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Hemorrhagic Fevers



Excerpts have been reprinted with permission from the APHA’s Control of Communicable Diseases Manual (CCDM). Please refer to the CCDM for complete information about each disease.


ARENAVIRAL HEMORRHAGIC
FEVERS IN THE WESTERN HEMISPHERE ICD-9 078.7; ICD-10 A96

JUNIN (ARGENTINIAN) HEMORRHAGIC FEVER ICD-10 A96.0
MACHUPO (BOLIVIAN) HEMORRHAGIC FEVER ICD-10 A96.1
GUANARITO (VENEZUELAN) HEMORRHAGIC FEVER ICD-10 A96.8
SABIÁ (BRAZILIAN) HEMORRHAGIC FEVER ICD-10 A96.8

1. Identification – Acute febrile viral illnesses; duration is 7-15 days. Onset is gradual with malaise, headache, retroorbital pain, conjunctival injection, sustained fever and sweats, followed by prostration. There may be petechiae and ecchymoses, accompanied by erythema of the face, neck and upper thorax. An enanthem with petechiae on the soft palate is frequent. Severe infections result in epistaxis, hematemesis, melaena, hematuria and gingival hemorrhage. Encephalopathies, intention tremors and depressed deep tendon reflexes are frequent. Bradycardia and hypotension with clinical shock are common findings, and leukopenia and thrombocytopenia are characteristic. Moderate albuminuria is present, with cellular and granular casts and vacuolated epithelial cells in the urine. Case-fatality rates range from 15% to 30% in untreated individuals. Diagnosis is made through virus isolation or antigen detection in blood or organs; by PCR, or serologically by IgM capture ELISA; or through the detection of neutralizing antibody or rises in the titre thereof by ELISA or IFA. Laboratory studies for virus isolation and neutralizing antibody tests require BSL-4.

2. Infectious agents – Among the 18 known New World arenaviruses belonging to the Tacaribe complex, 4 have been associated with hemorrhagic fever in humans: Junin for the Argentine disease; the closely related Machupo virus for the Bolivian; Guanarito virus for the Venezuelan; and the Sabiá virus for the Brazilian. These viruses are related to the Old World arenaviruses that include the agents of Lassa fever and lymphocytic choriomeningitis. A further virus, Whitewater Arroyo Virus, has been found in rodents in North America.

3. Occurrence – Argentine hemorrhagic fever was first described among corn harvesters in Argentina in 1955. Since then, the number of cases reported from the endemic areas of the Argentine pampa has ranged from 100 to 4000 per year …The region at risk has been expanding northwards and now potentially affects a population of 5 million. Disease occurs seasonally from late February to October, predominantly in males, 63% in the age group 20-49 … Bolivian hemorrhagic fever … occurs sporadically or in epidemics in small villages of rural northeastern Bolivia. In July-September 1994, there were 9 cases with 7 deaths. In 1989, an outbreak of severe hemorrhagic illness occurred in the municipality of Guanarito, Venezuela … To date, about 200 confirmed cases have been reported. Although the virus continued circulating in the rodent population, there was an unexplained drop in human cases between 1992 and 2002 (one outbreak with 18 cases).
Sabiá virus caused a fatal illness with hemorrhage and jaundice in Brazil in 1990, a laboratory infection in Brazil in 1992 and a laboratory infection treated with ribavirin in the USA in 1994.

4. Reservoir – wild rodents … The reservoir of Sabia virus is not known, although a rodent host is presumed.

5. Mode of transmission – Transmission to humans occurs primarily by inhalation of small particle aerosols from rodent excreta containing virus, from saliva or from rodents disrupted by mechanical harvesters. Viruses deposited in the environment may also be infective when secondary aerosols are generated by farming and grain processing, when ingested, or by contact with cuts or abrasions …

6. Incubation period – Usually 7-14 days (in extreme cases 5-21 days).

7. Period of communicability – Rarely transmitted directly from person to person, although this has occurred in both Argentine and Bolivian diseases.

8. Susceptibility – All ages … protective immunity of unknown duration follows infection. Subclinical infections occur.

9. Methods of control
A. Preventive measures: Specific rodent control … An effective live attenuated Junin vaccine has been administered to more than 150 000 persons in Argentina. In experimental animals, this vaccine is effective against Machupo but not Guanarito virus; it is still not known whether it provides effective cross-protection in humans.

