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4/25/13

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Emerging Infec,ons

Sarah Doernberg, MD Assistant Professor

University of California, San Francisco April 25, 2013

Disclosures

•  Nothing to disclose

Outline

•  What is an emerging infec,on? •  West Nile virus

•  Hantavirus •  Lyme and other Jck-‐borne illnesses

•  Novel coronavirus •  H7N9

What is an emerging infec,on?

•  Infec,on that has newly appeared in the popula,on, or have existed but are rapidly increasing in incidence or geographic range

•  Many historical examples: – Plague – Smallpox –  Influenza

Morse SS. Emerg Infect Dis. 1995 Jan-‐Mar;1(1):7-‐15; Spellberg B. Clin Infect Dis 2008;47:294.

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Morens DM, et al. Nature 430, 242-‐249(8 July 2004)

Worldwide emerging infec,ons Outline

•  What is an emerging infecJon? •  West Nile virus

•  Hantavirus •  Tick-‐borne illnesses •  Novel coronavirus •  H7N9

WNV Outbreak

•  CDC declared an outbreak in August, 2012 •  Focused in Dallas, TX, but ac,vity in all 48 con,nental states

•  Most cases in history of disease in USA

•  2734 neuroinvasive cases, 243 deaths

West Nile virus neuroinvasive disease, 2011

h[p://www.cdc.gov/ncidod/dvbid/westnile/Mapsincidence/surv&control11IncidbyState.htm

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West Nile virus neuroinvasive disease, 2012

h[p://www.cdc.gov/ncidod/dvbid/westnile/Mapsincidence/surv&control12IncidbyState.htm

WNV background

•  First isolated in 1937 from the West Nile district of Uganda

•  Part of the Japanese encephali,s virus family: Includes JE, St Louis encephali,s, others

•  Widely distributed throughout the world •  First reported in USA in 1999 –  Cluster of neuroinvasive disease recognized in Queens

•  Limited ac,vity un,l 2002 when there was an epidemic with ↑severity

h[p://www.cdc.gov/ncidod/dvbid/westnile/cycle.htm

Rare Spread of WNV

•  Mosquito bite •  Breastmilk

•  Blood •  Transplacental •  Organ transplantaJon •  OccupaJonal exposure (lab work)

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Clinical presenta,on

•  Incuba,on 2-‐14 days •  Vast majority of infec,ons are asymptoma,c •  20% WNV fever: Fever, myalgias, malaise, HA –  +/-‐rash (25-‐50%), +/-‐ LAD (rare)

•  <1% Neuroinvasive disease –  Encephali,s – Meningi,s –  Flaccid paralysis (polio-‐like syndrome)

•  Immunity is thought to be lifelong

Risk factors for severe WNV Factor Odds ra,o 95% CI

Age

18-‐59 y Ref Ref

60-‐69 y 2.0 1.4-‐3.0

≥ 70 y 6.5 3.9-‐10.7

Male 1.4 1.0-‐1.8

Race other than white, non-‐Hispanic

2.9 2.0-‐4.2

Hypertension 1.5 1.1-‐2.1

Diabetes 2.2 1.4-‐3.4

Any history of cancer (non-‐BCC) 3.7 1.8-‐7.5

Chronic renal disease 4.1 1.4-‐12.1

EtOH abuse 3.0 1.3-‐6.7 Lindsey NP, et al. Am J Trop Med Hyg. 2012 Jul;87(1):179-‐84.

WNV sequelae

•  RNA detected even years aker infec,on •  Fa,gue levels normalize in ~4 months •  > 50% with soma,c complaints at 1 year •  Abnormal neurocogni,ve tes,ng in some –  Motor speed, manual dexterity, execu,ve func,oning,

memory

•  New tremor in up to 20% Murray K, et al. J Infect Dis 2010;201(1):2. Loeb M, et al. Ann Intern Med 2008;149(4):232. Carson PJ, et al. Clin Infect Dis. 2006;43(6):723.

Diagnosis of WNV

Busch MP, et al. J Infect Dis. 2008 Oct 1;198(7):984-‐93

Viral RNA

IgM

IgG

Mosquito bite

~2 days

~13 days

~4 days ~3 days

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WNV diagnosis

•  Serum or CSF IgM – Can persist up to 6 months

– May need convalescent ,ters if ini,ally nega,ve – False posi,ves: Yellow fever/JE vaccines, dengue or other flavivirus infec,on

•  Serum or CSF nucleic acid tes,ng (PCR) – Lower sensi,vity – Can be helpful in immunocompromised pts

Preven,on

•  Avoid mosquito bites! •  Use EPA-‐approved insect repellants:

–  hpp://cfpub.epa.gov/oppref/insect/ for list –  DEET (okay to use with sunscreen) –  Picaridin –  Oil of Lemon Eucalyptus or PMD, the synthesized version –  IR3535

•  Screens on windows/doors •  No standing water •  Aerial spraying •  Screen blood donors •  Vaccine (phase I/II promising), equine licensed

h[p://www.cdc.gov/ncidod/dvbid/westnile/wnv_factsheet.htm Peterson LR and Fischer M. N Engl J Med. 2012 Oct 4;367(14):1281-‐4.

