Post on 20-Mar-2020
Viral Hemorrhagic Fevers
Pierre E. Rollin, MDSpecial Pathogens BranchCenters for Disease Control and Prevention
• Acute infection:fever, myalgia, malaise; progression to prostration
• Small vessel involvement:increased permeability, cellular damage
• Multisystem compromise (varies with pathogen)
• Hemorrhage may be small in volume(indicates small vessel involvement, thrombocytopenia)
• Poor prognosis associated with:shock, encephalopathy, extensive hemorrhage
VHF
Differential Diagnosis
• Febrile tropical illnesses:• Malaria• Typhoid fever• Bacterial gastro-enteritis• Rickettsial diseases
Laboratory Diagnosis
• Malaria smears• Blood cultures (closed system)• CBC, especially platelet count• Transaminases (prognostic value)• Creatinine, BUN• Coagulation factors
VHF: Viruses
• Enveloped, single stranded RNA viruses
• Similar syndromes; different pathogenesis & treatment
• Persistent in nature: rodents, bats, ticks, mosquitoes
• Geographically restricted by host
• Potential infectious hazards from laboratory aerosolsFiloviruses Ebola Hemorrhagic fever (Z, S, R, IC, B)
Marburg Hemorrhagic fever Arenaviruses Lassa fever
“New World Arenaviruses”Bunyaviruses Rift Valley fever (RVF)
Crimean Congo Hemorrhagic fever (CCHF)
Ebola
• 1-2 week incubation• Abrupt onset fever, headache, myalgia• GI symptoms, chest pain, delerium• 53-88% case-fatality• ~ 45% hemorrhage• Person-to-person transmission• African rainforest• Unknown reservoir (bat most probable)
Ebola Signs and Symptoms on PresentationEbola Signs and Symptoms on Presentation
0 10 20 30 40 50 60 70 80
EdemaVaginal bleeding
ConvulsionHematuria
HemoptysisAnuria
HiccupsDisorientation
*Bleeding-injection sitesEpistaxis
*Gum bleeding*Rash
Bloody stoolDyspnea
HematemesisRales/rhonchiSplenomegalyHepatomegaly
*Conjunctival injectionBack pain
*Right upper quadrant tenderness*Sore throat
Arthralgia/MyalgiaAbdominal pain
CoughChest pain
Abdominal tendernessNausea/Vomiting
*AnorexiaHeadache*AstheniaDiarrhea
Sign
or S
ympt
om
% Patients
Ebola
Non-Ebola
N = 206
1979, 20041979, 200419941994
1994, 1996, 19961994, 1996, 1996
1976, 19951976, 1995
1996*1996*
20002000
1976, 1979, 2004 1976, 1979, 2004
*Doctor returningfrom Gabon
Ebola Outbreaks
Congo2003
4,0002,000
kilometers
0
DRCDRCDRCDRCDRCDRCDRCDRCDRC(formerly Zaire)(formerly Zaire)(formerly Zaire)(formerly Zaire)(formerly Zaire)(formerly Zaire)(formerly Zaire)(formerly Zaire)(formerly Zaire)
GabonGabonGabonGabonGabonGabonGabonGabonGabon
South AfricaSouth AfricaSouth AfricaSouth AfricaSouth AfricaSouth AfricaSouth AfricaSouth AfricaSouth Africa
UgandaUgandaUgandaUgandaUgandaUgandaUgandaUgandaUganda
SudanSudanSudanSudanSudanSudanSudanSudanSudanIvory CoastIvory CoastIvory CoastIvory CoastIvory CoastIvory CoastIvory CoastIvory CoastIvory Coast
1995 Zaire
• 315 cases• 81% case-fatality• Point source outbreak• Unrecognized 3 months• 25% health care workers• 2 “super-spreaders”
EHF Risk Factors
2o attack rate of 16%
• Direct physical contactOR = undefined, p<0.01
• Body fluidsOR = 3.8, 95%CI (1.9-6.8)
• No contact = no disease
Suspected EHF cases, DRC, March-June 1995:by Source of Infection
02468
10121416
3/1 3/8 3/15
3/22
3/29 4/5 4/12
4/19
4/26 5/3 5/10
5/17
5/24
5/31 6/7 6/14
6/21
6/28
Date of onset
Num
ber
IDNUM 3IDNUM 2260Other source
02468
10121416
3/1 3/7 3/13
3/19
3/25
3/31 4/6 4/1
24/1
84/2
44/3
0 5/6 5/12
5/18
5/24
5/30 6/5 6/1
