Blame It On El Nino

     It’s not just a convenient cover for bizarre X-files phenomena. Hantavirus is real; its incidence is up; and autumn, its most prolific season, is on its way. Sin Nombre Virus, (SNV – or “virus without a name”) was first isolated from rodents collected on the premises of one of the initial HPS patients in the Four Corners region of the Southwestern United States in 1993. But the two diseases attributed to the hantavirus have been around for a long time – only recognized as caused by this group of viruses with the advent of sufficient technology to recognize the etiology.
     The hantaviruses that cause hemorrhagic fever with renal syndrome (HFRS) are carried by Old World rodents, and at least 6 such distinct viruses have so far been recognized. Four of the 8 recognized hantaviruses isolated from American rodents cause hantavirus pulmonary syndrome (HPS). All are considered emerging viruses that tend to appear in unexpected populations; and their number and disease potential are undoubtedly more significant than we are currently able to recognize.
     With only a handful of deaths attributed to it in the outbreak of HPS in 1993 in the Four Corners area, there was not much cause for global concern; but by January of 1995, HPS had been identified in 21 of the United States as well as Canada and Brazil, affecting 102 patients. As of June 22, 1998, the count stands at 185 in the United States, with cases confirmed in Argentina, Brazil, Canada, Chile, Paraguay, and Uruguay, making HPS pan-American zoonosis.
     Climate affects temperature, rainfall, humidity, and storm patterns, which in turn affect 1) distribution and quality of surface water, 2) life cycles of disease vectors, and 3) ecosystem dynamics of predator/prey relationships that control populations of disease vectors. While increases in precipitation favor proliferation of mosquitoes, fungi and owls, drought favors increases in populations of rodents partly because of the decline in owl populations. The original Four Corners outbreak followed the 1991-1992 El Nino patterns, whose climatic extremes ultimately effected increases in rodent populations and thus provided ample vectors for opportunistic microorganisms.
     Prevalence of hantavirus in rodent populations is currently hovering between 10% and 15%, which is below that seen during the 1993 outbreak. This figure follows a seasonal pattern showing increases in the spring followed by a leveling-off during the summer months and another increase to yearly highs in the autumn. Current El Nino conditions foster the belief that rodent populations and attendant prevalence increases may lead to another serious outbreak of the disease in humans this fall with continued elevations in incidence for several years to come.


Table 1. Statistics

Men 61.1%
Women 38.9%
Rural Residents 75%
Age Range 11 to 69 Age Mean 37

Racial/Ethnic Distribution of Cases
White 75.7%
Native American 21.2%
Hispanic 11.4%
Black 2.7%


HFRS

    HFRS attributed to hantaviruses is confined to the Old World, with the Hantaan virus (HTN) as the prototype virus and the Asian striped field mouse (Apdemus agrarius) as its host. Infection of the rodent host appears to cause no disease, and symptoms in humans can take days or weeks to become apparent. Humans affected develop fever and myalgia, flushing, and petechiae (pinpoint, non-raised, perfectly round, purplish red spots caused by intradermal or submucous hemorrhage). Thrombocytopenia, neutrophilia with left shift, atypical lymphocytes and hemoconcentration are common lab findings. Subconjunctival and gastrointestinal hemorrhage, hemodynamic instability, acute renal failure (of uncertain pathology), pulmonary edema, and shock can lead to death.
     The syndrome was first identified in 1951 during an outbreak among U.S. troops in Korea and dubbed “Korean hemorrhagic fever;” and it has since been recognized that some 100,000 people in China suffer the syndrome each year. A number of other hantaviruses are also associated with similar nephropathies throughout the Old World, with identified rodent vectors: Puumala virus (PUU), Belgrade Dobrava virus (DOB), and Seoul virus (SEO). SEO is unique in that its host vector (Rattus norvegicus) has become a worldwide infestation, making HFRS due to SEO a worldwide problem.


HPS Symptomatology

     In the initial outbreak of HPS in 1993, it was termed an unexplained adult respiratory distress syndrome (UARDS), a common pattern of symptoms seen in desperately ill patients with bacterial sepsis or trauma. A prodrome of fever, chills and myalgia is followed in 3 to 5 days by dyspnea, tachypnea, cough, hemodynamic instability, hypoxia, and tachycardia. Though cough and tachypnea usually do not appear before day 7, rapid progression with cardiopulmonary involvement after that typically requires ventilation by the following day. Fatalities are generally associated with severe myocardial depression leading to sinus bradycardia and electromechanical dissociation, fibrillation, or ventricular tachycardia.


