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Febrile #92 – Searching for Peace of Mind

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Summary

Future physician Sophie Samson, Dr. Kristen Bastug, and Dr. Beth Thielen discuss a case of a 7 year old girl who presented with new onset seizure, headache, and fever in Minnesota.

Table of Contents

Credits

Hosts: Sophie Samson, Sara Dong

Guests: Kristen Bastug, Beth Thielen

Writing/Infographics: Sophie Samson, Kristen Bastug, Beth Thielen

Editing, Cover Art: Sara Dong

Produced by Sara Dong with support from Infectious Diseases Society of America (IDSA)

Our Guests

Sophie Samson

Sophie is currently a third year medical student at the University of Minnesota Medical School.  She plan to train in pediatrics, and she has a particular interest in pediatric infectious disease and neurology.

Kristen Bastug, MD

Dr. Kristen Bastug is a pediatric ID fellow from the University of Minnesota. She is interested in the intersection of infectious disease, global child health, climate change and environmental health.

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Beth Thielen, MD, PhD, FAAP, CTropMed

Dr. Beth Thielen is an adult and pediatric infectious disease physician-scientist at University of Minnesota. She completed her MD/PhD training at University of Washington where she studied HIV pathogenesis in the Department of Global Health.  She then returned to Minnesota for both her med-peds residency and med-peds ID fellowship, where she acquired skills in molecular epidemiology and an outstanding team of future collaborators at the Minnesota Department of Health. 

Since 2020, she has led a translational research program focused on host-pathogen interactions in the human respiratory tract including innate immune signaling pathways induced by viral infections. Her lab is particularly interested in understanding the factors that influence the severity of respiratory viral infections, including viral sequence variants, respiratory microbiota composition and host genetic variation.  In addition to her interests in respiratory viral pathogenesis, she also has clinical interests in the care of immunocompromised patients, travel and tropical medicine, clinical immunology and mentorship of learners at all levels.

Check out her lab website here.

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Culture

Sophie: the novel Cloud Cuckoo Land by Anthony Doerr

Kristen: the documentary  Life on Our Planet

Beth: playing the accordion!  She mentioned visiting Castelfidardo and seeing the world’s large accordion!  Check out the pic!

Consult Notes

Case Summary

7 year old girl who presented with acute onset seizure, headache, and fever – found to have LaCrosse encephalitis

Key Points

Miscellaneous references from the episode

Beth spoke generally about use of serology vs molecular/nucleic acid-based tests in arboviral disease and then provided an interpretation of the episode case test results

  • For many arboviral infections, the period during which virus can be detected in any body fluid is typically quite short.  For this reason, PCRs can be helpful if positive but are not sensitive enough to rule out disease. 
  • Health departments may offer some PCRs, such as for West Nile Virus, but not all viruses in your differential.   Thus, serological testing is the mainstay for diagnosis.  
  • For serologies, a single positive IgG is difficult to interpret given the relatively high risk of past undiagnosed exposure in certain regions but a 4-fold rise between acute and convalescent samples would be supportive
      • For acute testing, we are really looking for positive IgMs to indicate acute infection.  However, IgMs may be falsely positive in other inflammatory disorders and cross-reactive against closely related viruses.
  • Thus, positive results are typically followed up with a plaque reduction neutralization assay, in which serial dilutions of the patient’s serum or CSF are incubated with virus in vitro to determine the concentration at which antibodies are able to inactivate the virus such that it can no longer infect cells and replicate in culture.  
      • Higher titers indicate a more specific reaction against that particular virus and would support it being a true pathogen and not cross-reactive.
      • Such confirmatory plaque neutralization assays are used commonly in arbovirology to distinguish between cross-reacting viruses, e.g. California serogroup bunyaviruses (Jamestown Canyon) and flaviviruses (West Nile, Yellow Fever, Dengue)
  • In this episode’s case, an initial screening Arbovirus IgM IFA that tests for California group encephalitis viruses, EEEV, WEEV and SLEV was positive for the California group
      • Initial IgM EIA testing done on serum was positive for Jamestown Canyon Virus, equivocal for Powassan and negative for WNV
      • Serum and urine PCR was negative for WNV
      • CSF IgM EIA testing was positive for  Jamestown Canyon Virus and Powassan and negative for WNV by both IgM and PCR.
      • Confirmatory testing was sent → and revealed
          • Serum IgM positive for Jamestown Canyon Virus and La Crosse by IgM capture ELISA and negative IgM for Powassan
          • La Crosse plaque reduction neutralization occurred at a >1:4096 titer but unfortunately there was not sufficient sample for Jamestown Canyon virus testing. 
          • PRNT was also performed on CSF and was positive at a 1:128 titer against La Crosse, 1:4 for Jamestown Canyon and was negative for Powassan.
      • Beth discussed on the initial testing was a bit confusing as it could support either/both a California group encephalitis virus (of which Jamestown Canyon was one) and Powassan, and there was not a screening IgM specific for La Crosse virus, which was actually the leading pathogen in the differential based on the patient’s age. This case is an example where the confirmatory PRNT assays were really critical.  Results came back with very high titers against La Crosse encephalitis with a much lower titer against Jamestown Canyon and a negative capture IgM against Powassan.  Thus, these results were interpreted as being confirmatory for La Crosse virus infection.

