Just Small Adults? Pediatric Considerations in Clinical Microbiology
“Children’s aren’t just small adults” is an old saw familiar to anyone who has attended a lecture or read a textbook chapter on any topic in pediatrics. The point of the aphorism is that pediatric medicine is qualitatively different from adult medicine: kids get different diseases, present in different ways, require different treatments, have different prognoses, and recover differently. But what about diagnostics for kids, and clinical microbiology for pediatric patients in particular? In many other cases, there are critical differences between children and adults in terms of the type of samples the clinical microbiology lab may receive, the tests ordered, and the implications of test results. A few examples are highlighted here.
Clostridioides difficile (formerly Clostridium difficile) infection (CDI) is one of the most dreaded side effects of antibiotic use. CDI manifests as toxin-mediated diarrhea and, in severe cases, as potentially deadly colitis and toxic megacolon. The cornerstones of CDI management are cessation of the antibiotics that precipitated the infection and treatment with (different) antibiotics. Rapid, sensitive (although somewhat complicated) C. difficile tests are widely available, but the Infectious Diseases Society of America (IDSA) advises that CDI testing should never be routinely sent in children under 12 months, and that it should only be used in children aged 1-2 years once other causes of diarrhea have been excluded. This isn’t because the IDSA doesn’t care about infants, but rather because the implications of finding C. difficile in the gut are very different when the gut in question belongs to an infant rather than an adult.
In the first month of life, approximately 40% of asymptomatic infants are colonized with C. difficile, so the mere presence of the organism is not indicative of disease. Perhaps even more importantly, infants are relatively resistant to symptomatic C. difficile disease. The reasons for this are not entirely clear, although the absence of toxin receptors, as seen in neonatal rabbits and pigs, is one proposed mechanism. The rate of asymptomatic C. difficile colonization declines gradually over the first year of life, and by age 2 it approximates the 0-3% rate seen in adults, so testing in older children is appropriate. Labs can help clinicians by including comments in electronic test order systems noting the unclear implication of a positive C. difficile test in infants or by restricting the test to children older than 2 years of age except in the case of certain unusual circumstances.
Viruses in Neonates
While C. difficile is generally less of a cause for alarm in infants than in adults, many pathogens are much more concerning in infants, especially neonates. Herpes simplex virus (HSV, Figure 1) is a prime example. To be sure, HSV can cause a devastating encephalitis in older children and adults, but it is far more commonly encountered in adults in the form of cold sores and genital lesions, which may be unpleasant and embarrassing but are rarely dangerous.
3D Reconstruction of the herpes simplex virus (HSV-1) capsid. Source.
In a newborn, however, any manifestation of HSV (typically acquired during delivery) is a cause for grave concern because the virus can have severe manifestations including liver failure, pneumonia, myocarditis, meningitis, seizures, cerebral hemorrhage, and death. Because of the risk of progression to these outcomes, even the most “minor” form of neonatal HSV, known as skin, eye, mouth (SEM) disease, is treated aggressively, with at least 2 weeks of intravenous acyclovir followed by months of suppressive oral therapy.
What does this mean for labs? Pediatricians will request a large battery of tests for neonates suspected of having HSV infection of any kind; the American Academy of Pediatrics (subscription required) recommends HSV culture or PCR of “surface swabs” from the mouth, nasopharynx, conjunctivae and anus and of scrapings from skin vesicles (if present), HSV PCR of cerebrospinal fluid (CSF), and HSV PCR of blood. The results of these tests will be anxiously awaited by the baby’s pediatrician and even more anxiously by the baby’s parents, so the lab may expect more calls than usual about the results of HSV testing.
In other cases, the diagnosis of a viral infection in a young infant may be important primarily because of the other infections that become less likely once the virus is diagnosed. Infants less than 1 to 2 months of age with even a one-time fever generally undergo what is called a “sepsis workup” or, more precisely, an evaluation for a serious bacterial infection. This is because a fever may be the only presenting symptom of invasive bacterial disease in newborns, who are at risk for infection with pathogens such as Streptococcus pneumoniae and Haemophilus influenzae type B that they are too young to have been vaccinated against.
The workup involves culture of blood, urine, and CSF and treatment with intravenous antibiotics for at least 48 hours. Most infants with fevers turn out not to have a serious bacterial infection, but the testing, hospitalization, and wait for results can be extremely stressful for parents. However, if a febrile baby tests positive for respiratory syncytial virus (RSV), this alternate explanation for fever reduces the probability that the infant has a serious bacterial infection, particularly meningitis, and may in some cases allow for close observation without additional testing, such as a lumbar puncture, or treatment. There is no specific therapy for RSV, so identifying this virus in an older child or adult with a cold has few implications for management, but for a newborn who is able to avoid a lumbar puncture and two days of hospitalization and intravenous antibiotics, it can have very significant implications indeed.
When babies are born, their immune systems are relatively immature, leaving them at increased risk of infection. They are not completely unprotected, however: during pregnancy, maternal immunoglobulin G (IgG) antibodies are transferred to the fetus through the placenta. These antibodies, which provide some protection against diseases to which the baby’s mother has immunity, persist in the infant’s blood for several months or longer. This is a good thing for the baby’s health, but it can cause confusion if a doctor tries to use serological testing to establish the diagnosis of certain infections in an infant (Figure 2). For example, the presence of cytomegalovirus (CMV) IgG in the serum of a newborn only shows that the baby’s mother has had CMV infection at some point in the past; it cannot be used to determine whether the baby is infected with CMV. (Other tests, including shell vial culture from urine or saliva and PCR from blood and CSF, must be used if a diagnosis of congenital or perinatal CMV is suspected).
An understanding of the persistence of maternal antibody is essential in caring for infants born to human immunodeficiency virus (HIV)-infected mothers. Appropriate antiretroviral therapy for mother and baby is highly effective in preventing mother-to-child transmission of HIV, but all babies born to women who are HIV-infected are tested several times during the first year of life to confirm that they have not acquired the virus. Maternal HIV antibody can persist in babies for up to 18 months, however, so testing for HIV in these babies must consist only of nucleic acid assays.
Blood Culture Volumes
Every now and then, from the perspective of a lab test, children really are like small adults. Take the example of blood cultures. For adults with suspected bloodstream infections and endocarditis, the IDSA/ASM guideline recommends obtaining two to four 20- to 30-mL blood culture sets during each septic episode. The resulting total volume of up to 120 mL may be a perfectly reasonable quantity from a 70-kg adult, but for a child whose entire blood volume is less than 200 mL (as is the case for many preterm neonates), this is, to put it mildly, an impractically large amount. So what do we do in this case? Simply put, we do a smaller test.
The IDSA/ASM guideline provides recommendations for specific volumes of blood to be drawn for culture in infants and children according to weight; these are as little as a single 2-mL culture for infants weighing less than 1 kg, although different organizations have different weight-based volume recommendations, and the amount of blood drawn in practice may be lower than any of these. Most automated blood culture systems offer a pediatric-specific bottle containing a small volume of particularly enriched broth, which may enhance recovery of organisms from small volumes. Nevertheless, the smaller volumes of blood obtained from children likely do cause lower rates of recovery of pathogens and also complicate the distinction between true pathogens and contaminants in pediatric blood cultures; a recent Journal of Clinical Microbiology (JCM) review provides an excellent overview of challenges in pediatric blood culture collection.
The topics highlighted in this post are only a few examples of the unique aspects of pediatric and neonatal clinical microbiology. For in-depth discussion of more areas, check out this JCM editorial and the articles it references.
The above represent the views of the author and does not necessarily reflect the opinion of the American Society for Microbiology.