Transcript Ebola Virus

Emerging Infections
Thomas M. File, M.D., M.Sc.
Chair, Infectious Disease Division
Summa Health System;
Professor of Internal Medicine,
Chair Infectious Disease Section
Northeast Ohio Medical University
It is time to
“close the book on
infectious diseases.”
Congressional testimony by the Surgeon General of
Congressional
testimony by the
the United States,
1969
Surgeon General of the United
States, 1969
EMERGING INFECTIONS
New,
Re-emerging, or
Drug-resistant
infections whose incidence in humans has
increased within the past 2 decades or
whose incidence threatens to increase in
the near future.
Institute of Medicine Report 1992
From:
Woolhouse M
Microbe 2006
1: 511
RECENT VIRAL OUTBREAKS
Requirement for Pandemic
Requirements
for Pandemic
SARS
Avian Flu
H1N1 2009 Flu
Novel Virus
+ (Coronavirus)
+ (H5N1)
+ (Hsw1N1)
Disease in
Humans
+
+
+
-
+**
Degree of spread +*
Human to human
*Transmissible only during symptomatic disease
**Transmissible prior to symptoms and many ‘subclinical ‘ cases
NEJM Feb 1, 2012; 366: 454-61
NEJM Feb 1, 2012; 366: 454-61
Ebola Virus
Prototype
Viral Hemorrhagic
Fever Pathogen
 Filovirus: enveloped,
non-segmented, negativestranded RNA virus
 Severe disease with high
case fatality
>20
previous Ebola and
Marburg virus outbreaks
2014
West Africa Ebola
outbreak (Guinea, Sierra
Leone, Liberia)
 Largest outbreak in history
 Absence of specific
treatment or vaccine
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Ebola Virus
Transmission
•The virus is spread through
• direct contact (through broken skin or mucous
membranes) with a sick person's blood or body
fluids (urine, saliva, feces, vomit, and semen)
• objects (such as needles) that have been
contaminated with infected body fluids
• infected animals
•Healthcare workers, burial workers, and the
family and friends in close contact with Ebola
patients are at the highest risk of getting sick
because they may come in contact with
infected blood or body fluids.
Pathophysiology of EBOLA Virus
UpToDate 2014
EVD: Expected diagnostic test results over time
Critical information: Date of onset of fever/symptoms
IgM
IgG
viremia
0
3
10
days post onset of symptoms
Fever
RT-PCR
ELISA IgM
ELISA IgG
IgM: up to 3 – 6 months
IgG: 3 – 5 years or more (life-long persistance?)
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EVD Clinical
Manifestations
•Acute onset: typically 8-10 days after
exposure (range 2-21 d)
•Stage I
• Fever, chills, HA, myalgias, malaise,weakness
• Diffuse erythematous Maculo papular rash (some)
• GI symptoms common: N/V, diarrhea, Abd pain
•Stage II (high mortality)
• Hemorrhage
• Hypotension; electrolyte Abn; Shock
• Lab: Cytopenia; Abn LFTs; Coag Abn; Renal Abn
Clinical Management of EVD:
Supportive, but Aggressive
Hypovolemia
and sepsis physiology
 Aggressive intravenous fluid resuscitation
 Hemodynamic support and critical care management if necessary
Electrolyte
and acid-base abnormalities
 Aggressive electrolyte repletion
 Correction of acid-base derangements
Symptomatic
management of fever and gastrointestinal
symptoms
 Avoid NSAIDS
Multisystem
organ failure can develop and may require
 Oxygenation and mechanical ventilation
 Correction of severe coagulopathy
 Renal replacement therapy
• Reference: Fowler RA et al. Am J Respir Crit Care Med. 2014
17
Investigational Therapies for EVD Patients
No
approved Ebola-specific prophylaxis or treatment
 Ribavirin has no in-vitro or in-vivo effect on Ebola virus
 Therapeutics in development with limited human clinical
trial data
• Convalescent serum
• Therapeutic medications
o
Zmapp – chimeric human-mouse monoclonal antibodies
o
Tekmira – lipid nanoparticle small interfering RNA
o
Brincidofovir – oral nucleotide analogue with antiviral activity
o
GS-5734—Filovirus inhibitor (highly effective in monkeys; IDWeek 2015)
 Vaccines – in clinical use
• Chimpanzee-derived adenovirus with an Ebola virus gene inserted;
Attenuated vesicular stomatitis virus with an Ebola virus gene inserted
• References: 1Huggins, JW et al. Rev Infect Dis 1989; 2Ignatyev, G et al. J Biotechnol 2000; 3Jarhling, P et al. JID 2007 S400; 4Mupapa, K et
al. JID 199 S18; 5Olinger, GG et al. PNAS 2012; 6Dye, JM et al. PNAS 2012; 7Qiu, X et al. Sci Transl Med 2013; 8Qiu, X et al. Nature 2014;
9Geisbert, TW et al. JID 2007; 10Geisbert, TW et al. Lancet 2010; 11Kobinger, GP et al. Virology 2006; 12Wang, D JV 2006; 13Geisbert,
.