B. Control of patient, contacts and the immediate environment:
1) Report to local health authority …
2) Isolation: Strict isolation during the acute febrile period. Respiratory protection may be desirable along with other barrier methods.
3) Concurrent disinfection …
4) Quarantine: Not applicable
5) Immunization of contacts: Not applicable.
6) Investigation of contacts and source of infection: Monitoring and, where feasible, control of rodents.
7) Specific treatment: Convalescent serum given within 8 days of onset reduced the case fatality rate in Argentine disease to less than 1%. Ribavirin is likely to be useful in all 4 diseases …
C. Epidemic measures: Rodent control; consider immunization …

ARTHROPOD-BORNE VIRAL HEMORRHAGIC FEVERS

II.B. OMSK HEMORRHAGIC FEVER ICD-9 065.1; ICD-10 A98.1
KYASANUR FOREST DISEASE ICD-9 065.2; ICD-10 A98.2

1. Identification – These two viral diseases have marked similarities: Onset is sudden with chills, headache, fever, pain in lower back and limbs and severe prostration, often associated with conjunctivitis, diarrhea and vomiting by the 3rd or 4th day. A papulovesicular eruption on the soft palate, cervical lymphadenopathy and conjunctival suffusion are usually present. Confusion and encephalopathic symptoms may occur in patients with Kyasanur Forest disease (KFD); often there is a biphasic course of illness and fever, and the CNS abnormalities develop after an afebrile period of 1-2 weeks.

Severe cases are associated with hemorrhages but with no cutaneous rash. Bleeding occurs from gums, nose, GI tract, uterus and lungs (rarely from the kidneys), sometimes for many days and, when severe, results in shock and death; shock may also occur without manifest hemorrhage. The febrile period ranges from 5 days to 2 weeks, at times with a secondary rise in the third week. Estimated case-fatality rate is from 1% to 10%. Leukopenia and thrombocytopenia are marked. Convalescence tends to be slow and prolonged.

Diagnosis is made through isolation of virus from blood in suckling mice or cell cultures (virus may be present up to 10 days following onset) or through serological tests.

2. Infectious agents – The Omsk hemorrhagic fever (OHF) and KFD viruses are closely related; they belong to the tick-borne encephalitis-louping ill complex of flaviviruses and are similar antigenically to the other viruses in the complex.

3. Occurrence – In the Kyasanur Forest of … Karnataka, India, principally in young adult males exposed in the forest during the dry season, from November to June … OHF occurs in the forest steppe regions of western Siberia, within the Omsk, Novosibirsk, Kurgan and Tjumen regions … Seasonal occurrence in each area coincides with vector activity. Laboratory infections are common with both viruses.

4. Reservoir – In KFD, probably rodents, shrews, and monkeys in combination with ticks; in OHF, rodents, muskrats and ticks.

5. Mode of transmission – Bite of infective (especially nymphal) ticks … direct transmission from muskrat to human occurs, with disease in the families of muskrat trappers.

6. Incubation period – Usually 3-8 days.

7. Period of communicability – Not directly transmitted from person to person …

8. Susceptibility and resistance – Men and women of all ages are probably susceptible; previous infection leads to immunity.

9. Methods of control – … A formalinized mouse-brain virus vaccine has been reported for OHF; tick-borne encephalitis vaccine also has been used to protect against OHF without proof of efficacy. An experimental vaccine has been used to prevent KFD in endemic areas of India.

EBOLA-MARBURG VIRAL DISEASES ICD-9 078.8; ICD-10 A98.4, A98.3
(African hemorrhagic fever, Ebola virus hemorrhagic fever,
Marburg virus hemorrhagic fever)

1. Identification – Severe acute viral illnesses, usually with sudden onset of fever, malaise, myalgia and headache, followed by pharyngitis, vomiting, diarrhea and maculopapular rash. In severe and fatal forms, the hemorrhagic diathesis is often accompanied by hepatic damage, renal failure, CNS involvement and terminal shock with multiorgan dysfunction. Laboratory findings usually show lymphopenia, severe thrombocytopenia and transaminase elevation (AST greater than ALT), sometimes with hyperamylasaemia, elevated creatinine and blood urea nitrogen levels during the final renal failure phase. Case-fatality rates for Ebola infections in Africa have ranged from 50% to nearly 90%; 25%-80% of reported cases of Marburg virus infection have been fatal.

Diagnosis is usually through a combination of assays detecting antigen or RNA and antibody IgM or IgG. RT-PCR or ELISA antigen detection can be used on blood, serum or organ homogenates … Virus isolation attempts in cell culture or suckling mice must be undertaken in a BSL-4 laboratory … Virus may sometimes be visualized in liver, spleen, skin and other tissue sections by EM … Laboratory studies represent an extreme biohazard and should be carried out only where protection against infection of the staff and community is available (BSL-4 containment).

2. Infectious agents – Virions … are respectively members of Ebolavirus and Marburgvirus genus in the family Filoviridae … The Ebola and Marburg viruses are antigenically distinct. In the Republic of Congo, Cote d'Ivoire, the Democratic Republic of the Congo (formerly Zaire), Gabon, Sudan and Uganda, 3 different subtypes of Ebolavirus (Cote d'Ivoire, Sudan and Zaire) have been associated with human disease. A 4th Ebola subtype, Reston, causes fatal hemorrhagic disease in nonhuman primates originated from the Philippines in Asia; few human infections have been documented and those were clinically asymptomatic.

