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5/17/12
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21ST CENTURY ISSUES IN PUBLIC HEALTH…….OR.. Rashes, Eschars and Other
Reasons to be Crazy….
Carol Glaser DVM, MPVM, MD Department of Pediatrics, UCSF
& California Department of Public Health
Outline
Cases presented that were referred to State Health Department with unknown etiology
Serve as Medical Officer, Viral and Rickettsial Disease Laboratory (VRDL)
Information pertinent to outpatient and inpatient—heterogeneous group of issues
Slides not identical to handout
Disclosures
I have nothing to disclose
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Case 1
16 month old female, previously healthy, presents with elevated temperature and rash
What is the most likely diagnosis?
1. Smallpox 2. Monkeypox 3. Disseminated Herpes 4. Enterovirus 5. Disseminated Varicella
Case 2
7 year old female from rural county presents to pediatrician with lesion above her eye. She had a history of tick bite ~ 2 weeks prior to presentation
What is the most likely diagnosis?
1. Lyme disease 2. Anthrax 3. Rickettsia infection 4. Methicillin-resistant Staph aureus 5. Spider bite
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Case 3
8 year old previously healthy girl from rural county in California presents with neurologic symptoms and admitted to your ICU. She is diagnosed with rabies. 1. No treatment is available, universally
fatal 2. Treatable with rabies vaccine 3. A small number of survivors have been
reported 4. IV Acyclovir is an effective treatment
for rabies
Case 4 What is the most common cause of pediatric
encephalitis in California?
1. Rabies virus 2. Herpes simplex encephalitis 3. West Nile virus 4. Western equine encephalitis 5. Anti-NMDAR encephalitis
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Previously “perfectly well” child 4 healthy siblings and 2 well parents No animals No travel No unusual exposures
Received VZV vaccine in September 2011
16 month old with rash
December 2011-
1-2 days prior to admission: “vesiculobullous eruption” on arms and legs
Day of admission:
Temperature 40 Very irritable Admitted to PICU
16 month old with rash
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Positive Enterovirus PCR from multiple specimen types (vesicles, respiratory specimens)
Enterovirus typed as Coxsackie A–6 virus (CAV-6)
Enteroviruses
RNA group of viruses Spread via fecal-oral and respiratory route Most occur June-October in US Polio and ‘non-polio’ viruses:
Group A coxsackieviruses Group B coxsackieviruses Echoviruses (many re-classified into Parechovirus) “numbered” enteroviruses (e.g. EV 68, EV 71)
Hand-Foot and Mouth Disease (HFMD) generally associated with: coxsackievirus A (especially A16) and EV71
Hand, Foot and Mouth-“classic”
SIGNIFICANCE OF CAV-6? (Coxsackie A–6 virus)
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CAV-6-Finland
Finland 2008 Nationwide outbreak of hand, foot and mouth Many were school-aged or adults: suggesting “low
herd” immunity Rash often worse Associated with onychomadesis (shedding of nails) 1-2 months after acute illness Nail fragments positive for CAV-6 virus Some patients had neurologic complications
– Emerg Infectious Disease 2009
CAV-6 Finland 2008
CVA-6-Taiwan
Taiwan 2010 Enhanced surveillance for EV because EV71 Of 130 patients positive for with HFMD rash:
66 (51%) with desquamation of palms/soles 48 (37%) with onychomadesis (compared with 5% of
HFMD with non-CAV6 infection
– BMC Infectious Diseases 2011
CAV6 Taiwan, 2010
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CVA-6 in Japan
June 2011 Sudden increase in hand, foot and mouth reported Of 709 HFMD and 156 herpangia-
93 clinical samples from 108 HFMD case patients • 74 + CAV-6
Also noted neurologic disease (encephalitis)
– Emerg Infect Diseases 2012
CAV6 Japan 2011 outbreak- ”typical clinical manifestations”
National data— MMWR 2012
MMWR March 2012-National perspective
November 7, 2011 – February 29, 2012:
63 persons with signs and symptoms HFMD: Alabama (38), California (7), Connecticut (1) and Nevada (7)
Of the 63 patients: 15 (24%) were adult > 18 years of age 44 (70%) had exposure to day care or school
-MMWR 2012
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MMWR March 2012-National perspective
Rash and fever more severe > “typical” HFMD As well as rash on hands, feet and mouth:
29 (46%) arms and legs 26 (41%) face 22 (35%) buttocks 12 (19%) trunk
2 (4%) shedding of nails
Enterovirus not reportable per se so we don’t have good baseline data
Comments from a Pediatric Dermatologist…
(Dr. Ilona Frieden)
“I have been a pediatric dermatologist for 30 years and these are unlike anything I have previously seen..”