16/1
76/2
36/2
9
Date of onset
Num
ber
Non-Healthcare workersHealthcare workers
EHF Cases by Date of Onset and Occupation, Bandundu Region, DRC, 1995
Marburg: Past Outbreaks• 1967Marburg, Frankfurt, & Belgrade25 primary6 secondary7 deathsAfrican green monkeys from Uganda
• 1975Australian travelerZimbabwe1 primary2 secondary1 death
Marburg: Past Outbreaks
• 1980EngineerN.W. Kenya1 primary1 secondary1 death
• 1987Danish travelerW. Kenya1 primary1 death
• 1998-2000Gold mineN.E. DRC76 cases52 deaths>150 cases through
follow-up
Marburg: Past Outbreaks
• 2005Uige, AngolaLargest and deadliest on record374 cases329 deaths88% CFRHome-based injection use
• 20074 casesKitaka mine, UgandaReservoir studies
• 2008Fatal case Netherlandsmild case USA
Uige,Angola ‘05
Durba, DRC ’98-00
Uganda ‘67
Kenya ‘87Kenya ‘80
Zimbabwe ‘75
Uganda,’07,08
02Uganda 2007sep09DRC 1999mayRav Kenya 1987aug3705 Uganda 2007aug
3989 Uganda 2007aug3849 Uganda 2007aug
01Uganda 2007jul4432 Uganda 2007aug3952 Uganda 2007aug4032 Uganda 2007aug3992 Uganda 2007aug
Ozo Zimbabwe 1975feb48 Gabon 2005apr
96 Gabon 2006jan31 Gabon 2005apr
Mus Kenya 1980janPop Germany 1967aug
02DRC 1999apr
1 change
Uganda Bat Sequencesconcatenated
NP and VP35 frags (~700bp)
Max Parsimony
Human isolatesUganda ‘07
04DRC 1999may03DRC 1999apr32DRC 2000aug19DRC 2000feb34DRC 2000aug07DRC 1999may06DRC 1999may
14DRC 2000jan30DRC 2000aug01DRC 1999apr
24DRC 2000apr23DRC 2000mar
29DRC 2000jul27DRC 2000jul
26DRC 2000may
17DRC 2000feb16DRC 2000feb12DRC 2000jan20DRC 2000feb
21DRC 2000feb
22DRC 2000may
18DRC 2000feb
13DRC 2000jan28DRC 2000jul
05DRC 1999may
15DRC 2000feb
33DRC 2000aug25DRC 2000apr
09Angola 2005apr
08Angola 2005apr
04Angola 2005mar
07Angola 2005apr05Angola 2005mar02Angola 2005mar01Angola 2005feb
06Angola 2005apr03Angola 2005mar
11Angola 2005may10Angola 2005apr
R. aegyptiacus
21% virus diversity
Bunyaviruses
• Rift Valley fever• Crimean Congo
hemorrhagic fever• Hemorrhagic fever
with renal syndrome
Rift Valley Fever distribution and outbreaks
Major Outbreaks
Countries at risk
Saudi Arabia 2000
Madagascar 1979, 1990-91, 2008
Mauritania1987, 1998-99, 2002
Egypt 1977-78, 1997-98, 2003
Kenya 1997-98, 2006-07
South Africa 1950-53, 1974-75, 1999, 2008
Somalia 1997-98, 2006-7
Tanzania 1997-98, 2007
Mozambique 1969
Senegal1999, 2002
Gambia1999, 2002
Zambia 1973-74, 1978, 1985
Zimbabwe 1955, 1957, 1969-70, 1978
Namibia 1955, 1974-75
Sudan1973, 2007
Yemen 2000
•Adapted from EFSA Journal (2005) 238, 1-128. “The Risk of a Rift Valley Fever Incursion and its Persistence within the Community"
Rift Valley Fever
• Mosquito-borne (Aedes spp.) vertical transmission in mosquitoes
• Disease of sheep and cattle• Transmission:
• Animal contact (birthing or blood) • Laboratory aerosol
• Mortality 1% overall• Therapy: Ribavirin not recommended• Live-attenuated vaccine (MP-12) undergoing trials
Rift Valley Fever: Clinical features
• 3-7 day incubation, 3-5 day duration
• Asymptomatic or mild illness• Fever, myalgia, weakness, weightloss• Photophobia, conjunctivitis
• Encephalitis• <5% hemorrhagic fever• 1-10% vision loss (retinal hemorrhage, vasculitis)
CLINICAL FEATURES RVF IN SAUDI ARABIA, 2001
VARIABLE n/N (%)
Fever 499/539 (92.6) Nausea 315/530 (59.4) Vomiting 280/532 (52.6) Abdominal pain 202/532 (38.0) Diarrhea 118/530 (22.1) Jaundice 96/530 (18.1) CNS manifestations 81/475 (17.1) Hemorrhagic findings 35/494 (7.1)Vision loss or scotomas 10/683 (1.5)
