, he added that discontinuing the treatments did “lead to a trend toward recovery [of bone density] over a 48-week follow-up period.”

Dr. Wilson went on to say that there are alternatives available to these PrEP treatments. He added, “None of this precludes the concept of using these drugs in this population,” although he did suggest that more follow-up on the study group is needed. However, there are “new drugs that lessen the impact on bone” that are much more expensive than TDF and FTC.

In his report to the panel, Dr. Wilson noted that the study group had some advantages that most young men taking PrEP drugs would not necessarily have, and that this could assist in reducing their risk levels for contracting HIV. “Remember that everything that happened in the trial happened with behavioral intervention and supportive staff,” he noted, explaining that the participants had a much higher level of interaction with medical practitioners than the average PrEP patient would have. Even with these increased levels of interaction, “We were still having rates of 7% annual seroconversions,” he said. “We have to be thinking of something more than the quarterly visits [to obtain more PrEP treatment],” he added. “There has to be more support care. There are more creative ways.”

European Review for Medical and Pharmacological Sciences

 a study indicating that vitamin D deficiency is “highly prevalent among HIV-positive subjects,” speculating that supplementing these patients with vitamin D could help prevent comorbidities. Dr. Wilson noted that, at present, a group is “rolling out protocols for a vitamin D supplemental therapy study” in Thailand to investigate how this type of supplementation may function as a protection against HIV. Since vitamin D also affects bone health, PrEP regimens could possibly be more effective with this supplementation although vitamin D has not been directly linked to HIV-infection prevention, he said.

Findings presented at the 2017 Pediatric Academic Societies Meeting show that this HIV prevention treatment appears to cause loss in bone denisty in young males. However, alternatives may be available.

PrEP May Cause Loss in Bone Density, but Alternatives Are Available

Infection with influenza tends to be more severe in preterm (PT) infants, and this population is at a much higher risk for related complications. Physicians often associate this risk with PT infants’ tendency to “experience rapid serum decay in antibody responses” to influenza infections and level of severity of symptoms. To address this correlation, a research team headed by Carl D’Angio, MD, a physician in the Department of Pediatrics at the University of Rochester Medical Center in Rochester, New York, compare flu vaccine response in PT versus FT infants.

In 2011, a group of doctors based in Calcutta published a similar 

 that examined the efficacy of vaccinating PT babies for measles given that these infants may have lower levels of antimeasles antibodies than their FT counterparts. In that study, the doctors determined that PT infants should receive their first measles vaccination at 5 months instead of 9 months — which is how it’s administered in FT babies – in order to balance out this inequality. Few studies have evaluated how this strategy would work for the flu vaccine, which is administered once annually (after 

In their study, Dr. D’Angelo and her colleagues set out to “investigate the relationships among the frequencies of influenza-specific antibody secreting cells (ASC) and ASC subsets (including LLPC) and antibody responses to influenza vaccines” among PT and FT infants. The study included 11 PT infants with a mean gestational age of 27.3 weeks at birth and 11 FT babies with a mean gestational age of 39.2 weeks at birth. All infants received their first flu vaccination between six and 17 months of age via 2 doses of inactivated, trivalent IV or quadrivalent IV during 2012-2013 and 2013-2014 flu seasons. The first round of vaccination occurred on day 0 of the study and the second on day 28. The researchers collected blood samples from the infants on days 0, 10, 35, and 56 days, and finally again at 9 months of age.

Not surprisingly, the PT infants weighed less at their first vaccination than did the FT infants, but the postnatal ages among infants in both groups were nearly identical, with PT infants receiving their first vaccination at a mean age of 8.1 months and FT infants receiving their first vaccinations at a mean age of 8.0 months. This is likely due to Centers for Disease Control and Prevention (CDC) guidelines specifying 

, “in the majority of cases, infants born prematurely, regardless of birth weight, should be vaccinated at the same chronological age and according to the same schedule and precautions as full-term infants and children,” with the exception of the hepatitis B vaccine. The same guidelines recommend against modifying dosages in most cases, and state, “Decreased seroconversion rates might occur among certain premature infants with low birth weights (i.e. <2,000 grams) [in Hep B vaccination specifically, but] by chronological age one month, all premature infants, regardless of initial birth weight or gestational age, are as likely to respond adequately as older and larger infants.”