Management

•  Suppor,ve care •  RCTs for novel therapies have failed due to low enrollment –  Intravenous immunoglobulin –  Interferon alpha – Ribavirin

Peterson LR, Fischer M.. N Engl J Med. 2012 Oct 4;367(14):1281-‐4; Agrawal AG, Petersen LR. J Infect Dis. 2003 Jul 1;188(1):1-‐4. Kalil AC, et al. Clin Infect Dis. 2005 Mar 1;40(5):764-‐6; Hrnicek MJ, Mailliard ME. Am J Gastroenterol. 2004;99(5):957. Chowers MY, et al. Emerg Infect Dis. 2001 Jul-‐Aug;7(4):675-‐8.

WNV take-‐home points

•  Generally transmiped by mosquitos •  Most infec,ons are asymptoma,c

•  Can cause severe CNS disease •  Diagnose with serum IgM

•  Prevent mosquito bites!

•  Suppor,ve care

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Outline




Hantavirus outbreak •  8/16/12: CADPH reports hantavirus in 2 visitors to Curry Village, Yosemite NP –  Closure of Curry Village

•  8/31: CDC issues a na,onal health advisory •  9/6: An individual staying at other Yosemite camps also becomes ill

•  9/12: All overnight visitors to Yosemite warned of risk

•  11/1: 10 confirmed cases, 3 deaths total

Hantavirus background

• Many viral species exist: –  Old World: Hemorrhagic fever w/ renal syndrome (HFRS)

–  New World: Hantavirus cardiopulmonary sx (HCPS)

•  Outbreaks throughout history •  First described by Western Medicine in 1950s aker HFRS outbreak among UN troops

•  1993: HCPS recognized in USA at New Mexico-‐Arizona border (sin Nombre virus)

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Hantavirus transmission in the USA

Deer mouse Co[on rat

Rice rat

White-‐footed rat

h[p://www.cdc.gov/hantavirus/rodents/index.html

•  Inhala,on of urine or droppings

•  Direct contact with urine or droppings

•  Rodent bite •  Person-‐to-‐person?

h[p://www.cdc.gov/hantavirus/surveillance/state-‐of-‐exposure.html

HCPS clinical presenta,on

•  Incuba,on: ~2-‐3 weeks •  Prodrome (2-‐8 days): Fevers/myalgias progressing to nausea, vomi,ng, weakness, headaches

– Absent URI symptoms •  Cardiopulmonary phase (2-‐7 days): Dry coughabrupt onset of shock, noncardiogenic pulmonary edema, coagulopathy

•  Oliguric/diure,c: Less prominent than HFRS

•  Convalescent (48 hours-‐much longer)

HCPS diagnosis •  Radiographic findings: B inters,,al infiltrates •  Laboratory findings:

–  Thrombocytopenia occurs early –  Lek shik with immunoblasts (>10% of lymphoid series)

–  Less specific: ↑LDH, ↑lactate, hepa,,s, anemia, coagulopathy

•  Serology: IgM + by symptom onset in acute infec,on, fourfold rise in IgG (not FDA approved)

•  RT-‐PCR less useful

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HCPS preven,on

•  Avoid rodent contact

•  Air out buildings •  Clean with dilute bleach • Wear gloves

Seal up Trap up Clean up

h[p://www.cdc.gov/hantavirus/hps/prevenJon.html

HCPS treatment

•  Suppor,ve care –  Early vasopressor use and cau,ous volume resuscita,on

–  Considera,on of ECMO

•  Ribavirin –  In vitro ac,vity –  Mortality in HFRS 2/2 Hantaan virus: 8.5% placebo vs. 2.4% IV ribavirin (p = 0.04)

–  Anemia is major SE –  2 studies with HCPS did not show clear benefit but small

Huggins JW, et al. J Infect Dis 1991 Dec;164(6):1119-‐27. Chapman LE, et al. AnJvir Ther. 1999;4(4):211 Mertz GJ, et al. Clin Infect Dis. 2004;39(9):1307.