3. Occurrence – Ebola disease was first recognized in 1976 in the western Equatoria province of the Sudan and 800 kilometers away in Zaire (now Democratic Republic of the Congo); more than 600 cases were identified in rural hospitals and villages; the case-fatality rate for these nearly simultaneous outbreaks was respectively about 55% and about 90%. A second outbreak occurred in the same area in Sudan in 1979. A new subtype of Ebola virus was recovered from one person probably infected while dissecting an infected chimpanzee in Coted'Ivoire in 1994. In 1995> a major Ebola outbreak with 315 cases and 244 deaths was centered on Kikwit (Democratic Republic of the Congo, formerly Zaire). Between the end of 1994 and the third trimester of 1996 three outbreaks reported in Gabon resulted in 150 cases and 98 deaths. A fatal secondary infection occurred in a nurse in South Africa.

Between August 2000 and January 2001 an epidemic (425 cases, 224 deaths) occurred in northern Uganda. From October 2001 to April 2003, several outbreaks were reported in Gabon and the Republic of Congo with a total of 278 cases and 235 deaths; high numbers of deaths were reported among wild animals in the region, particularly non-human primates. Antibodies have been found in residents of other areas of sub-Saharan Africa; their relation to the Ebola virus is unknown. End 2003> an outbreak in the Republic of Congo, with high case-fatality and thought to be related to contact with non-human primates, was rapidly controlled. In 2004 the Russian Federation and the USA reported 2 laboratory infections (1 fatal).

Ebolavirus, Reston subtype, have been isolated from cynomolgus monkeys (Macaca fascicularis) imported in 1989, 1990 and 1996 to the USA and in 1992 to Italy from the same export facility Philippines; many of these monkeys died. In Reston, 4 animal handlers with daily exposure to these monkeys in 1989 developed specific antibodies.

Marburg disease has been recognized on 5 occasions: in 1967, in Germany and what was then the Federal Republic of Yugoslavia, 31 humans (7 fatalities) were infected following exposure to African green monkeys (Cercopithecus aethiops) imported from Uganda; in 1975, the fatal index case of 3 cases diagnosed in South Africa had been infected in Zimbabwe; in 1980, 2 linked cases, 1 of which fatal, were confirmed in Kenya; in 1987, a fatal case occurred in Kenya. From 1998 to 2000, in the Democratic Republic of the Congo, at least 12 cases were confirmed among more than 145 suspected cases (case-fatality rate 80%) of Marburg viral hemorrhagic fever.

4. Reservoir – Unknown despite extensive studies …

5. Mode of transmission – Ebola infection of index cases seems to occur (i) in Africa, while manipulating infected wild mammals found dead in the rainforest; (ii) for Ebola Reston, while handling infected cynomolgus monkeys through direct contact with their infected blood or fresh organs. Person-to-person transmission occurs through direct contact with infected blood, secretions, organs or semen. Risk is highest during the late stages of illness … and during funerals with unprotected body preparation. Risk during the incubation period is low … Nosocomial infections have been frequent; virtually all patients who acquired infection from contaminated syringes and needles died. Transmission through semen has occurred 7 weeks after clinical recovery.

6. Incubation period – Probably 2 to 21 days for both Ebola and Marburg virus disease.

7. Period of communicability – Not before the febrile phase and increasing with stages of illness, as long as blood and secretions contain virus. Ebola virus was isolated from the seminal fluid on the 61st, but not on the 76th, day after onset of illness in a laboratory acquired case.

8. Susceptibility – All ages are susceptible.

9. Methods of control – No vaccine and no specific treatment available as yet for either Ebola or Marburg. See control measures for Lassa fever: 9B, C, D and E; plus protection of sexual intercourse for 3 months or until semen can be shown to be free of virus.


DENGUE FEVER ICD-9 061; ICD-10 A90

(Breakbone fever)



1. Identification – An acute febrile viral disease characterized by sudden onset, fever for 2-7 days (sometimes biphasic), intense headache, myalgia, arthralgia, retro-orbital pain, anorexia, nausea, vomiting and rash. Early generalized erythema occurs in some cases. A generalized maculopapular rash may appear about the time of defervescence. Rash is frequently not visible in dark-skinned patients. Minor bleeding phenomena, such as petechiae, epistaxis or gum bleeding may occur at any time during the febrile phase. With underlying conditions, adults may have major bleeding phenomena, such as GI hemorrhage in peptic ulcer cases or menorrhagia. These should be differentiated from dengue infections and DHF with increased vascular permeability, bleeding manifestations and involvement of specific organs. Recovery may be associated with prolonged fatigue and depression. Lymphadenopathy and leukopenia with relative lymphocytosis are usual; mild thrombocytopenia (less than 100 X 103 cells per mm3; or 100 SI units X 109 per L) and elevated transaminases occur less frequently. Epidemics are explosive, but fatalities are rare.

Differential diagnosis includes chikungunya and other epidemiologically relevant diseases listed under arthropod-borne viral fevers, influenza, measles, rubella, malaria, leptospirosis, typhoid, scrub typhus and other systemic febrile illnesses, especially those accompanied by rash.

