Dr. Allen Cherer is an accomplished neonatal care specialist with decades of medical experience.

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Author: Dr. Allen Cherer

Tackling Rotavirus

National Infant Immunization Week Blog-a-thon with woman holding baby. #ivax2protect

Rotavirus gastroenteritis is the leading cause of diarrhea-associated hospitalizations and death in children younger than 5 years of age. Rotavirus illness is caused by a virus which enters the body by mouth and infects the intestines. It is a particularly hardy and contagious virus, capable of surviving on inanimate surfaces for long periods and spreading readily from child to child and also to adults. Large quantities of virus are shed in the stool both prior and following acute illness which is characterized by fever, vomiting, and watery diarrhea. Illness typically lasts 3-7 days; death may ensue due to severe dehydration. Since the infection is caused by a virus, antibiotics and antiparasitic drugs are ineffective, and care is primarily supportive. Prior to the development of effective vaccines, 80% of children in the U.S. would develop rotavirus gastroenteritis. Elsewhere in developing countries, the numbers were staggering with more than 500,000 deaths occurring annually in children under 5 years old.

The first rotavirus vaccine, RotaShield (Wyeth Laboratories) was licensed in the United States in 1998 but was withdrawn in 1999 due to a suspected association with intussusception, a type of bowel obstruction. In 2006, RotaTeq (GlaxoSmithKline) was FDA approved, followed by Rotarix (Merck) in 2008. Both are live, attenuated, oral vaccines requiring either a 3 dose or a 2 dose series and have shown significant efficacy in the range of 80-90% in middle and high income countries. Prior to 2006 when routine rotavirus vaccination was recommended, rotavirus gastroenteritis was estimated to result in 400,000 visits to physician’s offices, 200,000 visits to Emergency Rooms, 55,000 hospitalizations, and 20-60 deaths annually among children under 5 years of age in the U.S. for an estimated total cost close to $300 million. Since introduction of the vaccine, the impact has been striking; hospitalizations and rotavirus-related Emergency Room visits have decreased by 80%. In addition, by vaccinating infants, serious rotavirus infections among older children and adults have demonstrated similar declines, presumably through the so-called “herd effect” resulting from wide-spread immunization practice. In summary, clinical trials and experience of rotavirus vaccines in middle and high income countries have demonstrated high efficacy against serious rotavirus disease. Rotavirus vaccination works!

Despite the high efficacy rates of RotaTeq and Rotarix vaccines in middle and high income countries, clinical studies consistently demonstrate lower efficacy rates in the range of 37-61% with either vaccine in the lowest income nations where the burden of rotavirus infection is greatest. Such performance is typical of other live oral vaccines in similar populations. The reasons are not completely understood, but factors such as earlier onset of recurrent episodes of infectious diarrhea, different gut microbiome, the presence of neutralizing antibodies, poor nutritional status, and varying circulating rotavirus strains may play a role. Nevertheless, even a moderately effective vaccine can have a huge public health impact when introduced into a population where the burden of disease is great, especially when combined with the herd protection that occurs when most children in an area are vaccinated and immune.

In 2000, the Global Alliance for Vaccines and Immunization (Gavi) was founded as a public-private global health partnership with the intent to improve childhood immunization coverage in poor countries and increase access to new vaccines. By design, Gavi leverages not only financial resources but also expertise to make vaccines more available, affordable, and their provision more sustainable. The two current rotavirus vaccines obtained prequalification by the World Health Organization (WHO) in 2008 which followed with UNICEF procurement of the vaccines through the financial support of Gavi. These vaccines have been introduced in 42 Gavi-eligible countries and in 6 additional countries classified as low and middle income and have had a major impact on rotavirus-associated hospitalizations and deaths in all settings.