HCPS take-‐home points

•  Transmiped by rodents •  Nonspecific prodrome evolving into severe respiratory illness

•  Laboratory abnormali,es can help to make diagnosis

•  Avoid rodents and clean up responsibly •  Suppor,ve care +/-‐ ribavirin

Outline


•  Hantavirus •  Lyme and other ,ck-‐borne illnesses


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Tick background

h[p://www.cdc.gov/Jcks/life_cycle_and_hosts.html

Diseases transmiped by ,cks

•  Anaplasmosis (Ixodes sp.) •  Babesiosis (Ixodes scapularis) •  Erlichiosis (Ambylomma americanum) •  Lyme disease (Ixodes sp.) •  Borrelia miyamotoi (Ixodes scapularis) •  R. parkeri (Ambylomma maculatum) •  RMSF (Dermacentor sp., brown dog ,ck) •  Tickborne relapsing fever (sok ,cks) •  Tularemia (Dermacentor sp., Ambylomma sp.) •  364D Rickepsiosis (Dermacentor occidentalis) •  Abroad: Crimean-‐Congo hemorrhagic fever, rickepsial spoped

fevers (esp. R. africae), ,ckborne encephali,s

h[p://www.cdc.gov/lyme/stats/maps/map2011.html

Lyme background

•  Caused by a spirochete –  In USA, Borrelia burgdorferi –  In Europe, B. afzelii, B. garinii > B. burgdorferi

•  Transmiped by Ixodes ,cks, which can spread other diseases: – USA: Human granulocy,c anaplasmosis, babesiosis

–  Europe: Tick-‐borne encephali,s •  Require > 48 hrs of apachment but less important for other ,ckborne illnesses

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h[ps://vpn.ucsf.edu/lyme/transmission/,DanaInfo=www.cdc.gov+blacklegged.html

How to remove a ,ck

h[p://www.cdc.gov/Jcks/removing_a_Jck.html

Early localized Lyme

•  3-‐30 days aker ,ck bite •  80% of pa,ents •  25% recall ,ck bite •  Erythema migrans

– May start solid, then develop central clearing – Mul,ple EM lesions in up to 20% –  Similar lesion in STARI

•  Nonspecific flu-‐like symptoms

Early disseminated Lyme

• Weeks to months aker bite •  Neurologic:

– Meningi,s (lymphocy,c)

–  Cranial nerve palsies (esp facial) – Other neuropathies

•  Cardi,s: AV block, myopericardi,s

•  Ocular: Conjunc,vi,s > others •  +/-‐ arthralgias, systemic symptoms

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Late disseminated Lyme

• Months to years aker ,ck bite •  Arthri,s:

–  Intermipent or persistent

–  Large joints (knee)

•  Neurologic: –  Lyme encephalopathy –  Chronic axonal neuropathyspinal radicular pain, distal paresthesias

•  Skin: Acroderma,,s chronica atrophicans (Europe)

Post Lyme syndrome

• Most people respond well to an,bio,cs • Minority have ongoing subjec,ve symptoms

–  Fa,gue, MSK pain, cogni,ve complaints

•  “Lyme-‐literate” physicians believe that B. burgdorferi infec,on is the culprit – Diagnosis on clinical grounds – Use of unvalidated tes,ng or different cut-‐offs –  Long courses of an,bio,cs rx’d

Feder HM Jr., et al. N Engl J Med 2007 Oct 4;357(14):1422-‐30

Four categories of “chronic” Lyme

1.   Symptoms of unknown cause with no evidence of B. burgdorferi infec,on

2.   A well-‐defined illness unrelated to Lyme (e.g. MS)

3.   Symptoms of unknown cause with serologic evidence of B. burgdorferi but no objec,ve findings

4.   Post-‐lyme disease syndrome, previous treatment with ongoing symptoms

•  For further advice about managing these pa,ents: –  Supplement to: Feder HM Jr, Johnson BJB, O’Connell S, et al. N Engl J

Med 2007;357:1422-‐30. Feder HM Jr., et al. N Engl J Med 2007 Oct 4;357(14):1422-‐30

Coinfec,on

Region Lyme Anaplasma Babesia Coinfec,on 2 pathogens

Coinfec,on 3 pathogens

CA 4-‐7% 3-‐7% -‐-‐ 1-‐1.3% -‐-‐

NE 22-‐52% 2-‐53% 1-‐23% 1-‐28% 0

WI 11% 8% -‐-‐ 2% -‐-‐

Swanson SJ, et al. Clin Microbiol Rev 2006 Oct;19(4):708-‐27

•  Coinfec,on reported in 2-‐40% of pa,ents diagnosed with Lyme disease (most studies in NE) •  Most frequently babesia + lyme •  Consider if failure to respond to an,bio,cs or CBC abnormali,es

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h[p://www.cdc.gov/lyme/healthcare/clinician_twoJer.html

What not to send

•  Capture assays for an,gens in urine •  Culture, immunofluorescence staining, or cell sor,ng of cell

wall-‐deficient or cys,c forms of B. burgdorferi •  Lymphocyte transforma,on tests •  Quan,ta,ve CD57 lymphocyte assays •  “Reverse Western blots” •  In-‐house criteria for interpreta,on of immunoblots •  Measurements of an,bodies in joint fluid (synovial fluid) •  IgM or IgG tests without a previous ELISA/EIA/IFA

h[p://www.cdc.gov/lyme/diagnosistesJng/LabTest/OtherLab/index.html

MMWR, CDC Surveillance Summary, 2005, 54:125.