Laboratory confirmation of dengue infection is through detection of virus either in acute phase blood/serum within 5 days of onset or of specific antibodies in convalescent phase serum obtained 6 days or more after onset of illness … The IgM capture ELISA is the most commonly used serological procedure for diagnosis … A positive test result in a single serum indicates presumptive recent infection; a definitive diagnosis requires increased antibody levels in paired sera … PCR with specific primers can distinguish among the dengue virus serotypes; PCR with nucleotide sequencing and restriction enzyme analysis can characterize dengue strains and genotypes.


2. Infectious agent – The viruses of dengue fever are flaviviruses and include serotypes 1, 2, 3 and 4 (dengue-1, -2, 3, -4).

3. Occurrence – Dengue viruses of multiple types are endemic in most countries in the tropics. In Asia, 2-5 year dengue/DHF epidemic cycles are established in southern Cambodia, China, Indonesia, Lao Democratic Republic, Malaysia, Myanmar, the Philippines, Thailand and

Viet Nam, with increasing epidemic activity and geographic spread in Bangladesh, India, Maldives, Pakistan, and Sri Lanka, and lower endemicity in New Guinea, Singapore and Taiwan (China). Dengue viruses of several types have regularly been reintroduced into the Pacific and into northern Queensland, Australia, since 1981. Dengue-1, -2, 3 and -4 are endemic in Africa. In large areas of western Africa, dengue viruses are probably transmitted epizootically in monkeys … In recent years, outbreaks of dengue fever have occurred on the eastern coast of Africa from Ethiopia to Mozambique and on offshore islands such as the Comoros and the Seychelles, with a small number of dengue and DHF-like cases reported from the Arabian peninsula. Successive introduction and circulation of all 4 serotypes in tropical and subtropical areas of the Americas has occurred since 1977; dengue entered Texas in 1980, 1986, 1995 and 1997. As of the late 1990s, two or more dengue viruses are endemic or periodically epidemic in virtually all of the Caribbean and Latin America including Brazil, Bolivia, Colombia, Ecuador, the Guyanas, Mexico, Paraguay, Peru, Suriname, Venezuela, and central America. Dengue was introduced into Easter Island, Chile in 2002 and reintroduced into Argentina at the northern border with Brazil. Epidemics may occur wherever vectors are present and virus is introduced, whether in urban or rural areas.

4. Reservoir – The viruses are maintained in a human/Aedes aegypti mosquito cycle in tropical urban centers; a monkey/mosquito cycle may serve as a reservoir in the forests of southeastern Asia and western Africa.

5. Mode of transmission – Bite of infective mosquitoes, principally Ae. aegypti …

6. Incubation period – From 3 to 14 days, commonly 4-7 days.

7. Period of communicability – No direct person-to-person transmission. Patients are infective for mosquitoes from shortly before the febrile period to the end thereof, usually 3-5 days. The mosquito becomes infective 8-12 days after the viraemic blood-meal and remains so for life.

8. Susceptibility – Susceptibility in humans is universal, but children usually have a milder disease than adults. Recovery from infection with one serotype provides lifelong homologous immunity but only short-term protection against other serotypes and may exacerbate disease upon subsequent infections (see Dengue hemorrhagic fever).

9. Methods of control

A. Preventive measures:

1) Educate the public and promote behaviours to remove, destroy or manage mosquito vector larval habitats … e.g. old tires, flowerpots, discarded containers for food or water storage.

2) Survey the community to determine the abundance of vector mosquitoes, identify the most productive larval habitats, promote and implement plans for their elimination, management or treatment with appropriate larvicides.

3) Personal protection against day biting mosquitoes …


B. Control of patient, contacts and the immediate environment:

1) Report to local health authority: Obligatory report of epidemics

2) Isolation: Blood precautions. Until the fever subsides, prevent access of day biting mosquitoes to patients by screening the sickroom or using a mosquito bednet, preferably insecticide-impregnated, for febrile patients, or by spraying quarters with a knockdown adulticide or residual insecticide.

3) Concurrent disinfection: Not applicable.

4) Quarantine: Not applicable.

5) Immmunization of contacts: Not applicable …

6) Investigation of contacts and source of infection: Determine patient's place of residence during the 2 weeks before onset of illness and search for unreported or undiagnosed cases.

7) Specific treatment: Supportive, including oral rehydration. Acetylsalicylic acid (aspirin) is contraindicated because of its hemorrhagic potential.


C. Epidemic measures:

1) Search for and destroy Aedes mosquitoes in sites of human habitation, and eliminate or apply larvicide to all potential Ae. aegypti larval habitats.

2) Use mosquito repellents for people exposed to vector mosquitoes.

D. Disaster implications: Epidemics can be extensive …

E. International measures: Enforce international agreements designed to prevent the spread of Ae. aegypti via ships, airplanes and land transport. Improve international surveillance and exchange of data between countries. WHO Collaborating Centres … Further information on http://www.who.int/denguenet and http://www.who.int/health_topics/dengue/en.