According to WHO estimates in 2013, approximately 215,000 children under 5 years of age die each year from vaccine-preventable rotavirus infections with almost half of them in 4 countries: India, Pakistan, Nigeria, and Democratic Republic of Congo. Ten countries account for almost 2/3 of all deaths. It is in this context that findings recently published in the New England Journal of Medicine related to a new vaccine against rotavirus are incredibly encouraging. The study reported by Isanaka et al. was conducted in Niger in Sub-Saharan Africa, a region with the highest rate of death associated with rotavirus disease and where the current cost of vaccines is probably unsustainable and where refrigeration and transportation are unreliable. The new vaccine, BRV-PV (Rotasil), is a live, oral rotavirus vaccine manufactured by Serum Institute of India and is lower in cost relative to existing vaccines and heat stable for as long as 6 months at 104 degrees F. and for 2 years at 98.6 degrees F. In a double-blind, placebo-controlled randomized trial including over 4000 healthy infants, the new vaccine was found to have a calculated efficacy rate of 67% with no apparent short term adverse events. Since existing vaccines are costly and require refrigeration, the new vaccine provides major advantages in resource-constrained countries where the burden of rotavirus is greatest. If further surveillance continues to yield good findings, the new vaccine promises to provide a giant step in the progress against rotavirus.

 

Congenital Cytomegalovirus Infection and Hearing Loss

ongenital Cytomegalovirus Infection and Hearing Loss

It has been over 50 years that the association between congenital Cytomegalovirus (CMV)  infection and hearing loss was described by Medearis et al. During that time, advances in understanding the pathogenesis and the natural history of the disease have been made. It is now acknowledged that CMV infection is not only the most common congenital viral infection in the world but also the leading non-genetic cause of childhood sensorineural hearing loss. The world-wide incidence of congenital CMV infection is estimated to range from 0.06% – 2.4% of all live births. As many as 10-15% of infected neonates are symptomatic at birth, presenting with a variety of signs/symptoms including growth failure, anemia, extramedullary hematopoiesis, thrombocytopenia, hepatosplenomegaly, intracranial calcifications, microcephaly, and chorioretinitis. Mortality is <5%, but as many as 50% of survivors will demonstrate  long-term sequelae, primarily sensorineural hearing loss and neurodevelopmental delay. On the other hand, the great majority of congenitally infected neonates are asymptomatic and may be totally unrecognized. They generally have a much better prognosis. Notably, however, approximately 10% of these asymptomatic infants will also manifest sensorineural hearing loss, often late in onset and progressive in nature, and some element of neurodevelopmental delay. Hence the global burden of congenital Cytomegalovirus infection is significant.

Cytomegalovirus is ubiquitous in humans and infects 50-85% of adults in the United States by 40 years of age. Virus excretion rates from urine and saliva in children from 1-3 years of age in child care centers are reported to range from 30-40% but can be as high as 70%. Generally, acquired infection  in adults and children is mild and inconsequential in terms of long-term sequelae. CMV, like Herpes Simplex and Varicella Zoster, belongs to the herpesvirus family. All three may cause congenital and perinatal infections. Transmission of the virus can occur vertically to the fetus during pregnancy with the highest risk of infection occurring during the first half of gestation. Maternal infection can occur following initial exposure, with reactivation of the virus following previous infection, or with reinfection with a different strain of the virus. Symptomatic infection occurs with similar frequency in newborns born to women with initial CMV infection (primary infection) and those born to women who were seropositive before pregnancy (non-primary infection). Then too, the severity of newborn disease and the rates of CMV-associated sensorineural hearing loss do not differ between primary and non-primary infection. Studies since 2003 have reported treatment benefit in terms of hearing  and neurodevelopmental outcome of intravenous ganciclovir for 6 weeks and subsequently in 2013 with its oral prodrug valganciclovir for 6 months. The American Academy of Pediatrics Red Book, 2015 edition, recommends antiviral treatment for those newborns with symptomatic congenital CMV infection with or without CNS involvement provided it can be initiated within the first month of life. The quandary, of course, arises when the definition of “symptomatic” is not clear. Suggestions have been offered, but none has been universally accepted. In addition, the Red Book specifically advises against antiviral treatment for those asymptomatic patients with congenital CMV infection, although a number of them are at risk for long-term sequelae.

