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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

  Carol.glaser@cdph.ca.gov   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