DENGUE HEMORRHAGIC FEVER/ DENGUE SHOCK SYNDROME (DHF/DSS) ICD-9 065.4; ICD-10 A91



1. Identification – A severe mosquito-transmitted viral illness endemic in much of southern and southeastern Asia, the Pacific and Latin America, characterized by increased vascular permeability, hypovolaemia and abnormal blood clotting mechanisms. It is recognized principally in children but occurs also in adults. The WHO proposed case definition for

DHF is: (1) fever or history of recent fever lasting 2-7 days; (2) thrombocytopenia; 100 X 103/mm3 or less (SI units 100 X 109/L or less); (3) at least 1 of the following hemorrhagic manifestations: positive tourniquet test, petechiae/ecchymoses/purpura/hematemesis/melaena, other overt bleeding; (4) evidence of plasma leakage by at least 1 of the following: (>20% rise in hematocrit or >20% drop in hematocrit following volume replacement, pleural effusion, ascites, hypoproteinaemia). Dengue shock syndrome (DSS) includes all above criteria plus signs of shock: (1) rapid, weak pulse; (2) narrow pulse pressure (less than 20 mm Hg); (3) hypotension for age; (4) cold, clammy skin and restlessness. Prompt oral or intravenous fluid therapy may reduce hematocrit rise and require alternate observations to document increased plasma leakage.

Illness begins abruptly with fever and, in children, mild upper respiratory complaints, often anorexia, facial flush and mild GI disturbances. Coincident with defervescence and decreasing platelet count, the patient's condition suddenly worsens in severe cases, with marked weakness, restlessness, facial pallor and often diaphoresis, severe abdominal pain and circumoral cyanosis. The liver may be enlarged, with occasional tenderness just before shock. Warning signs include intense continuous abdominal pain with persistent vomiting.

Hemorrhagic phenomena occur frequently (see earlier). GI hemorrhage is an ominous sign that usually follows a prolonged period of shock. In severe cases, findings include accumulation of fluids in serosal cavities, low serum albumin, elevated transaminases, a prolonged prothrombin time and low levels of C3 complement protein. DHF cases with severe liver damage (with or without encephalopathy) have been observed during large epidemics of dengue-3 in Indonesia and Thailand. Case-fatality rates in mistreated shock have been as high as 40%-50%; with good physiological fluid replacement therapy, rates should be 1%-2%.

Serological tests show a rise in antibody titre against dengue viruses … Infection with dengue viruses with or without hemorrhagic manifestations is covered above …

2. Infectious agent – See Dengue fever. All 4 dengue serotypes (in descending order of frequency: types 2, 3, 4 and 1) can cause DHF/DSS.

3. Occurrence – Recent epidemics of DHF have occurred in Asia … and in the Americas … In an unprecedented pandemic in 1998, 56 countries reported 1.2 million cases of dengue and DHF. In tropical Asia, DHF/DSS is observed primarily among children of the local population under 15. In outbreaks in the Americas, the disease is observed in all age groups although two-thirds of fatalities occur among children. Malaysia, the Philippines, and Thailand report an increase in the number of DHF adult cases. Occurrence is greatest during the rainy season and in areas of high Ae. aegypti prevalence.

4., 5., 6. and 7. Reservoir, Mode of transmission, Incubation period and Period of communicability – See Dengue fever.

8. Susceptibility – The best-described risk factor is the circulation of heterologous dengue antibody, acquired passively in infants or actively from an earlier infection. Such antibodies may enhance infection of mononuclear phagocytes through the formation of infectious immune complexes. Geographic origin of dengue strain, age, gender and human genetic susceptibility are also important risk factors …

9. Methods of control

A. Preventive measures: See Dengue fever.

B. Control of patient, contacts and immediate environment:

1), 2), 3), 4), 5) and 6) Report to local health authority, Isolation, Concurrent disinfection, Quarantine, Immunization of contacts and Investigation of contacts and source of infection: See Dengue fever.

7) Specific treatment: Hypovolaemic shock resulting from plasma leakage often responds to oxygen therapy and rapid replacement with fluid and electrolyte solution (lactated Ringer solution or physiological saline at 10-20 ml/kg/hour). In more severe cases of shock, plasma and/or plasma expanders should be used … A continued rise in hematocrit value in the presence of vigorous IV fluid administration indicates a need for plasma or other colloid … Aspirin is contraindicated because of its hemorrhagic potential.

G, D, and E. Epidemic measures, Disaster implications and

International measures: See Dengue fever.



HANTAVIRAL DISEASES
Hantaviruses infect rodents worldwide; several species are known to infect humans with varying severity, with primary impact effect on the vascular endothelium, resulting in increased vascular permeability, hypotensive shock and hemorrhagic manifestations. Many of these agents have been isolated from rodents but are not associated with human cases. In 1993, an outbreak of disease caused by a previously unrecognized hantavirus occurred in the USA; the principal target organ was not the kidney (the usual target organ in human hantaviral infections) but the lung. Because they are caused by related causal organisms and have similar features of epidemiology and pathology (febrile prodrome, thrombocytopenia, leukocytosis and capillary leakage), both the renal and the pulmonary syndrome are presented under Hantaviral diseases.