TW et al. JID 2011; and 14Gunther et al. JID 2011
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EVD Management
Patient Recovery
Case-fatality
rate 71% in the 2014 Ebola outbreak
Fatality rate is lower with access to intensive care
Patients
who survive often have signs of clinical
improvement by the second week of illness
Associated with the development of virus-specific AB
Antibody against Ebola persists greater than 12 years
Prolonged
convalescence
Includes arthralgia, myalgia, abdominal pain, extreme
fatigue, and anorexia; some symptoms may persist for >21
months
Skin sloughing and hair loss has also been reported
• References: 1WHO Ebola Response Team. NEJM 2014; 2Feldman H & Geisbert TW. Lancet 2011; 3Ksiazek TG et
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al. JID 1999; 4Sanchez A et al. J Virol 2004; 5Sobarzo A et al. NEJM 2013; and 6Rowe AK et al. JID 1999.
POST EBOLA SYNDROME
•Manifestations
• Arthralgias/Arthritis
• Paresthesias
• Short term memory loss
• Headache
• Vision changes
•Santuary sites
• Eye
• Joints
• Testes
• CSF
•3 patients
• US physician with severe vitritis
• 2 UK nurses with encephalitis
• 27 patients; median age 36;70% male
• Treatment: ICU care; 85% received
investigational agents
• Mortality 18.5%
NEJM 2016; 374: 636-46
• 8638 patients administered vaccine
• Well tolerated27 patients; median age
36;70% male
• Treatment: ICU care; 85% received
investigational agents
NEJM 2016; 374: 636-46
• Mortality 18.5%
EBOLA concern in Akron, Ohio
OHIO: Monitored 164 contacts of
EBOLA concern in Akron, Ohio
• VISIT BY CDC;
• DAILY CONFERENCES WITH COUNTY HEALTH;
• FREQUENT TELCONF WITH OHIO DEPART HEALTH
EBOLA concern in Akron,
OH
Novel betacoronavirus (HCoV)
• MERS (Middle East Resp Syndrome
• Sept 2012: 2 patients with severe
pneumonia (Saudi Arabia; Qatar) in
otherwise healthy
• Sept 2016: 1800 cases (Middle East; Travel
from Middle East--UK, France, Italy, US,
Korea, 27 countries);
• 30-40% mortality
• Similar to SARS virus
• Source: bats, camels
• Human to human (low)
NEJM Oct 17,2012
29
WHO SHOULD BE EVALUATED FOR MERS
PATIENTS WHO MEET THE FOLLOWING:
FEVER AND PNEUMONIA OR ACUTE RESPIRATORY
DISTRESS SYNDROME AND EITHER:
 HISTORY OF TRAVEL FROM COUNTRIES IN OR NEAR THE
ARABIAN PENINSULA1 WITHIN 14 DAYS OF SYMPTOMS OR
 CLOSE CONTACT2 WITH A SYMPTOMATIC TRAVELER WHO
DEVELOPED FEVER AND ACUTE RESPIRATORY ILLNESS (NOT
NECESSARILY PNEUMONIA) WITHIN 14 DAYS AFTER TRAVELING
FROM RISK COUNTRIES OR
 IS A MEMBER OF A CLUSTER OF PATIENTS WITH SEVERE ACUTE
RESPIRATORY ILLNESS (E.G., FEVER AND PNEUMONIA
REQUIRING HOSPITALIZATION) OF UNKNOWN ETIOLOGY IN
WHICH MERS-COV IS BEING EVALUATED
OR: CLOSE CONTACT2 OF A CASE OF MERS
Whirlpool Folliculitis
From File and Stevens. Handbook of Skin Infections. 2010
56 y/o with recurrent cellulitis of leg
Photo courtesy of T. File MD
Photo courtesy of T. File MD
Recurrent Cellulitis of lower extremity in
patients with prior Heart Surgery
•Almost always due to hemolytic Streptococcus
• Usually NOT Grp A Strep
• Responsive to most antimicrobials
•Associated with disruption of venous and/or
lymph drainage
• Can occur after injury
• Can be seen in upper extremeties (e.g., after breast
surgery)
•Look for associated tinea pedis or other
chronic skin condition
• Treat with antifungal
• Use antibacterial soaps
•Double blind study 28 hospitals
England/Ireland
• PCN 250 mg BD vs placebo over 3 years
• 274 patients
•Results--Recurrences:
• PCN 22% (626 days to 1st recurrence)
• Placebo 37% (532 days to 1st recurrence)
• P=0.01
Thomas et al. 2013; 368: 1695
35
Case
• 32 y/o preg woman from
Connecticut presets in
July at 26 weeks
gestations with slight
fever, arthralgia, HA and
rash
• How should she be
managed?