So the rest of this Consult Note will be focused on La Crosse encephalitis - the final diagnosis! La Crosse encephalitis (LAC) clinical evaluation and disease

  • Consider in person with febrile or acute neurologic illness with recent exposure to mosquitos, especially during the summer months in areas where virus activity has been reported. Most common in children
  • Ddx includes more common causes of encephalitis and aseptic meningitis such as HSV, enteroviruses, other arboviruses (West Nile, St. Louis encephalitis, eastern equine encephalitis, Powassan virus)
  • Most LAC virus infections will be undiagnosed and asymptomatic
  • Incubation period ranges from 5-15 days
  • Initial symptoms include fever, headache, nausea, vomiting, fatigue, lethargy
  • Disease can progress to encephalitis, meningoencephalitis, or aseptic meningitis.  Symptoms can also include altered mental status, seizures, speech changes, paresis or paralysis, movement disorders, and cranial nerve palsies
  • Approximately 1% of cases are fatal.  Neurologic sequelae, including epilepsy, hemiparesis, and cognitive and neurobehavioral abnormalities, have been reported in 6-15% of all diagnosed cases
  • CDC La Crosse Encephalitis Virus > Clinical evaluation & disease

Diagnostic Testing of La Crosse encephalitis

  • LAC virus is difficult to isolate from clinical samples
  • Almost all isolates (and positive PCR results) have come from brain tissue or rarely CSF
  • In absence of sensitive and non-invasive virus detection method, serologic testing remains the primary method for diagnosis → lab diagnosis is generally accomplished by testing serum or CSF for LAC virus-specific IgM and neutralizing antibodies
      • LAC virus IgM tests are available commercially, in some state health department labs, and at the CDC
      • There is potential cross-reactivity in the IgM assay to related viruses (eg Jamestown Canyon), so a positive LAC virus IgM test result should be confirmed by neutraizing Ab testing of serum specimens at state public health lab or CDC
  • Viral cultures and tests to detect viral RNA like PCR can be performed on serum, CSF, and tissue specimens collected early in the course of illness
  • Immunohistochemistry can detect LAC virus antigen in formalin-fixed tissue
  • CDC La Crosse Encephalitis → Diagnostic Testing

Epidemiology of La Crosse encephalitis

  • First described in the literature in 1965 in 4-year-old child living in Minnesota who sought care in La Crosse, Wisconsin and ultimately died from an acute neurological illness
  • Majority of cases are pediatric
  • LAC virus disease is a nationally notifiable conditions and cases are reported to CDC by state and local health departments
      • 30-90 La Crosse encephalitis (LAC) virus neuroinvasive disease cases are reported each year in the US
      • Substantial under-diagnosis and under-reporting of less severe cases of LAC disease; therefore, reported LAC neuroinvasive disease cases are used to compare trends over time and place. (serological surveys from Winona, MN region in showed up to 28% seropositivity in rural areas)
  • Occurs primarily from late spring through early fall, but in subtropical endemic areas (such as Gulf states), cases can occur in winter as long as mosquitos are active
      • Historically, geographically localized to upper midwest and Appalachia (Ohio/Kentucky/West Virginia)
      • Recently more cases have been reported in other states in Northeast, Mid-Atlanta, and Southeast US (NC, TN, WV, GA, VA, KY, RI)
  • Check out current year data and historic data from ArboNET (National Arbovirus Surveillance System)
  • Not clear why only a small fraction of exposed people developing neuroinvasive disease.  However, there are some interesting new data from a study of adults who developed neuroinvasive WNV infection. Autoantibodies neutralizing type I IFNs underlie West Nile virus encephalitis in ∼40% of patients.