I. HEMORRHAGIC FEVER WITH RENAL SYNDROME ICD-9 078.6; ICD-10 A98.5
(Epidemic hemorrhagic fever, Korean hemorrhagic fever,
Nephropathia epidemica, Hemorrhagic nephrosonephritis, HFRS)

1. Identification – Acute zoonotic viral disease with abrupt onset of fever, lower back pain, varying degrees of hemorrhagic manifestations and renal involvement. Severe illness is associated with Hantaan (primarily in Asia) and Dobrava viruses (in the Balkans). Disease is characterized by 5 clinical phases which frequently overlap: febrile, hypotensive, oliguric, diuretic and convalescent. High fever, headache, malaise and anorexia, followed by severe abdominal or lower back pain, often accompanied by nausea and vomiting, facial flushing, petechiae and conjunctival injection characterize the febrile phase, which lasts 3-7 days. The hypotensive phase lasts from several hours to 3 days and is characterized by defervescence and abrupt onset of hypotension, which may progress to shock and more apparent hemorrhagic manifestations. Blood pressure returns to normal or is high in the oliguric phase (3-7 days); nausea and vomiting may persist, severe hemorrhage may occur and urinary output falls dramatically.

The majority of deaths (the case-fatality rate ranges from 5% to 15%) occur during the hypotensive and oliguric phases. Diuresis heralds the onset of recovery in most cases, with polyuria of 3-6 liters per day. Convalescence takes weeks to months.

A less severe illness (case-fatality rate < 1%) caused by Puumala virus and referred to as nephropathia epidemica is predominant in Europe. Infections caused by Seoul virus … are clinically milder, although severe disease may occur with this strain. They show less clear distinction between clinical phases.

Diagnosis is through demonstration of specific antibodies using ELISA or IFA; most patients have IgM antibodies at the time of hospitalization. The presence of proteinuria, leukocytosis, hemoconcentration, thrombocytopenia and elevated blood urea nitrogen supports the diagnosis … Leptospirosis and rickettsioses must be considered in the differential diagnosis.

2. Infectious agent – Hantaviruses (a genus of the family Bunyaviridae, the only genus without an arthropod vector) … More than 25 antigenically distinguishable viral species exist, each associated primarily with a single rodent species …

3. Occurrence – Prior to World War II, Japanese and Soviet authors described the disease in Manchuria along the Amur River. In 1951, it was recognized among United Nations troops in Asia and later in both military personnel and civilians-the virus was first isolated from a field rodent (Apodemus agrarius) in 1977 near the Hantaan river. The disease is considered a major public health problem in China and the Republic of Korea. Occurrence is seasonal, most cases occurring in late autumn and early winter, primarily among rural populations. In the Balkans, a severe form of the disease due to Dobrava virus affects a few hundred people annually, with fatality rates at least as high as those in Asia (5%-15%). Most cases there are seen during spring and early summer.

Nephropathia epidemica, due to Puumala virus, is found in most of Europe, including the Balkans and the Russian Federation West of the Ural mountains. It is often seen in summer and in the autumn and early winter. Seasonal occupational and recreational activities probably influence the risk of exposure, as do climate and other ecological factors of rodent population densities. Among medical research personnel and animal handlers in Asia and Europe, the disease has been traced to laboratory rats infected with Seoul virus, which has been identified in captured urban rats worldwide, including Argentina, Brazil, Thailand and USA; only in Asia has it been regularly associated with human disease. The availability of newer diagnostic techniques has led to increasing recognition of hantaviruses and hantaviral infections.

4. Reservoir – Field rodents … Humans are accidental hosts.

5. Mode of transmission – Presumed aerosol transmission from rodent excreta … though this may not explain all human cases or all forms of inter-rodent transmission. Virus occurs in urine, feces and saliva of persistently infected asymptomatic rodents, with maximal virus concentration in the lungs. Nosocomial transmission of hantaviruses has been documented but is believed rare.

6. Incubation period – From a few days to nearly 2 months, usually 2-4 weeks.

7. Period of communicability – Not well defined. Person-to-person transmission is rare.

8. Susceptibility – Persons without serological evidence of past infection appear to be uniformly susceptible. Inapparent infections occur; second attacks have not been documented.

9. Methods of control

A. Preventive measures:
1) Exclude and prevent rodent access to houses and other buildings.
2) Store human and animal food under rodent-proof conditions.
3) Disinfect rodent-contaminated areas by spraying a disinfectant solution (e.g. diluted bleach) prior to cleaning. Do not sweep or vacuum rat-contaminated areas; use a wet mop or towels moistened with disinfectant. In so far as possible, avoid inhalation of dust by using approved respirators when cleaning previously unoccupied areas.
4) Trap rodents and dispose using suitable precautions. Live trapping is not recommended.
5) In enzootic areas, minimize exposure to wild rodents and their excreta.
6) Laboratory rodent colonies … must be tested to ensure freedom from asymptomatic hantavirus infection.