In order to measure levels of antibodies in the infants after vaccination, the group used hemagglutination inhibition (HAI) measures at 0 days, 56 days, and 9 months, vaccine-specific ASC numbers at 10 and 35 days, and ASC subsets at 0, 10, and 35 days. “PT infants had post-vaccine HAI titers greater than or equal to those of the FT infants at 56 days and nine months after the initial immunization,” said Dr. D’Angio, adding that ASC numbers were higher in PT infants than FT ones as 35 days and positively correlated with HAI numbers at 56 days. “We also concluded that there were no statistical differences between PT and FT infants [except that] ASC subset numbers at 35 days were marginally higher in PT than in FT infants,” he said, adding, “Influenza-specific ASC numbers in both FT and PT infants correlated with peak antibody titers, but we could not detect an ASC subset that correlated with the durability of antibody response.”

A research team headed by Carl D’Angio, MD, a physician in the Department of Pediatrics at the University of Rochester Medical Center in Rochester, New York, compare flu vaccine response in PT versus FT infants.

How Does the Flu Vaccine Effect Preterm Vs. Full-Term Infants?

Low levels of vitamin D (25[OH]D) and vitamin D-regulated antimicrobial peptide (AMP) human cathelicidin (LL-37) are associated with increased risk of severe influenza infections in pediatric patients, according to results from a preliminary study.

In research presented at the 2017 Annual Pediatric Academic Societies Meeting (PASM), a group of physicians headed by Eleanor Reid, MSc, from the Department of Nutritional Sciences at the University of Toronto in Toronto, Canada, evaluated 82 pediatric patients all less than 18 years of age. These patients were recruited from inpatient units from 4 Canadian pediatric referral centers in Toronto, Ottawa, Montreal, and Quebec. All of the patients were healthy with the exception of a lab-confirmed influenza A or B diagnosis.

“We wanted to examine the relationship between serum 25(OH)D levels and symptom severity in this population of otherwise-healthy children,” the team explained during an oral poster session at PASM. The group also investigated associations between LL-37 and two other AMPs, beta-defensin 3 (BD3) and beta-defensin 2 (BD2), and influenza severity in the study group.

 on vitamin D and influenza, published in the 

, Gerry Schwalfenberg, MD, a physician at the University of Alberta in Edmonton, Canada, wrote that “there is a seasonality to influenza that correlates well with the seasonal drop in vitamin D.” He added in this article that vitamin D “as a prophylactic for influenza has shown promise in prevention of illness and reduction of secondary asthma in children” and speculated that falling vitamin D levels in wintertime, which would likely keep much of the Canadian population indoors, “would put the Canadian population at risk of a number of medical conditions.”

Dr. Reid’s team conducted follow-up assessments of their Canadian pediatric population at 48 hours, one week, two weeks, and four weeks after enrollment in the study to “obtain data on symptoms and influenza-related complications.” They also collected blood samples when the opportunity presented itself and used the Comprehensive Severity Index (CSI) score to quantify influenza severity. The study group of 82 patients were nearly two-thirds male (55) and had a median age of 5 years, with only 9 patients being 10 years old or older. Only 7 had received a flu vaccine; 9 were less than 6 months of age, so this measure was considered nonapplicable.

Of the 82 evaluated patients, 78 provided opportunity to assess vitamin D and AMP levels. Mean levels were 52.2 nmol/L for serum 25(OH)D, and patients with levels <50nmol/L “had significantly higher maxCSI scores than those with adequate serum levels,” the group noted. The team also found that of the 3 measured AMPs, “LL-37 levels were inversely associated with maxCSI scores.” BD2 levels were not associated with symptom severity, and 96% of patient samples contained BD3 levels too low to detect, so the team did not draw any conclusions on BD3 levels and symptom severity.