More widespread skin disease and in particular spread to areas of previous skin disease or skin damage (e.g. atopic dermatitis, sunburn, irritant dermatitis)
More extensive facial skin lesions Many have more widespread papules (resembling Gianotti-Crosti) Larger blisters More hemorrhagic skin lesions Onychomadesis
Additional reports in California… A few weeks later..
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Significance of CAV-6
Rash is more extensive, often involving entire extremities, face and sometimes trunk (culture negative, molecular testing/PCR needed)
Adults and older children
Mis-diagnosis: Eczema herpeticum Kawasaki Disease Atypical impetigo Vasculitis
Seasonality--what will the summer bring?
CASE 2
Case 2
Call from Infectious Disease Service, Bay Area concerning: 7 year old female with fever, eschar and history
of tick bite
Case 2
11 days after her tick bite seen by PMD fever (102.3), headache (severe), and body pains,
area above left eye was red and swollen with cutaneous lesion (‘scab’)
Treated with Amoxicillin for possible Lyme Disease
She did not improve so referral made to Infectious Disease Clinic
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Fever & Eschar following tick bite 7 year old female
Physicians from Infectious Disease Clinic contacted State Health Department
Because of history of tick bite, eschar and resident of rural county:
Recommended testing for Rickettsia (specifically for 364-D)
Consider Rx with doxycycline
Samples sent to Viral and Rickettsia Disease Laboratory for rickettsia testing
A few days later…
…the 7 y/o female feeling better…. However….
17 year old sibling had presented with fever, headache, eschar on nape of neck
Recommended Rickettsia testing
Testing results
In both cases: Rickettsia titers (Rocky Mountain Spotted Fever-
RMSF) Rickettsia PCR positive from eschar material—typed
as Rickettsia 364-D
A week later—another patient presented with similar findings from Contra Costa county
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WHAT IS RICKETTSIA 364-D?
Rickettsia 364D R. philipii, sp. proposed One of 5 spotted fever
group rickettsiae causing human infections in US
Detected in California ticks since 1966 and suspected to be a cause of human infection
Only detected in Dermacentor occidentalis (Pacific Coast Tick)
Rickettsia 364-D
Rickettsia 364D: A Newly Recognized Cause of Eschar*-Associated Illness in California
• Clinical Infectious Disease 2010
Unknown clinical spectrum of illness because so few recognized cases
*eschar : a thick, coagulated crust or slough which develops following a thermal burn or chemical or physical cauterization of the skin [Stedmans]
How common is this and what are typical
manifestations? Of 8 recognized probable/confirmed cases in CA
Age range: 5-80 years (3 in pediatric age range) Symptoms:
Eschar 100% (this is how they were recognized) Headache 88% Fever 63% Lymphadenopathy 63% Myalgias 50%
Eschar locations: hairline (1), eyebrow (1), arms/shoulders (5), hip (1)
Uncommonly recognized but probably not uncommon
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Where has it been found?