Lyme-stages
• Early (days to weeks after tick bite; minority recall)
• Erythema migrans (80%), fatigue, malaise , HA, myalgia,
arthralgia, regional lymphadenopathy
• Early disseminated: (weeks to months)
• Musculoskelatal; neuro 15% (lymph meningitis, cranial neruropathy);
carditis 1%
• Late (months to years)
• MS 60%; Neuro
Lyme-Diagnosis
•Early-clinical with rash; serology little value
•Serology
• 2 tiered: ELISA then Western Blot
• VisE C6 ELISA
• Measures AB to major protein sequence
• More accurate, also good for European strains
• Antibodies may persist for years after Lyme disease
has been treated and cured
•PCR
Criteria for Western Blot for Lyme
Type of
Infection
First few
weeks
After month
Isotope
Bands for Dx
IgM
Two of: 24,39,41
IgG
Five of:
18,23,30,39,41,45,58,66,
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Case
Shapiro NEJM 2014; 370:1724
• Skin lesion consistent with erythema migrans.
• 500 mg of amoxicillin three times a day for 14 days,
doxycycline is contraindicated in pregnant women.
• Outcomes are excellent and that congenital Lyme
disease has never been documented.
• Chemoprophylaxis would not have been indicated,
because only doxycycline has been shown to be
effective as chemoprophylaxis.
How to Manage the following patients
23
y/o HIV infected man who lives with a person
recently diagnosed with active TB. CD4# 130. Neg. CXR
44 y/o Respiratory therapist with “positive”
Quantiferon test. Asymptomatic; CXR neg.
62 y/o female with rheumatoid arthritis scheduled to
start anti-TNF agent; has ‘indeterminant’ Quantiferon
43 y/o male immigrant from Nepal with one month
history of cough, fever, weight loss. CXR shows upper
lobe infiltrates.
TB Classification System
Class
0
Stage of Disease
No exposure, no infection
1
Exposure, no evidence of infection
2
TB infection, no disease
3
TB, clinically active
4
TB, not clinically active
5
TB suspect
TB Exposure; No Infection
Patients
with immunocompromising conditions who
are close contacts of active TB should be treated
similar to LTBI regardlsess of results of skin test or
interferon release assay (prevent infection).
Repeat skin test or interferon release assay 8-10
weeks later; if negative can DC treatment
Latent TB
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Latent TB infection vs TB Disease
Latent TBI
TB Disease
Positive Skin test or Interferon Gamma
Release Assay (IGRA)
Skin Test or IGRA usually +
CXR normal
CXR usually Abnormal
No signs or symptoms
Signs, symptoms present
Culture neg.
Smear, Culture + 50%
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Latent TB (Quantiferon)
• Less subjectively than Skin Test
• No affect of BCG; but may have cross reactivity
with M. kansaii, marinum or szulgari
• Interpretation of Quantiferon test
Quantiferon
Result
comment
Mitogen – Nil
Should be > 0.5
If < 0.5=
“indeterminant”
TB Ag – Nil
Positve > 0.35;
Neg. < 0.35
BUT most < 1.0
are unlikely
LTBI!!
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General Recommendations for Using
IGRAs
Preferred
when testing persons
Who might not return for TST reading
Who have received BCG vaccination
Immune suppressed
Generally should not be used to test children
<5 years of age, unless used in conjunction
with TST
STD-2016 GENERALIZATIONS
Anyone is at Risk!!!
–1/3 of Americans age 15-55 will have STD
• Sequelae: Infertility, Ectopic preg, Cong/Perinatal
Infection, Cancer
• If one STD increases likelihood of another!!!
• Simple urine test for painless diagnosis and highly
effective, single dose therapies for chlamydia and
gonorrhea
• Quinolones and Cefixime no longer recommended
for empiric GC therapy
• Mycoplasma genitalium
• Promise of HPV Vaccines
29 y/o male presents with urethral
discharge. What is your approach?