“Of course, we had a small sample size [for this study],” Dr. Reid said, also noting that the team only collected serum samples at one point during the study period. She added that other researchers “have postulated that serum 25(OH)D concentrations may vary over the course of an acute inflammatory response.”

Researchers from the University of Toronto evaluated 82 patients under 18 years of age from Toronto, Ottawa, Montreal, and Quebec.

Low Vitamin D Levels Associated with Increased Risk of Severe Flu in Children

Although most physicians report that they are “comfortable with recommending and prescribing a topical microbicide to youths” to assist in preventing the spread of HIV, they also indicated that there are a few key barriers to using this method of prevention.

According to Tanya Mullins, MD, MS, a physician at the Cincinnati Children’s Hospital Medical Center, who presented her research team’s findings at the 2017 Pediatric Academic Societies Meeting (PASM), physicians would be more likely to prescribe topical microbicides if they were covered by insurance, came with better patient education, and were available without a prescription. “Although many physicians voiced comfort with recommending and prescribing [topical microbicides], physician educational materials and clinical guidelines should be developed,” Dr. Mullins said.

In 2010, the Centers for Disease Control and Prevention (CDC) 

 that nonspecific topical microbicides were “ineffective” and “should not be recommended for STDs/HIV prevention” by physicians. Since then, the CDC has not revised this announcement, although, in 

, the CDC’s Clinical Prevention Guidance noted that several “topical antiretroviral agents exist for the prevention of HIV” and are currently under evaluation. Dr. Mullins and her team believe that “biomedical HIV prevention methods, such as topical microbicides, have the potential to significantly reduce new HIV infections.” The methods she specifically highlights are a tenofovir vaginal gel, and dapivirine administered through a vaginal ring. “Because microbicides are likely to require a prescription by a healthcare provider when they become available, and [because] youth are likely to seek such services from their primary care providers, [we chose to interview these providers to learn their thoughts because] these results could determine preconceived barriers to prescription,” the team noted.

Dr. Mullins and her team conducted a series of audio-recorded, semi-structured, face-to-face interviews with 38 physicians in an unspecified “large midwestern city.” Eight of the interviewees practice general pediatrics, eight are in obstetrics/gynecology, eight practice family medicine, six work in internal medicine, and eight practice adolescent medicine. Of these physicians, 27 were female, and the group had a mean of 19 years’ experience since graduating from medical school. Overall, the group had a total of 9 HIV-infected youth currently in their practices, and 7 had an existing familiarity with microbicides.

The physicians identified “numerous benefits of prescribing microbicides to adolescents,” Dr. Mullins said. Those benefits included: decreased acquisition of HIV, improved provision of sexual health services, improved patient awareness of risk behaviors, better adherence to prophylactic measures, patient empowerment to control their own sexual health, and non-partner-reliant prevention. However, they also noted a number of barriers to prescribing such agents, including: lack of acceptability to patients (66%), concerns about ease of use (24%), and lack of patient knowledge and perceived personal risk of HIV (21%). The physicians also identified several physician-level barriers to prescription, including: parental barriers (45%), adherence concerns (53%), safety and side effects issues (42%) and lack of provider education (24%). About a fifth (18%) also said that they would be concerned that such topical treatments might lead to riskier sexual behaviors, and 89% said that the treatments would cost too much and would likely not be covered by insurance.

In addition to these general concerns, several physicians identified specific needs that they felt would simplify the process of prescribing topical microbicides. “As far as gels and things like that, I would want some... teaching device to show somebody how to put it wherever they need to put it,” said one study participant, while another recommended simply putting these microbicides “right next to the condoms, and don’t lock [them] up” to make the treatment both accessible and easy for patients to get without a prescription.