Lyme disease prophylaxis

•  If all criteria met: –  Tick is adult or nymphal Ixodes scapularis

–  Tick apached at least 36 hours –  Prophylaxis is begun w/i 72 hours of ,ck removal –  Local rate of ,ck infec,on at least 20% – Doxycycline is not contraindicated

•  Doxycycline 200 mg PO x 1 dose

•  If doxy is not an op,onwatchful wai,ng

Wormser GP, et al. Clin Infect Dis 2006; 43:1089

Treatment Syndrome Doxycycline

100 mg q12h Amoxicillin 500 mg TID

Cefuroxime 500 mg Q12h

Cekriaxone 2 g IV qday

EM 10-‐21 d 14-‐21 d 14-‐21 d

CN VII palsy 14-‐28 d

Other neurologic 10-‐28 d

1st degree AV block 14-‐21 d 14-‐21 d 14-‐21 d

Other cardi,s 21-‐28 d

Arthri,s alone 28 d 28 d 28 d

Recurrent arthri,s 28 d 28 d 14-‐28 d

Treats HGA Yes No No No

Treats Babesia No No No No

Wormser GP, et al. Clin Infect Dis 2006; 43:1089

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Lyme take-‐home points

•  Requires prolonged exposure to ,ck • Most people have EM rash alone

•  Responds well to an,bio,cs •  Ongoing symptoms can occur, not treated with further an,bio,cs unless arthri,s

•  Diagnose with IFA/ELISA + WB confirma,on

•  Consider coinfec,on if ongoing sxs or CBC abnormali,es

Outline

• What is an emerging infecJon? • West Nile virus



Novel coronavirus HCoV-‐EMC •  17 cases reported in 2012-‐13, 11 deaths •  Jordan, Saudia Arabia, Qatar, UK, UAE •  Possible person-‐to-‐person spread •  Pa,ent under inves,ga,on:

–  Acute respiratory infec,on w/ PNA or ARDS –  Travel to Arabian Peninsula or neighbors w/i 10 days –  Contact to someone who has recent travel –  Nega,ve tes,ng for other e,ologies –  Report if cluster of severe respiratory illness in HCW

Zaki AM, et al. N Engl J Med. 2012 Nov 8;367(19):1814-‐20 h[p://www.cdc.gov/coronavirus/ncv/

H7N9 Virus •  Influenza A H7 normally circulate among birds –  Prior sporadic human infec,ons but not w/ H7N9

•  First reported in humans 3/31/13 in China

•  Severe pneumonia

•  > 100 cases, 21 deaths •  Transmission route not known

•  Sensi,ve to neuroaminidase inhibitors

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Respiratory virus take-‐homes

•  High index of suspicion needed • When in doubt, report to your local DPH

•  Take a travel history! •  Infec,on control •  Suppor,ve care +/-‐ an,virals

Thank you!

Ques,ons?

Risk factors for neuroinvasive disease

Factor Odds ra,o 95% CI

Diabetes 4.2 2.6–6.6

Age > 64 y 2.2 1.6–3.1

Hypertension 2.1 1.4-‐3.0

Male 1.6 1.2–2.1

Jean CM, et al. Emerg Infect Dis. 2007 Dec;13(12):1918-‐20

WNV and pregnancy

•  Mother-‐to-‐child transmission has been reported –  CDC registry: report to department of public health

•  PrevenJon is key •  AsymptomaJc women should not be screened •  Okay to conJnue breaspeeding during illness •  Clinical evaluaJon of infants

h[p://www.cdc.gov/ncidod/dvbid/westnile/qa/breaspeeding.htm

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Bacon RM, et al. MMWR Surveill Summ 2008 Oct 3;57(10):1-‐9.

ReinfecJon vs. relapse

•  17 paJents with paired episodes of erythema migrans

•  B. burgdorferi isolated from skin or blood culture in research seqng

•  All with different genotypes at iniJal and second episode

•  Confirms reinfecJon rather than relapse

•  Only in early disease because immune response thought not protecJve

Nadelman RB, et al. N Engl J Med. 2012 Nov 15;367(20):1883-‐90.

MeeJng the challenge of emerging infecJons

•  Rapid clinical diagnosis •  Response and containment

David M. Morens, Gregory K. Folkers & Anthony S. Fauci. Nature 430, 242-‐249(8 July 2004)

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