In 2000, the Joint Committee on Infant Hearing endorsed Universal Newborn Hearing Screening (UNHS). Prior to that time, only at risk newborns for hearing impairment were screened, and it was estimated that close to 50% of all children with hearing loss were undiagnosed until 18 months to 3 years of age. It is generally accepted that in order to achieve linguistic and communicative competence, diagnosis and intervention must take place before 6 months of age. The aim of UNHS is to screen all newborns before 1 month of age and have confirmation of hearing loss in infants who do not pass through a complete audiologic evaluation by 3 months of age. A limitation of UNHS is not all cases of childhood hearing loss, especially those with late onset and/or progressive loss, will be detected. Clearly, newborns with congenital CMV infection, specifically those who are asymptomatic and have not been identified, may be missed altogether.

Based on the global nature and incidence of congenital CMV infection, the frequency of late onset hearing loss, and the benefits of early intervention, newborn screening for congenital  CMV infection has been explored  but has not yet been adopted. Dried blood spot  (DBS) PCR for CMV was initially encouraging but recent studies suggest poor sensitivity, and blood viral load does not appear to be sensitive or specific in predicting which infants will develop late onset hearing loss. Newborn saliva and urine PCR for CMV are best to identify congenital CMV infection, but  to date no specific biomarkers have been found to reliably predict which infants will develop late onset hearing loss. Ideally, maternal infection with CMV would be eliminated. An alternative would be to prevent transmission to the fetus or newborn. In the meantime, research continues to better identify and treat  those newborns with congenital infection and prevent the serious sequelae.

Supporting Universal Antenatal Pertussis Vaccination

Pertussis (Whooping Cough) is a serious health issue, especially in the very young infant. It is caused by a bacteria, Bordetella pertussis, and is transmitted person to person via aerosol droplets usually by coughing or sneezing. The illness typically begins with cold-like symptoms which may then progress to the characteristic paroxysms of cough terminating with an inspiratory whoop.

In young infants, the illness can proceed to cyanosis, severe respiratory fatigue, apnea, and even death. Although whole-cell and acellular vaccine formulations against B. pertussis  are available, primary immunization generally does not start until 6-8 weeks and as late as 3 months of age in some countries, leaving the  infant unprotected during a most vulnerable period.

The incidence of pertussis has steadily increased in the United States and elsewhere since the 1980s and especially since 2005. Since 2010, 10-50,000 cases of whooping cough have been reported each year in the United States with every state represented. More than 48,000 cases were reported in 2012, and in California alone, greater than 10,000 cases were reported in 2014. Although all ages are affected, the highest rates of disease and hospitalization occur in infants less than one year of age. The numbers have been accompanied by an alarming increase in the number of deaths, almost exclusively among infants less than 3 months of age.

One of the causes thought to explain the resurgence of pertussis is the rapid waning of the immunity induced by  current vaccines. Prior to the 1990s, a whole-cell vaccine was used and the immunity it induced was longer lasting. Since then, acellular pertussis vaccines have been used exclusively in the United States primarily due to less frequent adverse reactions.

However, these vaccines have been shown to induce immunity which wanes rapidly over a period of several years. As a result, pertussis immunization is required more frequently and the likelihood of non-protection is much greater, especially for older children  and adults. This is particularly alarming since such persons are often the caretakers and closest contacts of young infants. Thus, when considering prevention strategies for pertussis, it is critical to include approaches that prevent pertussis transmission to young infants.

In 2001, the Global Pertussis Initiative (GPI) was established in response to the resurgence of pertussis and in an effort to raise global awareness about pertussis and to develop evidence-based recommendations for vaccination strategies . Over the years, the GPI has focused particular attention on protection of the very young infant and has emphasized as a primary strategy maternal immunization during pregnancy which directly protects the infant through the passive transfer of pertussis antibodies from mother to fetus.

Numerous studies have demonstrated that a pregnancy booster (Tdap) provides the necessary protection to the very young from birth until infant-generated immunity is achieved from the primary series of pertussis immunizations. Based on studies that demonstrate robust maternal antibody production within 2 weeks of booster immunization and ready immunoglobulin transfer after 30 weeks’ gestation, current recommendations call for Tdap immunization between 28 and 38 weeks’ gestation.