Human cases in Lake, Contra Costa and Santa Clara counties
Positive ticks in several counties Approximately 6% of Dermacentor ticks positive for
this organism Lassen, Mendocino, Nevada, Los Angeles, Orange,
Plumas, Riverside, Siskiyou, Ventura (and probably others…)
Dermacentor occidentalis ticks, particularly nymphs, appear associated
with 364D cases
Seasonality D. occidentalis nymphs, Sonoma County preliminary data; Padgett et al; VBDS
• Seasonality of cases coincides with D. occidentalis nymphal tick seasonality
• D. occidentalis nymphal ticks collected around most 2011 case exposure areas
Adult Female
D. Occidentalis Life Cycle
Adult Male
Nymph
Challenges for Diagnosis
Considerations for diagnosis: Many “look-alikes” Tick-bite history helpful (helpful to have tick for
identification) In 2011-5 cases recognized
Tick-bite reaction
http://www.textbookofbacteriology.net/Anthraxlesion.gif
Cutaneous anthrax
CDC.gov. Day 4
Parapox virus
CASE 3
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Case 3
8 year-old female from Humboldt County, CA Presented to PMD (5 days prior to admission)
Sore throat Emesis (while taking medications)
Over the next few days, she had problems swallowing
Went to Emergency Room (2 days prior to admission) Administered intravenous fluids for hydration Laboratory studies: CBC and urinalysis
WBC elevated [17.9 (80% PMNs)] U/A: positive ketones
Case 3
Returned to Emergency Room (1 day prior to admission) abdominal pain neck and back pain discharged to home
Returned again to ER (day of admission) sore throat, poor swallowing generalized weakness in legs worse abdominal pain – concerns for appendicitis
Case 3
Exam in Emergency room Unremarkable except for “confused”
During imaging studies, asked to drink oral contrast Choking event Intubated to protect airway
Laboratory studies Head/Chest and Abdominal CT: unremarkable
Started on antibiotics and IV fluids Air lifted to UC Davis Medical Center Pediatric ICU
Case 3
Pediatric Intensive Care: Ascending weakness with flaccid paralysis
“Like a rag doll”
Intubated Became less alert, change in mental status Fever
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Case 3
MRI: abnormalities in cortical and subcortical regions periventricular white matter changes
Rx: broad-spectrum antibiotics and supportive care
State Health Department (California Encephalitis Project) contacted for diagnostic assistance
Case 3
Clinical picture: Trouble swallowing Ascending weakness Inflammation of the brain
Differential West Nile virus infection: none reported in state Botulism: no ingestion home-canned food Tick paralysis: no ticks on physical exam Polio-like viruses: (e.g., Enterovirus 71)
Rabies…this became our focus
VRDL Testing
May 4 (HD #4): CEP → rabies testing: PCR: saliva, nuchal biopsy – rabies VNA
negative DFA on nuchal biopsy – negative for rabies virus
Ag Positive Antibodies to rabies in serum by IFA
(IgG=1:16, IgM=1:20) Results confirmed by CDC Rabies laboratory May 11: IFA titers peaked (IgG=1:64, IgM=1:160) Serial testing of saliva by PCR remained negative No rabies neutralizing antibody titers detected by
RFFIT May 3-June 9
Interpretation
Meets standard case definition Possible exposure – feral cats or other
unrecognized exposure Compatible illness Unvaccinated but seropositive
CSF antibodies IgM antibodies Increasing titers during course of illness
No known cross-reactive Lyssaviruses in North America
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Rabies virus
Typically transmitted via saliva from rabid animal usually from bite
Rare in the United States but ~50,000 cases internationally
Mammalian reservoirs (include bats, skunks, foxes, cats, dogs)
Causes a severe, rapidly progressive encephalitis “Preventable” with post-exposure prophylaxis (PEP)
but not necessarily “treatable”
Considered to be 100% fatal in humans (until recently)
53 Days at UCD Children’s Hospital
Human Rabies Survivors- Prior experiences in U.S.
Recovery (without rabies PEP)
15 year old female, Wisconsin, 2004
17 year old female, Texas, 2009 [“Abortive Case”]
Both met case definition for human rabies based on clinical manifestations and rabies specific
Rabies virus, antigen, nucleic acid was not detected
from these patients
Similar to our case, antibody identified “early” – New Eng J Med 2005
– MMWR 2010
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CASE 4…..JUST ONE MORE REASON TO BE CRAZY….