A. Obtain
culture and await
results
B. One dose of a fluoroquinolone
C. Obtain nucleic acid test for
GC & Chlamydia & await results
D. Obtain nucleic acid test for
GC and Chlamydia and treat
with ceftriaxone and one dose
of azithromycin
E. Treat with a fluoroquinolone
and one dose of azithromycin
Testing GC and Chlamydia
•Positive test influences compliance and
partner notificaton
•Noninvasive:
• Nucleic acid amplification tests, NAAT (on
urethral secretions or first void urine)
•Minimally Disruptive
• Patient obtained vaginal swabs
•Reduces incidence of PID
Neisseria gonorrhea
Cervix, Urethra, Rectum
Ceftriaxone (Rocephin) 250 mg IM*
or , if not an option:
Cefixime (Suprax) 400 mg po
PLUS CHLAMYDIAL THERAPY
*Acceptable for pharyngeal GC also
•Beta-lactam ‘Allergy’
• Crossover for ceftriaxone probably < 1%
• Spectinomycin
• Azithromycin 2 mg PO?
Non Specific Urethritis
Chlamydia trachomatis:
Treatment
• AZITHROMYCIN 1 GM AS SINGLE ORAL
DOSE*
• DOXYCYCLINE 100 MG PO BID X 7 DAYS
• OFLOXACIN 300 MG PO BID X 7 DAYS
• LEVOFLOXACIN 500 MG PO X 7 DAYS
• ERYTHROMYCIN 500 MG QID X 7 DAYS
*MOST COST EFFECTIVE
Azithro vs Doxycycline
for Chlamydia
• Randomized trial adolescents in correctional facilities1
• Azithro (1 gm X 1) 5/155 (3%) had treatment failure
• Doxy (100 mg BD X 7 d) 0/155 had treatment failure
• Unclear why difference: resistance unlikely; azithro levels
may not be sufficient in some patients
• Editorial: “not reasonable to recommend doxy over azithro as
preferred….In populations in which adherence can be
monitored and ensured, 7-da7 doxy might be preferred; if
adherence ? Azithro still excellent option for the ease of
use..”2
1. Geisler et al NEJM 2015; 373: 2512; 2. Quinn et al NEJM 2573
Mycoplasma genitalium
(CDC STD Guidelines 2015)
•Causes 20% of non gonococcal
urethritis; Cases of cervicitis ?
•Resistant to doxycycline
•NO commercial test
•AZITHROMYCIN 1 GM AS SINGLE
ORAL DOSE
• ? Resistance
•If fails azithromycin---moxifloxacin 400
mg X 7-14 days
Genital ulcer
1.Painless, indurated ulcer
2. Painful, mulitple ulcers
a. Syphilis
b. Chancroid (ceftriaxone 250 mg X1; azithro 1 gm)
Primary syphilis - chancre
Primary syphilis - chancre
SYPHILIS
•Diagnosis
•Darkfield
•Serology
•RPR
•FTA
SYPHILIS; stages
•Incubation (10-90 days) ave. 3 weeks
•Primary (chancre)
• Initial site infection; heals within few weeks
•Secondary (rash, fever, HA, malaise,
adenoapthy)
• Weeks to months later; resolve
•Latent (early ≤ 1 year; late > 1 year)
•Tertiary (many years later)
• CNS; Cardiovascular; Gumma
•http://www.cdc.gov/std/treatment/2015/default.htm
32 y/o woman presents with rash of 3
days duration. Last sexual encounter
4 weeks earlier
Lab: RPR 1:256; FTA +; HIV -
42 y/o with 2 week history of
nonpruritic rash. Treated in ER
with prednisone
THERAPY: EARLY SYPHILIS
•Primary, Secondary, Early Latent (<1 yr)
•Therapy
- Benzathine PCN 2.4 million units 1M x
1
•Alternative (data limited)
- Doxycycline 100 mg po BID x 14 days
- (Ceftriaxone 1 gm IM QD x 10-14
days)
Guidelines for STD, USPH & CDCP
The patient is treated and
repeat serology is done 6
months afterwards.
RPR + 1:32. Should this
patient receive additional
testing and/or management?