B. Control of patients, contacts and the immediate environment:
1) Report to local health authority: In endemic countries where reporting is required …
2) Isolation: Not applicable.
3) Concurrent disinfection: Not applicable.
4) Quarantine: Not applicable.
5) Immmunization of contacts: Not applicable.
6) Investigate contacts and source of infection: Exterminate rodents in and around households if feasible.
7) Specific treatment: Bed rest and early hospitalization are critical. Jostling and the effect of lowered atmospheric pressures during airborne evacuation of cases can be deleterious to patients critically ill with hantavirus. Careful attention to fluid management is important to avoid overload and minimize the effects of shock and renal failure. Dialysis is often required. Ribavirin IV as early as possible during the first few days of illness has shown benefit.

C. Epidemic measures: Rodent control; surveillance for hantavirus infections in wild rodents. Laboratory-associated outbreaks call for evaluation of the associated rodents and, if positive, elimination of the rodents and thorough disinfection.

D. Disaster implications: Natural disasters and wars often result in increased numbers of rodents and rodent contact with humans.

E. International measures: Control transport of exotic reservoir rodents.


II. HANTAVIRUS PULMONARY SYNDROME ICD-9 480.8; ICD-10 B33.4
(Hantavirus adult respiratory distress syndrome, Hantavirus
cardiopulmonary syndrome)

1. Identification – An acute zoonotic viral disease characterized by fever, myalgias and GI complaints followed by the abrupt onset of respiratory distress and hypotension. The illness progresses rapidly to severe respiratory failure and shock. Most cases show an elevated hematocrit, hypoalbuminaemia and thrombocytopenia. The crude fatality rate is approximately 40%-50%. In survivors, recovery from acute illness is rapid, but full convalescence may require weeks to months. Restoration of normal lung function generally occurs, but pulmonary function abnormalities may persist in some individuals. Renal and hemorrhagic manifestations are usually absent except in some severe cases.

Diagnosis is through demonstration of specific IgM antibodies using ELISA, Western blot or strip immunoblot techniques. Most patients have IgM antibodies at the time of hospitalization. PCR analysis of autopsy or biopsy tissues and immunohistochemistry in specialized laboratories are also established diagnostic techniques.

2. Infectious agents – Many hantaviruses have been identified in the Americas: Andes virus (Argentina, Chile), Laguna Negra virus (Bolivia, Paraguay), Juquitiba virus (Brazil), Black Creek Canal and Bayou viruses (southeastern USA), New York-1 and Monongahela viruses (eastern USA). Sin Nombre virus was responsible for the 1993 epidemic in southwestern USA and many other cases in North America.

3. Occurrence – The disease was first recognized in the spring and summer of 1993 among resident Native American populations; cases have been confirmed in Canada and in many eastern and western regions of the USA. Sporadic cases and several outbreaks have been reported in South America … The disease is not restricted to any ethnic group. Incidence appears to coincide with the geographic distribution and population density of infected carrier rodents and their infection levels.

4. Reservoir – The major reservoir of Sin Nombre virus appears to be the deer mouse … Other hantavirus strains have been associated mainly with other rodent species of the subfamily Sigmodontinae.

5. Mode of transmission – As with hantaviral hemorrhagic fever with renal syndrome, aerosol transmission from rodent excreta is presumed. The natural history of viral infections of host rodents has not been characterized. Indoor exposure in closed, poorly ventilated homes, vehicles and outbuildings with visible rodent infestation is especially important.

6. Incubation period – Incompletely defined … approximately 2 weeks with a range of a few days to 6 weeks.

7. Period of communicability – Person-to-person spread of hantaviruses has been reported during an outbreak in Argentina.

8. Susceptibility – All persons without prior infection are presumed to be susceptible. No inapparent infections have been documented to date, but milder infections without frank pulmonary oedema have occurred. No second cases have been identified, but the protection and duration of immunity conferred by previous infection is unknown.

9. Methods of control

A. Preventive measures: See section I, 9A.

B. Control of patient, contacts and the immediate environment:
1), 2), 3), 4), 5) and 6) Report to local health authority, Isolation, Concurrent disinfection, Quarantine, Immunization of contacts and Investigation of contacts and source of infection-See section I, 9B1 through 9B6.
7) Specific treatment: Provide respiratory intensive care management, carefully avoid overhydration that might lead to exacerbation of pulmonary oedema. Cardiotonic drugs and pressors given early under careful monitoring help prevent shock. Strictly avoid hypoxia, particularly if transfer is contemplated. Ribavirin is under investigation and as yet of no proven benefit. Extracorporeal membrane oxygenation has been used with some success.

C. Epidemic measures: Public education regarding rodent avoidance and rodent control in homes is desirable in endemic situations and should be intensified during epidemics … See section I, 9C.