Case 4
15 year old female admitted to psychiatric unit for odd behavior, “completely out of her mind” abnormal movements high heart rate, hypotension
State Health Department (California Encephalitis Project) contacted because clinicians were concerned about rabies
The workup before referall
CSF PCR HSV 1&2 (-) VZV (-) HHV6 (-) Enterovirus (-)
Parvo B19 DNA (-) IgG 5.3 IgM <0.1
West Nile (-) HIV-1 PCR <50 CMV IgG (+), IgM (-) EBV IgM <0.90, IgG 3.27 VRDL NR
Strongyloides Ab 0.29 Schistosoma Ab 0.0 G. lamblia Ag (-) Tropheryma whipplei (-) Bartonella panel (-) Cryptococus (-) C. immitis (-) RPR NR HBc IgM NR HBV DNA <40 HBc Ab (+) HCV Ab NR HAV IgG (+) Mumps Ab (+)
Rickettsia Panel IFA Typhus IgG (-) RMS IgG (-) E. chaffeensis IgG (-) A phagocytophilla IgG (-) Q fever phase I and II IgG
(-) Arbo Panel pending M pneumo IgM 307, IgG
1.24 H capsulatum Ab <8 pANCA (-) cANCA (-) Heavy Metal Screen (WNL)
β-HCG (-) α-fetoprotein 1.5 VGCC Ab Pemphigus Ab Screen ANNA titers GAD 65 Ab <0.5 Neuroimm Thyroid Peroxidase Ab
<10 TSH 2.93 T4 1.65 DS DNA Ab (-) ANA (-)
Workup of Case -continued…
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Contacted State Health Department
We didn’t think she had rabies and recommended:
1) Anti-N-methyl-D-aspartate receptor (anti-NMDAR) testing
2) abdominal/pelvic ultrasound
U/S positive for teratoma Antibody positive for anti-NMDAR antibody WHAT IS ANTI-NMDAR
ENCEPHALITIS?
What is anti-NMDAR encephalitis?
2005: report of a female with ovarian teratoma who presented with psychosis
2007: 12 female patients with ovarian teratomas presenting with behavioral, seizure and/or disturbance in memory-- antibody binding to NMDAR NR1 subunit in brain had been identified (NR1 expressed in brain tissue) [Ann Neurology 2007]
Dysfunction of NMDARs associated with schizophrenia, epilepsy and
dementia
What is anti-NMDAR encephalitis?
2008 report of 100 cases, mostly females and many with associated tumor [Lancet Neur 2008]
2009 frequently occurs in children, tumors less common > young adults [Ann Neurol 2009]
2012 most common cause of encephalitis in individuals < 30 years [Clin Inf Dis 2012]
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Anti-NMDAR encephalitis
THE leading diagnosis in individuals < 30 years of age
Comparison to Viral Agents California encephalitis project data
(2007-present)
0
5
10
15
20
25
30
35
EV WNV HSV-1 VZV NMDAR
< 30 years of age
Summary Enterovirus: “novel” type of EV (Coxsackie A-6)
circulating, often with severe, atypical rash. Nail abnormalities may be seen a few weeks later
Rickettsia 364-D: new type of Rickettsia infection identified in California. Only handful of cases reported to date but probably occurs just not recognized
Rabies: Spectrum is changing. Not 100% fatal
Anti-NMDAR: Leading cause of encephalitis in pediatric population, potentially treatable
Diagnostic issues
If you are interested in testing Always contact your local health department first
[email protected] 510 307 8613
Viral and Rickettsial Disease Laboratory 510 307 8585
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Acknowledgements • California physicians: Julie Kulhanjian, Samantha
Johnston, Ann Petru, Dan Kelly, Erin Mathes, Paul Stanger, Ilona Frieden, Jean Weideman, Tara Greenhow
• California Department of Public Health, Vector control: Kerry Padgett, Anne Kjemtrup
• California Department of Public Health, Viral and Rickettsia Disease Laboratory: Dave Schnurr, Shigeo Yagi, Sharon Messenger, Rick Berumen, Debra Wadford, Heather Sherriff, Annie Shin, Dave Cottam
• Dr. Josep Dalmau