Since maternal antibody levels decline significantly I year post immunization and are almost non-existent 2 years post immunization, the Advisory Committee on Immunization Practices (ACIP) of the Centers for Disease Control and Prevention (CDC) in 2012 recommended booster immunization during every pregnancy.

To date, research finds that vaccination against pertussis during pregnancy is well tolerated and not associated with any adverse obstetric, birth, or neonatal outcomes. Recently, a study from the United Kingdom evaluating antenatal booster immunization and efficacy in preterm births demonstrated with a mean gestational age of 29 weeks at time of immunization and birth at a mean gestation of 32 weeks, protective antibody  levels were found at the start of the primary immunization series.

Unfortunately, despite strong recommendations by the CDC, the American College of Obstetrics and Gynecology, the  American Academy of Family Physicians, and the American Academy of Pediatrics , pertussis immunization rates during pregnancy remain very low. Clearly, education of caregivers and patients  must be a goal. Until a new pertussis vaccine with longer duration of protection is available, large-scale pertussis outbreaks will continue and the burden of disease will continue to be particularly felt by the very young infant.

Tetanus Elimination: An Amazing Public Health Achievement

Neonatal tetanus is one form of a devastating illness with a very high mortality rate. The illness was recognized by Hippocrates as early as the 5th century BC. The causative bacterium and its exotoxin were identified in the late 1800s.

An effective toxoid vaccine was developed in 1924 and widely used during World War II to prevent tetanus induced by battle wounds. The illness itself is characterized by generalized rigidity and painful convulsive spasms of skeletal muscles.

The infectious agent, Clostridium tetani, is a spore-forming anaerobe found in the soil and in the gastrointestinal tract of animals. It generally enters the body through a break in the skin, such as a cut or a puncture wound with a contaminated object. The bacteria produce a potent biological toxin which is responsible for the clinical signs. The spores which cause tetanus are ubiquitous, so the only prevention is immunization.

Newborns typically receive passive immunity from their immunized mothers and are therefore protected. However, if mothers have not been immunized, not only are they at risk for developing tetanus but so are their unprotected babies. In many countries, deliveries take place in unhygienic circumstances putting both mothers and babies at risk for life-threatening infections.

Maternal and neonatal tetanus are among the most common lethal consequences of unclean (out of health care facilities and/or not assisted by medically trained assistants) deliveries.

In newborns, the site of infection is generally an unhealed umbilical cord stump, particularly when the cord is cut with a non-sterile instrument.
In 1988, the World Health Organization (WHO) estimated that 787,000 newborns died of neonatal tetanus.

The numbers are particularly staggering and alarming since deaths can be prevented by hygienic delivery and cord care practices and/or by immunizing mothers with tetanus vaccine that is both inexpensive and efficacious.

Subsequently, the WHO and partner organizations such as UNICEF and UNFPA initiated a public health campaign with the goal to eliminate maternal and neonatal tetanus. Tetanus cannot be eradicated such as polio and small pox due to the worldwide distribution of spores in the environment.

The goal, however, to eliminate the disease sets a target of less than 1 case/1000 live births. Persistent and painstaking efforts throughout all 6 WHO Regions to enhance vaccination of pregnant women and children as well as to increase skilled birth attendance and to educate regarding clean umbilical cord practices have achieved remarkable success.

As of 2013, the WHO estimated that 49,000 newborns died from neonatal tetanus, a 94% reduction from that of the late 1980s. As recently as May 2016, the WHO reported that the South-East Asia Region, an area comprising 25% of the global population, had successfully eliminated maternal and neonatal tetanus. India, a member nation of the South-East Asia Region had previously met the goal in 2015.

While progress continues to be made, by June 2016, 19 countries have not reached elimination status. Activities to achieve the goal are ongoing in these countries, with many likely to achieve maternal and neonatal tetanus elimination in the near future.

Despite the resounding success of the campaign, efforts can not cease and must continue to maintain and enhance high population immunity with tetanus vaccination during infancy, for women of childbearing age, and during adolescence through school immunization programs.