Table 2. Other Common Symptoms of HPSShortness of breath Headache

Nausea/vomiting Arthralgia
Unproductive cough Dizziness
Abdominal pain

Diarrhea

Lightheadedness

MalaiseChest or back pain

Sweating



     Radiological examination reveals diffuse interstitial infiltrate; while lab findings include thrombocytopenia, neutrophilia with immature forms, atypical lymphocytes, elevated serum lactate dehydrogenase. Mortality in this initial Four Corners outbreak was about 80%; but with prompt recognition and proper supportive treatment, overall mortality has since been reduced to about 40%. A diagnosis of HPS is unlikely in the presence of conjunctival or other hemorrhages, conjunctival or throat erythema, rashes, petechiae, or periorbital or peripheral edema. Care should be taken to differentiate the pulmonary edema of HPS from that of silent myocardial infarction by early ECG and echocardiogram. Cardiac output in the HPS patients does not respond to fluid challenge, as it does in ARDS.
     CBC and blood chemistry should be examined every 8 to 12 hours for these events:Fluid shift from the circulation into the lungs can be heralded by rising hematocrit and declining serum albumin.Onset of pulmonary edema can be anticipated by elevated white cell count with left shift, percentage of white cell precursors up to 50% with atypical lymphocytes (circulating immunoblasts).Unlike other viral infections, hantavirus may cause left-shifted neutrophilia with circulating myelocytes.The cardiopulmonary phase may also be marked by a drop in platelet count to below 150,000 units.Severe cases can be marked by disseminated intravenous coagulation (DIC).Elevated transaminases, CPK, creatinine, and amylase are not uncommon.Increases in PT (up to 29.8) and PTT (over 240) and fibrin split products (over 4000) are frequent.Atypical lymphocytes, significant bandemia, and thrombocytopenia with pulmonary edema is almost diagnostic of hantavirus infection.Metabolic acidosis, elevated serum lactate levels (over 4.0 mmol/L), cardiac index less than 2.2L/min/m2, and prolonged PT and PTT portend poor prognosis.
     Since hantavirus and HPS are relatively rare, efforts at diagnosis should include screening for other conditions that may mimic the acute cardiopulmonary deterioration seen in HPS. Most of the conditions in this table occur with greater frequency than HPS, so unless there is reason to suspect hantavirus, these are more likely causes of presenting cardiopulmonary symptoms.

Table 3. Other Conditions To
Suspect In The Diagnostic Process

Leptospirosis
Legionnaire’s disease
Mycoplasma
Q fever
Chlamydia
Septicemic plague
Tularemia
Coccidiodomycosis
Histoplasmosis
Goodpasture’s syndrome
Influenza A
Cytomegalovirus
Cryptococcus
Aspergillus
Graft vs. host disease

Virology
  
     Hantaviruses belong to the Bunyavirus family, of which the 5 genera of negative-sensed, single-stranded RNA viruses arthropod-borne except Hantavirus, which is rodent-borne. Enveloped viruses with a genome of three single-stranded RNA segments (designated S, M, and L for small, medium, and large), all hantaviral genes are encoded in the negative (genome complementary) sense. The S RNA encodes the nucleocapsid (N) protein. The M RNA encodes a polyprotein that is cotranslationally cleaved to yield the envelope glycoproteins G1 and G2. The L RNA protein functions as the viral transcriptase/replicase.
     Hantaviruses replicate exclusively in the host cell cytoplasm, entry to which is gained by attachment of virions to cellular receptors followed by endocytosis.


Ecology

     The deer mouse, Peromyscus maniculatus, with wide distribution in New Mexico and California, was identified as the primary reservoir for the Four Corners (FC or SNV) virus in the original outbreak. It is a highly successful species living in peridomestic areas and commonly gaining entrance to homes in search of food. Since then, though, SNV has been identified as the etiologic agent of HPS in areas not inhabited by that rodent species, indicating broader vector populations for that particular virus. At the same time, several other pathogenic varieties of hantavirus have also been identified with their own favorite rodent hosts:Black Creek Canal virus (BCCV) infects the cotton rat, Sigmodon hispidus, with human disease seen in Florida.Bayou virus infects the rice rat, Oryzomys palustris causing human disease in Texas and Louisiana.New York-1 favors the white-footed mouse, Peromyscus leucopus, and Peromyscus maniculatus, causing human disease in the northeastern United States.
     The various genetic similarities between hantaviruses and those of their various rodent hosts lend credence to the idea that the association is long-standing, perhaps even ancient and evolutionary. Thus, the viruses are probably not a product of recent genetic alterations to cause virulence in humans. The emergence of human HPS is more likely a function of ecological proximity between infected rodent vectors and human habitations.


Table 4. Viral Distributions In Rodent Phylogeny

Family: MuridaeSubfamily: MuridaeA. agrarius Rattus norvegicusSubfamily: Arvicolinae

Genus: Microtus – PH, Tula virs (TUL), Isla Vista virus (IV) and Bloodland Lakes virus (BL) – None have proven responsible for HPS in humans.