D. Disaster implications: See section I, 9D.

E. International measures: Control transport of exotic reservoir rodents.


LASSA FEVER ICD-9 078.8; ICD-10 A96.2

1. Identification – Acute viral illness of 1-4 weeks duration. Onset is gradual, with malaise, fever, headache, sore throat, cough, nausea, vomiting, diarrhea, myalgia and chest and abdominal pain … Inflammation and exudation of the pharynx and conjunctivae are common. About 80% of human infections are mild or asymptomatic; the remaining cases have severe multisystem disease. Disease is more severe in pregnancy; fetal loss occurs in more than 80% of cases. In severe cases, hypotension or shock, pleural effusion, hemorrhage, seizures, encephalopathy and oedema of the face and neck are frequent, often with albuminuria and hemoconcentration. Early lymphopenia may be followed by late neutrophilia. Platelet counts are moderately depressed, but platelet function is abnormal. Transient alopecia and ataxia may occur during convalescence, and eighth cranial nerve deafness occurs in 25% of patients, of whom only half recover some function after 1-3 months. The overall case-fatality rate is about 1%, up to 15% among hospitalized cases and even higher in some epidemics. The rate is particularly high among women in the third trimester of pregnancy and fetuses. AST levels above 150 and high viraemia are of poor prognosis. Inapparent infections, diagnosed serologically, are common in endemic areas.
Diagnosis is through IgM antibody capture and antigen detection (ELISA) or detection of the viral genome by PCR; isolation of virus from blood, urine or throat washings; and IgG seroconversion by ELISA or IFA. Laboratory specimens must be handled with extreme care including BSL-4 containment, if available. Heating serum at 60°C (140°F) for 1 hour will
largely inactivate the virus, and the serum can then be used to measure heat-stable substances such as electrolytes, blood urea nitrogen or creatinine.

2. Infectious agent – Lassa virus, an arenavirus, serologically related to lymphocytic choriomeningitis, Machupo, Junin, Guanarito and Sabia viruses.

3. Occurrence – Endemic in Guinea, Liberia, regions of Nigeria, and Sierra Leone …

4. Reservoir – Wild rodents …

5. Mode of transmission – Primarily through aerosol or direct contact with excreta of infected rodents deposited on surfaces such as floors and beds or in food and water. Laboratory infections occur … through inoculation with contaminated needles and through the patient's pharyngeal secretions or urine. Infection can also spread from person to person by sexual contact.

6. Incubation period – Commonly 6-21 days.

7. Period of communicability – Person-to-person spread may theoretically occur during the acute febrile phase when virus is present in the throat. Virus may be excreted in urine of patients for 3-9 weeks from onset of illness.

8. Susceptibility – All ages are susceptible; the duration of immunity following infection is unknown.

9. Methods of control
A. Preventive measures: Specific rodent control.

B. Control of patient, contacts and the immediate environment:
1) Report to local health authority: Individual cases should be reported …
2) Isolation: Institute immediate strict isolation in a private hospital room … strict procedures for isolation of body fluids and excreta must be maintained. Recourse to a negative pressure room and respiratory protection is desirable, if possible. Male patients should refrain from unprotected sexual activity until the semen has been shown to be free of virus or for 3 months … laboratory tests should be kept to the minimum necessary for proper diagnosis and patient care, and only performed where full infection control measures are correctly implemented. Technicians must be alerted to the nature of the specimens and supervised ... Dead bodies should be sealed in leakproof material and cremated or buried promptly in a sealed casket.
3) Concurrent disinfection: Patient's excreta, sputum, blood and all objects with which the patient has had contact, including laboratory equipment used to carry out tests on blood, must be disinfected with 0.5% sodium hypochlorite solution or 0.5% phenol with detergent, and, as far as possible, effective heating methods, such as autoclaving, incineration, boiling or irradiation, as appropriate …
4) Quarantine: Only surveillance is recommended for close contacts (see 9B6).
5) Immunization of contacts: Not applicable.
6) Investigation of contacts and source of infection: Identify all close contacts (people living with, caring for, testing laboratory specimens from or having noncasual contact with the patient) in the 3 weeks after the onset of illness. Establish close surveillance of contacts as follows: body temperature checks at least 2 times daily for at least 3 weeks after last exposure. In case of temperature above 38.3°C (101°F), hospitalize immediately in strict isolation facilities. Determine patient's place of residence during 3 weeks prior to onset; search for unreported or undiagnosed cases.
7) Specific treatment: Ribavirin, most effective within the first 6 days of illness, should be given IV, 30 mg/kg initially, followed by 15 mg/kg every 6 hours for 4 days and 8 mg/kg every 8 hours for 6 additional days.

C. Epidemic measures: Rodent control; adequate infection control and barrier nursing measures in hospitals and health facilities; availability of ribavirin; contact tracing and follow-up.

D. Disaster implications: …

E. International measures: Notification of source country and to receiving countries of possible exposures by infected travellers. WHO Collaborating Centres.