SYPHILIS THERAPY
Follow-Up
• Repeat Serology 6, 12 Months (Also 3 if HIV
and 24 if late syphilis)
• Consider Failure if:
- Titers Increase
- Failure to Decline Fourfold
- Signs or Symptoms Persist/Develop
• Consider CSF Exam
• Retreat - 7.2 Benzathine PCN if CSF Neg
Guidelines for STD, USDH-CDCP
THERAPY: LATER SYPHILIS
• Late Latent (> 1 yr or Unknown Duration)
- Benzathine PCN 2.4 Million U IM Qwk x 3
(7.2 total)
- Pen Allergic (Non Preg; data limited):
Doxycycline 100 mg BID x 4 wks
- Pen Allergy and Pregnant: Desensitize
• Tertiary (Gumma, Cardiovascular)
- If Symptomatic, do CSF Exam
- Benzathine PCN 2.4 Million U IM Q wk x 3
(7.2 total)
NEUROSYPHILIS
•Consider if:
- Neurologic, Ophthalmic, (Auditory) Manifestations
- Tertiary Disease
- Treatment Failure
- HIV
• CSF:
WBC, Protein, + VDRL (+FTA less specific)
• Therapy: Aqueous PCN G 18-24 Million U/d x 10-14
days; Alternative - Procaine PCN 2.4 Million U/d +
Probenecid 500 mg QID for 10-14 days (AllergyDesensitize); ? Ceftriaxone 2 gm IM QD x 10-14 d
CASE
•56 y.o male referred for + RPR (1:8)
• History movement disorder and RPR
ordered as part of Neurology evaluation
• No known history of prior infection or test
•LP:
• Protein 78; glucose normal; WBC 5
(lymphs)
• VDRL +
•Treatment:
• 14 days 18 million units Pen G/day
Syphilis: New Testing
•New testing method
•Reversed sequence: Treponemal test
followed by RPR
•Cost effective in laboratory
•Treponemal test remains + after first
infection
• Cannot distinguish past vs. re-infection
•Need RPR for following infection (hope
to go to neg. or low titer)
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US Preventative Services Task Force:
“Increase Screening for Syphilis”
•Incidence in US increased 15% from 2013 to
2014
•Focus groups:
• HIV
• Men who have sex with men
• Men ages 20-29
•Promote Safe Sex Practices-especially
condom use
JAMA June 2016
Herpes, female
Therapy for Genital Herpes
• Primary
• Acyclovir 400mg tid X 7-10d
• Valacyclovir 1000mg bid X 7-10d
• Famciclovir 250 mg tid X -10d
• Recurrent
• Acyclovir 400 mg tid X5d (800 bid x 5d or 800 mg tid
X 2 d); Valacyclovir 500 mg bid X 3d or 1 gm QD X
3d; Famciclor 125 mg bid X 5d (1 gm bid x 1 d)
• Suppressive
• Acyclovir 400 bid; Valacyclovir 500mg or 1 gm qd;
Famvir 250 bid
• Acyclovir-Resistant HIV
• Foscarnet; Cidofovir; Trifluridine
Vaginitis
features
Candidiasis
Bacterial
Vaginosis
diagnosis
Pruritis, ;
Whitish
discharge;
dyspareunia
pH < 4.5;
Morphology
of stain or wet
mount;
Culture
Malodorous pH > 4.5,
discharge
“clue” cells
on wet mount
Trichomonas Copious
foamy
Ph > 4.5; wet
mount
treatment
Topical, oral
azoles
Metronidazol
e (po or vag);
clinda vag
cream
Metronidazol
e 2 gm X1
STD: multiple pathogen testing
•STD: multiple pathogen testing
•Nucleic acid amplification test (PCR) based
• GC, HSV 1 and 2,
• Trichomonas vaginalis (TVA), and Chlamydia
• Mycoplasma, Ureaplasma,
•Urethral/Vaginal/cervical Swab
•Diatherix proprietary
Quinter C et al. ICAAC 2013
77
STD-2016: Take Home
• If one STD increases likelihood of another!!!
–Check for HIV
• Simple urine test for painless diagnosis and
highly effective, single dose therapies for
chlamydia and gonorrhea
• Penicillin drug of choice for syphilis
• Quinolones and Cefixime no longer
recommended for empiric GC therapy
• Promise of HPV Vaccines
Painless chronic skin ulcer enlisted person
coming home from Iraq
Cutaneous Leishmaniasis
Treatment: pentavalent antimonial compound, pentamidine, or
amphotericin B
Case: Patient presents to ER with fever,
cough, chest pain
The diagnosis is
most likely by?
a. Sputum culture
b. Blood culture
c. Sputum PCR
d. IgM ELISA
e. Urinary Antigen
EMERGING INFECTIONS
“Humanity has but three great
enemies: fever, famine and war; of
three by far the greatest, by far the
most terrible, is fever.”
Sir William Osler