Genus: Clethrionomys -- PUUSubfamily: Sigmodontinae – BCC, NY-1, FC, Rio Segundo hantavirus (RS), and El MoroHarvest mouse cotton ratwhite-footed mousedeer mouse Canyon hantavirus (EMC). Serological Diagnosis

     Early efforts at viral identification in HPS incorporated antigens derived from cultures of SEO, PUU, HTN, and PH hantaviruses reacting with antibodies for the infecting virus in tissues of patients post-mortem. Results were disappointing; but antigens derived from FC are now available, produced by recombinant DNA technology. The University of New Mexico Health Sciences Center produced a western blot assay of the viral nucleocapsid protein and glycoprotein G1 of the FC; while the CDC’s test is an ELISA (enzyme-linked immunosorbent assay) for expressed recombinant nucleocapsid protein of FC. Though both successfully detect hantavirus, the nucleocapsid antigen is common among a number of hantaviruses, cross-reacting to preclude definitive identification. The FC G1 glycoprotein, though, is unique to FC and thus provides rapid identification of FC in both rodents and humans.


Transmission and Prevention

     Though infection is evidently asymptomatic or even non-pathogenic for the rodent hosts, hantaviruses are shed prolifically in urine, feces, and saliva of infected animals for a period lasting several weeks. It is presumed that the primary means of transmission to humans is via inhalation of viruses in aerosolized rodent excreta or of dried excreta that has become powdered and airborne by disturbance. Transmission should also be viable by introduction of such viral-laden particles of either variety to a human’s broken skin (by simple contact or the bite of an infected rodent), digestive tract (by contaminated hands to mouth or contaminated food or water), or eyes.
    People likely to come into close proximity to rodent excreta, especially in rural areas known to be inhabited by infected animals, should take precautions to avoid such exposure. Those At Risk Of InfectionThose working in fields, barns, or outbuildingsThose entering dwellings previously unoccupied and/or likely inhabited by rodentsThose disturbing rodent-infested areas while camping or hiking
     Though no cases of person-to-person transmission have been documented in this country or in Asia, such transmission was strongly suspected in Argentina during an outbreak in 1996. It is important to note that transmission via infected arthropods (ticks and fleas from infected rodents) or biting insects has never been demonstrated. Nosocomial transmission seems unlikely, so universal precautions are appropriate.


Management

     Since no effective cure is yet available, treatment is supportive:Broad-spectrum antibiotics should be administered to suspected victims until the virus is identified.Early intensive care is essential.Immediate efforts to monitor and correct pulmonary, hemodynamic, and electrolyte disturbances can be effected by Fluid administrationAdministration of inotropic agents to augment myocardial contractility. Dopamine can be given at a rate of 4 to 8 mcg/kg/minute; or dobutamine at 5 to 20 mcg/kg/min.Flow-directed catherization of the pulmonary artery can facilitate detection and monitoring of decreased cardiac index, increased vascular resistance, and low pulmonary wedge pressure.

     Cardiovascular support via ECMO (extracorporeal membrane oxygenation) can enhance survival.Though ribavirin has been used with success in HFRS from Old World hantaviruses, its effectiveness in New World virus infection has not been demonstrated in preliminary trials. It is postulated that symptoms may be more from immune response to infection than to infection itself; or initiation of antiviral therapy may have been too late in the disease process to make a significant clinical impact.


Conclusions

     Though only relatively small numbers of humans are affected by hantavirus infection, the mortality and nature of HPS are severe enough to warrant serious precautions and education efforts in suspected endemic areas. Since a cure is not an immediate reasonable expectation and treatment only supportive, prevention through education is the best policy. Persons likely to contact rodents or rodent excreta in any form, especially in rural or semi-rural areas where hantaviruses have been detected, should take appropriate precautions to avoid such contact. With El Nino weather patterns and the occurrence of cases in 29 states in this country, the affected area should not be underestimated.
     For updates on control, prevention, and treatment, the CDC can be contacted at (404) 332-4565, and official reports are readily available at the CDC website at http://www.cec.gov/ncidod/diseases/hanta/hps/noframes/phys/treat.htm.


References

Hjelle, B. Hantaviruses, with emphais on Four Corners Hantavirus. UNM School of Medicine. http://www.ac.za/microbiology/hanta.html.All About Hantavirus. Technical Information. Centers for Disease Control and Prevention. http://www.cdc.gov/ncidod/diseases/hanta/hps/noframes/epi.htm.Wells, R., et al. Hantavirus Transmission in the United States. Emerging Infectious Diseases 3(3):361-365, 1997. Centers for Disease Control. El Nino: Special Report. El Nino & the Hantavirus: the connection. NOVA Online. http://www.globility.com/~haqiqat/1998elnino.html.