Additionally, achieving high coverage of skilled birth attendance and promoting appropriate umbilical cord care are essential goals necessary to maintain maternal and neonatal tetanus elimination.

The Zika Virus and Microcephaly

Zika virus is an arthropod-borne flavivirus discovered in Africa in 1947. When infected by the virus, most persons are asymptomatic or demonstrate generally mild, self-limited illness characterized by fever, rash, arthralgia, and conjunctivitis. The first widespread outbreak of the Zika virus was recognized on Yap Island, Federated States of Micronesia, in 2007, followed by outbreaks in Southeast Asia and the Western Pacific, including a large outbreak in French Polynesia in 2013-14.

Since the identification of the Zika virus infection in Brazil in May, 2015, the virus has spread rapidly throughout the Americas, and as of February 2016, thirty-one countries and territories had reported cases.

A bite of the Aedes aegypti mosquito is the main route of exposure, but sexual, maternal-fetal, and intrapartum transmission have all been documented. To date, all cases reported in the continental United States have been travel-associated, whereas in the U.S. territories (American Samoa, Puerto Rico, and U.S. Virgin Islands), the vast majority of cases have been locally acquired vector-borne.

Although infection with the Zika virus generally leads to mild disease, its emergence in the Americas has coincided with a marked increase in babies being born with microcephaly, a neurological disorder present at birth and defined as head circumference at least 2 SD smaller than the mean for sex, age, and ethnicity and with head circumference at least 3 SD smaller being deemed severe. Congenital microcephaly is a condition associated with a reduction in brain volume and is often caused by genetic or environmental factors that affect fetal brain development.

Prenatal viral infections, such as rubella and cytomegalovirus, hypertensive disorders, and maternal alcohol have also been associated with the condition. Cases have been reported after intrauterine infection with West Nile virus (also a flavivirus) and Chikungunya virus. Given the widespread nature of the Zika virus epidemic in the Americas, the temporally associated increase in microcephaly cases in Brazil, and the retrospective findings of a cluster of microcephaly and neurologic disorders associated with the Zika virus in French Polynesia, the WHO declared Zika virus a Public Health Emergency of International Concern on February 1, 2016.

In order to reduce the risk of microcephaly, recommendations included avoidance of travel to affected countries by pregnant and childbearing aged women, use of condoms with partners returning from affected countries, and pregnancy delay.

In order to better quantify the risk of microcephaly associated with the Zika virus infection, a retrospective study based on data from the completed Zika virus outbreak in French Polynesia in 2013-14 was reported in The Lancet by Simon Cauchemez, PhD, and colleagues from the Institut Pasteur.

Based on four datasets providing information on all cases of microcephaly, weekly number of consultations for suspected Zika infection, seroprevalence for Zika virus antibodies, and the number of births during the outbreak, the researchers developed a mathematical and statistical model to illustrate the association between the Zika virus and microcephaly and demonstrated the risk for microcephaly to be greatest during the first trimester of pregnancy.

According to the analysis, it is estimated that the risk for microcephaly for mothers with the Zika virus infection during the first trimester is about 1%. Although the risk appears low compared to other intrauterine viral infections (e.g., rubella, cytomegalovirus), the incidence of the Zika virus infection is very high during outbreaks (eg, 66% in French Polynesia and 73% in the island of Yap). Therefore, despite the relatively low fetal risk, infection with the Zika virus is an extremely important public health matter.

Antibiotics and Severe Acute Malnutrition

Childhood undernutrition is a major global health problem and severe acute malnutrition remains a major cause of childhood mortality. It is estimated that 19 million preschool age children, mostly from the World Health Organization African and South-East Asia Regions, suffer from severe acute malnutrition, contributing to major childhood morbidity, mortality, intellectual impairment, and disease susceptibility.

Of  the 7.6 million deaths annually among children who are under 5 years of age, approximately 35% are nutrition related and 4.4% of deaths are specifically attributable to severe wasting. Children with severe acute malnutrition suffer severe wasting that may (kwashiorkor) or may not (marasmus) be accompanied by swelling of the body from fluid retention. It occurs when infants and children do not have adequate energy, protein, and micronutrients in their diet, and at times is combined with recurrent infections.