Vision loss 8/683 (1.2) Scotomas 2/683 (0.3)
From Madani, et al, CID, 2003;37:1084
RVF: Encephalitis
Meningeal signs 67Confusion 81Stupor or coma 78Hypersalivation and teeth grinding 11Hallucinations 43Hemiparesis 5Focal Signs 27CSF pleocytosis 86CSF protein > 40 mg% 57Fatal outcome 11Residua 7
* Percent of total from a series of 37 reported cases
%*%*
1997-1998 East Africa Outbreak
• 478 deaths• 115 VHF deaths• 9% IgM+• ~89,000 cases• 70% animal loss
Rift valley fever outbreak alert and response
0102030405060708090
Num
ber o
f Cas
es
TIME
Animal outbreak
Human outbreak
Control Opportunity
Amplification
Mass Animal Vaccination
Rapid Response
Early DetectionForecasting
Readiness
Courtesy Pierre Formenty WHO
CRIMEAN CONGO HEMORRHAGIC FEVER(CCHF)
• Extensive geographic distribution(Africa, Balkans, and western Asia)
• Transmission:• Tick-borne (Hyalomma spp.) • Contact with animal blood or products• Person-to-person transmission
by contact with infectious body fluids• Laboratory worker transmission documented
• Mortality 15-40%• Therapy: Ribavirin
Distribution of CCHF virus
CCHF: Clinical features
• 4-12 day incubation after tick exposure• 2-7day incubation after direct contact with infected fluids• Abrupt onset fever, chills, myalgia, severe headache• Malaise, GI symptoms, anorexia• Leukopenia, thrombocytopenia, hemoconcentration,
proteinuria, elevated AST• Hemorrhages may be profuse (hematomas, ecchymoses)
PREVENTION OF CCHF
• DEET repellents for skin• Permethrin repellents for clothing –
(0.5% permethrin should be applied to clothing ONLY)• Check for and remove ticks at least twice daily. • If a tick attaches, do not injure or rupture the tick.
Remove ticks by grasping mouthparts at the skin surface using forceps and apply steady traction.
CCHF: Pathogenesis
• Viremia present throughout disease• IFA becomes positive in patients destined to survive days 4-6,
often simultaneously with viremia• Recovery may be due to CMI or neutralizing antibodies• Patients that die usually still viremic• Virus grows in macrophages and other cells• DIC often present• Poor prognosis signaled by early elevated AST and clotting
Arenaviruses
• New world• Junin• Machupo• Guanarito• Sabia• Chapare
• Old world• Lassa• Lujo
Lassa Fever
• West Africa• Rodent-borne (Mastomys natalensis)• Person-to-person transmission
• Direct contact• Sex• Breast feeding
• Mortality 1-3% overall, 20% among hospital patients• Therapy: Ribavirin
Lassa: Clinical features
• 80% asymptomatic
• Fever• Retro-sternal pain• Exudative pharyngitis• Myalgias, headache• Abdominal pain, vomiting• Facial edema and conjunctivitis• Mucosal bleeding• Proteinuria
New WorldArenaviruses
TamiamiSigmodon hispidus
GuanaritoZygodontomys brevicauda
Tacaribe Artibeus bat
AmaparíNeacomys guianae
Sabiá??
OliverosBolomys obscurus
JunínCalomys musculinus
ParanáOryzomys buccinatus
LatinoCalomys callosus
MachupoCalomys callosus
FlexalOryzomys spp.
PinchindéOryzomys albigularis
PiritalSigmodon alstoni
Whitewater Arroyo Neotoma albigula
Bear CanyonPeromycus californicus
CupixiOryzomys capito
AllpahuayoOecomys bicolor
Chapare??
Junin (Argentine hemorrhagic fever)
• Argentine pampas, autumn grain harvest• Rodent borne (Calomys musculinus)• Person-to-person transmission uncommon,
sexual transmission documented.• Mortality 15-30%• Therapy: Immune plasma, Ribavirin(?)