“Patient educational strategies, physician educational materials, and clinical guidelines recommending the use of microbicides should be developed [to optimize prescription],” Dr. Mullins concluded.

Physicians call for more education for themselves and the patient before recommending the use of topical microbicides.

Topical Microbicides for HIV Prevention Available for Youths, But Barriers Remain

At the 2017 Annual Pediatric Academic Societies Meeting (PASM) in San Francisco, California, Gail Bolan, MD, director of the Centers for Disease Control and Prevention (CDC)’s Division of STD Prevention and the National Center for HIV/AIDS, Viral Hepatitis, STD, and TB Prevention, referred to 2015 as “an unprecedented time for…the CDC” due to disturbing trends regarding the number of sexually transmitted infections (STIs) that had been reported.

In her talk, Dr. Bolan delved into the CDC’s latest STI treatment guidelines. She began by noting that the CDC’s surveillance systems for STIs is “diagnostic, not case-by-case surveillance, [so] we have an underestimate of STIs in this country.”

In 2015, when the CDC’s STI Treatment Guidelines were originally published, reported cases of chlamydia were up by 5.9%, while reported gonorrhea cases were up by 13%. The increase in gonorrhea diagnoses was largely driven by an 18% increase in the male population reporting diagnoses, said Dr. Bolan Primary and secondary (

) syphilis cases increased by 19%, with this increase primarily driven by a 27% increase in women reporting P & S diagnoses. Furthermore, Dr. Bolan noted, “Men having sex with men (MSM) accounted for 60% of all P&S cases.” She added that 

 syphilis, which occurs in children whose mothers have syphilis and pass the infection through the placenta to the fetus, is, once again, appearing across the United States. “We should not be seeing congenital syphilis. We have the resources to prevent it, but it is becoming evident again,” she warned.

Dr. Bolan noted that a decline in reporting of chlamydia among adolescent women has CDC analysts concerned, as well. “Starting in about 2011, we have been seeing declines in reported cases of chlamydia in adolescent women, and we are concerned because this generation has the most to lose in terms of reproductive health,” she said.

Although a decline in reported cases might, at first, appear to be good news, CDC researchers believe that the drop in numbers os a result of fewer women seeking and receiving treatment for infection, not a result of a decrease in actual infections. “There [has] been a number of changes in healthcare, including changes in Pap smear recommendations and older adolescents and young adults who, starting in 2011, could remain on their parents’ health insurance at a college age,” Dr. Bolan noted. “Those students do not want parents to see the bill [for chlamydia treatment] and there are some providers who do not really think chlamydia is a priority preventative service.”

Dr. Bolan concluded that these troubling trends should lead to annual cervical and vaginal chlamydia screenings for adolescents and women under 25 years of age. She added that, due to a prevalence of syphilis in young, gay, men, some physicians might wish to start screening for syphilis in this higher-risk group as well—although, she said, in general, syphilis has not been very common among adolescents. Dr. Bolan also noted that, for all STI screenings, “bring your own partner,” or BYOP treatment — which allows a provider to send medication with the patient for the partner if the partner is not likely to come in for treatment on their own – may also be an option. “The legal landscape has dramatically changed to allow this delivery,” she said, although, she added this is still prohibited in Kentucky and West Virginia.

Dr. Bolan concluded by emphasizing that medical practitioners must be prepared not just to answer questions from patients about STIs, but to discuss these infections with patients who may be at risk. “If you can’t talk about it, you’re not going to identify sites of exposure that need to be tested or diagnose infections,” she warned. She added that in many cases, STI testing will rely on the practitioner to identify an at-risk patient and encourage testing, since many standard guidelines exclude individuals who appear to be at possible risk — for example, young, gay males for syphilis. “We’re trying to come up with some guidelines to define ‘high prevalence’ and ‘at-risk’ communities,” she said.

At the 2017 Annual Pediatric Academic Societies meeting, Gail Bolan, MD, from the CDC, explained why trends in STD reporting in 2015 may be disturbing.

Carole Ellis

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