# Presentation: 717854

## Viral Hemorrhagic Fevers

- Michael Bell, MD
- Special Pathogens Branch
- Division of Viral & Rickettsial Diseases
- Centers 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

- 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

## Viral Hemorrhagic Fever viruses

- Filoviruses		Ebola	Hemorrhagic fever (EHF)
- 					Marburg virus
- Arenaviruses		Lassa fever
- 					“New World Arenaviruses”
- Bunyaviruses	Rift Valley fever (RVF)
- 					Crimean Congo Hemorrhagic fever (CCHF)

## 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)

## VHF: Viruses

- Encapsulated, single stranded RNA viruses
- Similar syndromes; different pathogenesis & treatment
- Persistent in nature: rodents, bats, mosquitoes
- Geographically restricted by host
- Potential infectious hazards from laboratory aerosols

## Filoviruses

- Ebola
- Zaire
- Sudan
- Marburg

## 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

## 1979, 2004

**1994**

**1994, 1996, 1996**

**1976, 1995**

**1996***

**2000**

**1976, 1979, 2004 **

***Doctor returning**
**from Gabon**

**Ebola Outbreaks**

**Congo**
**2003**

## 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 contact
- OR = undefined, p<0.01
- Body fluids
- OR = 3.8, 95%CI (1.9-6.8)
- No contact = no disease

## Suspected EHF cases, DRC, March-June 1995:by Source of Infection

**IDNUM 3**

**IDNUM 2260**

**Other source**

## EHF Cases by Date of Onset and Occupation, Bandundu Region, DRC, 1995

- Non-Healthcare workers

- Healthcare workers

## Marburg

- 1967
- Marburg, Frankfurt, & Belgrade
- 25 primary
- 6 secondary
- 7 deaths
- African green monkeys from Uganda

- 1975
- Australian traveller
- Zimbabwe
- 1 primary
- 2 secondary
- 1 death

## Marburg

- 1980
- Engineer
- N.W. Kenya
- 1 primary
- 1 secondary
- 1 death

- 1987
- Danish traveller
- W. Kenya
- 1 primary
- 1 death

- 1998-200
- Gold mine
- N.E. DRC
- 76 cases
- 52 deaths
- >150 cases through follow-up

## Bunyaviruses

- Rift Valley fever
- Crimean Congo hemorrhagic fever

## Distribution of Rift Valley Fever (RVF) Virus(Countries with outbreak of RVF, periodic isolations of virus, or serologic evidence of RVF 1910-1999)

## Rift Valley Fever

- Disease of sheep and cattle
- Humans: Asymptomatic-to-mild
- Rare VHF, encephalitis, retinitis

## Rift Valley Fever

- Mosquito-borne (*Aedes *spp*.*)
- 	vertical transmission in mosquitos
- Transmission:
- Animal contact (birthing or blood)
- Laboratory aerosol
- Mortality 1% overall
- Therapy:	Ribavirin?
- Live-attenuated vaccine (MP-12) undergoing trials

## Slide 20

## 1997-1998 East Africa Outbreak

- 478 deaths
- 115 VHF deaths
- 9% IgM+
- ~89,000 cases
- 70% animal loss

## 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)

## Slide 23

## RVF: Encephalitis

**Meningeal signs****	****67**
**Confusion****	****81**
**Stupor or coma****	****78**
**Hypersalivation and teeth grinding****	****11**
**Hallucinations****	****43**
**Hemiparesis****	****5**
**Focal Signs****	****27**
**CSF pleocytosis****	****86**
**CSF protein > 40 mg%****	****57**
**Fatal outcome****	****11**
**Residua****	****7**

- * Percent of total from a series of 37 reported cases

**%***

## CRIMEAN CONGO HEMORRHAGIC FEVER(CCHF)

- 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)

## Slide 28

## 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.

## Slide 30

## 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

## CCHF: Slaughterhouses

- Sheep and cattle become viremic without disease
- Blood and fresh tissues infective by contact
- Possibility of establishing transmission of CCHF in holding pens by *Hyalomma* or other tick vectors

## Arenaviruses

- Old world
- Lassa
- New world
- Junin
- Machupo
- Guanarito
- Sabia

## 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
- Myalgia, headache
- Abdominal pain, vomiting
- Facial edema and conjunctivitis
- Mucosal bleeding
- Proteniuria

## Lassa: Clinical features

- Hearing loss, 25%, may be persistent
- Spontaneous abortion

## New World

- Arenaviruses

## Junin (Argentine hemorrhagic fever)

- Argentine pampas, autumn grain harvest
- Rodent borne (*Calomys musculinus*)
- Person-to-person transmission uncommon, sexual transmission documented.
- Mortality 15-20%
- Therapy:	Immune plasma, Ribavirin(?)

## Machupo (Bolivian Hemorrhagic Fever)

- Bolivia, Beni Department
- Rodent borne (*Calomys callosus*)
- Person-to-person transmission probable
- Mortality 20%
- 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

## 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

- 	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

## Ribavirin: indications

- Filoviruses				No
- Rift Valley				No...
- CCHF					Yes
- Lassa					Yes
- Argentine HF				Yes
- Other New world Arena		Maybe

## Ribavirin: toxicities

- Teratogenic
- Extravascular hemolysis
- Bone marrow suppression
- Rigors with abrupt iv administration
- Reversible hyperbilirubinemia, hyperuricemia with oral administration
- Pruritus, nausea, depression, cough

## Infection Control

##  Laboratory safety: BSL-4

- In contrast to patient-care,
- high-level protection required for:
- Laboratory manipulation
- Mechanical generation of aerosols
- Concentrated infectious material
- Viral culture

## 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

## History of Infection Control Precautions

- 1877	Separate facilities for infectious diseases
- 1910	Antisepsis and disinfection
- 1950-60	Closure of Infectious disease and TB hospitals
- 1970	CDC:“Isolation Techniques for use in Hospitals”
- 		(7 categories, “over-isolation”)

## History of Infection Control Precautions

- 1983	CDC Guideline: Isolation Precautions in Hospitals
- 			(Disease-specific + category-based including blood and body-fluids)
- 1985	Universal precautions
- 1987	Body substance isolation

## History of Infection Control Precautions

- 1996		CDC/HICPAC revised guidelines:  				Standard Precautions

## 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.

## 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.

## www.cdc.gov/ncidod/hip/isolat/isolat.htm

- Complete text of the current CDC/HICPAC Isolation Precautions are available on-line.

## www.cdc.gov/ncidod/dvrd/spb/index.htmwww.cdc.gov  “viral hemorrhagic fevers”