Machupo (Bolivian Hemorrhagic Fever)
• Bolivia, Beni Department• Rodent borne (Calomys callosus)• Person-to-person transmission probable• Mortality 25%• Therapy: Ribavirin(?)
Guanarito (Venezuelan Hemorrhagic Fever)
• Venezuela, central plains• Rodent borne (Zygodontomys brevicauda)• Person-to-person transmission not documented• Mortality 20-30%• Therapy: Ribavirin(?)
South American Hemorrhagic Fevers: Clinical features
• 1-2 week incubation• Gradual onset fever, malaise, myalgias, anorexia• Headache, abdominal pain, nausea, vomiting,
orthostasis• Petechiae (axillae, palate), gingival hemorrhage• Neurologic signs (hyporeflexia, tremor, lethargy,
hyperesthesia)• Leukopenia, thrombocytopenia, proteinuria
South American Hemorrhagic Fevers: Clinical features
• 70% Recovery in 7-8 days without sequelae, prolonged fatigue and weakness common.
• Severe disease• Severe hemorrhage• Delerium, coma, convulsions• Combined hemorrhagic/neurologic disease• High mortality
VHF - Diagnosis
TimeTime33--5 days RVF/CCHF5 days RVF/CCHF55--10 days others10 days others
33--5 days RVF5 days RVF1010--15 days Lassa15 days Lassa
Fever
Virus/Ag/RNA
IgG / Neutralizing Antibody
IgM Antibody
• Rule out or treat febrile illnesses:malaria, rickettsia, leptospirosis, typhoid, dysentery
• Early hospitalization• Distant medical evacuation associated with high mortality• Cautious sedation and analgesia• Careful hydration• Pressors, cardiotonic drugs• Support of coagulation system
VHF: Supportive therapy
Ribavirin
• Guanosine nucleoside analog: blocks viral replication by inhibiting IMP dehydrogenase
• Licensed for treatment of RSV and HCV• Potential adverse effects:
• Dose dependent reversible anemia• Pancreatitis• Teratogen in rodents
• Same regimen: loading dose 30mg/kg (max of 2 grams)16 mg/kg every 6 hours for 4 days8 mg/kg every 8 hours for 6 days
• Post-exposure treatment
Ribavirin: indications
• Filoviruses No• Rift Valley No…• CCHF Yes• Lassa Yes• Argentine HF Yes• Other New/Old world Arena Maybe
Ebola Treatment
Experimental only, require NHP protectionEbola vaccines
DNA Vaccine +Boost Adenovirus (phase II)Adenovirus (phase I)VSVParainfluenza
Marburg vaccinesVEE RepliconVSV
Filovirus Vaccines
VHF: Human-to-Human transmission
• None: Yellow fever, Dengue, Rift Valley fever, Kyasanur, Omsk (arboviruses), hantaviruses
• Low: Lassa and South American Arenaviruses
• High: Ebola, Marburg, Crimean-Congo HF
Standard Precautions
• Constant use of gloves and handwashing(plus face-shields, masks or gowns if splashes are anticipated) for any contact with blood, moist body substances, mucous membranes or non-intact skin.
• Additional, Transmission-based Precautions
Standard Precautions
Transmission-based Precautions•Airborne (TB, Chicken pox, Measles, Smallpox)
•Droplet (Diphtheria, Pertussis, Meningococcus, Influenza, Mumps....)
•Contact (Enteric infections, Respiratory infections, Skin infections, Conjunctivitis…. )
VHF: Contact management
• Casual contacts: e.g., shared airplane or hotel,No surveillance indicated
• Close contacts: Direct contact with patient and/or body fluids during symptomatic illness.Fever watch during incubation period
• High risk contacts: Needle stick, mucosal exposure to body fluids, sexual contact.Fever watch, consider inpatient observation.
Outbreak responseEbola - Marburg
ISOLATION – PPE
Sometimes a woman would clutch his sleeve, crying shrilly:”Doctor, you’ll save him, won’t you?” But he wasn’t there for saving life; he was there to order a sick man’s evacuation. How futile was the hatred he saw on faces then! “You haven’t a heart!” a woman told him on one occasion. She was wrong; he had one. It saw him through his twenty-hour day, when he hourly watched men dying who were meant to live.
(Albert Camus, The Plague, 1947)