Diagnostically, it is defined as a mid-upper arm circumference less than 115 mm or a weight for height that is severely reduced. There is strong epidemiological evidence that low weight-for-height, weight-for-length, or mid-upper arm circumference are highly associated with a 5-20 fold increased risk of mortality.

For decades, the primary management for severe acute malnutrition comprised inpatient rehabilitation with fortified milk formulas. Management guidelines then transitioned to incorporate the use of ready-to-use therapeutic food (RUTF), usually a fortified spread of peanut paste, milk powder, oil, sugar, and a micronutrient supplement, in outpatient settings in those cases of severe acute malnutrition where appetite was preserved and there were no evident complicating medical clinical signs.

Nevertheless, a significant number of children failed to recover. Since many studies had demonstrated a high percentage of clinically significant infections among children with severe malnutrition, treatment guidelines recommending the use of routine antibiotics were developed. In 2013, a double-blind, randomized, placebo-controlled clinical trial in rural Malawi conducted by Trehan and colleagues was reported in the New England Journal of Medicine.

The study found that the routine addition of a seven day course of amoxicillin or cefdinir to the outpatient management of severe acute malnutrition was associated with marked improvement in recovery and mortality rates and significant increases in weight and mid-upper arm circumferences.

Subsequently, the 2013 WHO guidelines (previously updated in 1999) for treatment of children with severe acute malnutrition without health complications requiring hospitalization called for high energy food and routine antibiotics. The new guidelines were considered superior to previous ones in that they reflected new opportunities and technologies in caring for greater numbers of children in the outpatient setting. In addition, the guidelines specifically addressed children with severe acute malnutrition who were less than 6 months of age or were infected with HIV.

Most recently, a study from the Harvard T. H. Chan School of Public Health and published in the New England Journal of Medicine in 2016 calls into question the routine use of antibiotics in the management of severe acute malnutrition. The double-blind, randomized trial of amoxicillin vs. placebo in a population of children in Niger between October 2012 and November 2013 demonstrated no superiority in terms of recovery rate among children treated with amoxicillin and no differences in overall mortality.

The implication is that in an era of increasing antibiotic resistance, routine antibiotic administration may pose a greater risk to child health. Nevertheless, the study did demonstrate on secondary analysis a faster rate of recovery (28 days vs 30 days) among children treated with amoxicillin, decreased risk of death in children over 24 months of age, and decreased risk of transfer for clinical complications.

Since the study population too was not comparable to that of Trehan and colleagues in Malawi and the level of ancillary care and follow up was not the same, further studies are indicated prior to recommending a change in current treatment guidelines. For more information regarding these studies, please visit this link. 

Stunted Growth & Diet

Although nutritional interventions such as Ready to Use Therapeutic Foods (RUTF) have been effective in the management of severe acute malnutrition, the presence of growth failure among the world’s children suggests persistent chronic malnutrition and begs a better understanding of its pathophysiology. Globally, approximately 25% of all children less than 5 years of age demonstrate stunted growth or short for age. Many of these children also demonstrate cognitive delay and increased disease susceptibility.

A recent study published online in EBioMedicine provides new insights into the mechanisms of the problem. Researchers from Washington University School of Medicine, the Johns Hopkins University, University of Maryland, the National Institutes of Health, and the University of Malawi used a targeted metabolomic approach to measure serum amino acids, sphingolipids, glycerophospholipids, and other metabolites in 313 children, aged 12-59 months, residing in rural Malawi. Among the study patients, 62% were classified as short for age based on WHO criteria.

The findings showed that all such children had lower serum concentrations of all nine essential amino acids, conditionally essential amino acids, non-essential amino acids, and six different sphingolipids. In addition, all stunted children demonstrated alterations in serum glycerophospholipid concentrations.

The findings support the notion that children with a high risk of stunting may not be receiving an adequate dietary intake of essential amino acids and choline, an essential nutrient for the synthesis of sphingolipids and glycerophospholipids.The study paves the way for further research using similar methodology to determine more appropriate dietary management for these children.

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