Treatment & Prevention of La Crosse encephalitis

  • There is no specific treatment, clinical management is supportive
  • Sophie shared what she learned speaking with an epidemiologist on the vector-borne disease unit at the Minnesota Department of Health
  • Strategies include:
      • Protection against mosquito bites (as noted below)
      • Stop mosquitoes from laying eggs in or near water:
        • The mosquito that spreads LAC virus, Aedes triseriatus, prefers to lay its eggs in tree holes. You can reduce the number of mosquitoes around your home by filling tree holes that collect water.
        • LAC virus can survive the winter in mosquito eggs that will hatch into infected mosquitoes in the spring. Stop mosquitoes from laying eggs in or near water.  Once a week, empty and scrub, turn over, cover, or throw out items that hold water, such as tires, buckets, planters, toys, pools, birdbaths, flowerpots, or trash containers. Drill holes in tire swings so water drains out. Empty children’s wading pools and store on their side after use.
        • Check for water-holding containers both indoors and outdoors
      • Use screens on windows and doors. Repair holes in screens to keep mosquitos outdoors
      • Use air conditioning if available
      • Neighborhood surveillance and education for houses at risk
  • No LAC virus vaccines are available for use in humans
  • CDC Mosquito Control at Home
  • CDC La Crosse Encephalitis Virus Prevention

Kristen discussed several approaches to reduce the risk of mosquito bites

  • Insect repellants (bug spray) can be used on the skin whenever there is a risk for exposure to mosquitos or ticks.  In the episode, they mention particularly from April through November in Minnesota given the case scenario.  Many products are available, but you want to make sure it is registered by the Environmental Protection Agency. Here are a few effective active agents:
      • DEET (N,N-diethyl-3-methylbenzamide)
          • Effective against mosquitoes, biting flies, chiggers, fleas, and tickets (often considered a gold standard of insect repellants given the provide spectrum and extended duration of action)
          • DEET is available in many products with variable concentrations.  The American Academy of Pediatric recommends selecting a concentration of DEET that matches your expected outdoor exposure time.  For example, 10% DEET provides protection for about 2 hours, and 30% DEET protects for about 5 hours. The maximum concentration you likely need to buy in most cases is 50%, because anything beyond that does not provide longer protection despite a potentially higher price to purchase it.  
          • AAP does not recommend using DEET products in children under 2 months of age.  For older infants and children, 10-30% DEET should be safe and effective
          • Products containing both DEET and sunscreen are not recommended for children, because reapplication for the sunscreen component may result in excessive DEET exposure
      • Picaridin (KBR 3023)
          • Effective against mosquitoes, ticks, sand fly
          • Similar to DEET, the concentration correlates with duration of protection. 5% picaridin provides protection for about 3 to 4 hours, while 20% can provide protection for 8 to 12 hours.  
          • Higher concentrations of picardin (20%) have similar efficacy to DEET when used for short periods, although DEET has longer duration of activity
          • Excellent tolerability as it is odorless, nonsticky, nongreasy, doesn’t irritate skin, stain fabrics, or degrade plastics
      • Oil of lemon eucalyptus aka PMD (P-menthane-3,8-diol)
          • NOT the same as lemon oil.  You should make sure that your OLE product is registered by the EPA
          • It should not be used in children under 3 years old. 
          • OLE of 8% to 10% concentration can protect for up to 2 hours, and 30% to 40% concentration can provide 6 hours of protection. 
      • For all of these products it is important to read the label and avoid applying directly to a child’s hands to avoid the risk of ingestion or eye irritation. When using insect repellent with sunscreen, the sunscreen should be applied first
      • Check out this blog resource from AAP healthychildren.org on choosing insect repellent: https://www.healthychildren.org/English/safety-prevention/at-play/Pages/Insect-Repellents.aspx
  • Other than topical bug spray, you can also: 
      • Wear loose-fitting, long sleeved clothing
      • Pre-treat clothes with permethrin
      • Avoid areas with dense vegatation
      • Mosquito nets are also a great option and can be treated with insecticide.

Episode Art & Infographics

Infographics

Find all the Febrile infographics here!

Goal

Listeners will be able to evaluate for suspected arboviral encephalitis

Learning Objectives

After listening to this episode, listeners will be able to:

  • Compare and contrast the use of serology vs molecular based tests for diagnosis of arboviral disease
  • Describe the epidemiology and typical clinical presentation of La Crosse virus encephalitis
  • Discuss prevention opportunities to reduce risk of mosquito-transmitted infection

Disclosures

Our guests (Sophie Samson, Kristen Bastug, Beth Thielen) as well as Febrile podcast and hosts report no relevant financial disclosures

Citation

Samson, S., Bastug, K., Thielen, B., Dong, S. “#92:  Searching for Peace of Mind ”. Febrile: A Cultured Podcast. https://player.captivate.fm/episode/c4e1a903-d085-447e-8132-3b9296928ad1

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