Hantavirus

51 Infectious Diseases Newsletter 10(6) June 1991 lysis-centrifugation-derived blood culture plates. It differs from previously described pathogens, but its fastidious nature and resemblence to R. quintana in cellular fatty acid composition suggest it may be a cultivable rickettsia. Its prevalence, habitat, and mechanism of pathogenesis remain largely undetermined. It is a pathogen that should be sought in the

setting of cryptogenic fever, especially in persons with defective cellmediated immunity.

Bibliography Lucey D, Dolan M, Garcia M, et al: Bacteremia with a Gram-negative rod reactive with antisera to the cat scratch bacillus. Abstracts of the 30th Interscience Conference on Antimicrobial

Agents and Chemotherapy. Am Soc Microbiol 566:180, 1990. Slater LN, Welch DF, Hensel D, Coody DW: A newly recognized fastidious Gram-negative pathogen as a cause of fever and bacterernia. N Engl J Med 323:1987-1993, 1990. Address correspondence to Leonard N. Slater, MD, Oklahoma Memorial Hospital, South Pavilion, P.O. Box 26901, Oklahoma City, OK 73190,

Hantavirus John Sinnott, IV, MD, FACP, Lowella Esperanza, BS, Douglas A. Holt, MD, Frank Thompson, BS Department of Internal Medicine, The University of South Florida College of Medicine, Tampa, Florida

During the Korean conflict a dramatic epidemic of renal failure of unknown cause afflicted the more than 3,000 American men and women in the service there. Clinically, the mysterious malady was characterized by the abrupt onset of fever, coagulopathy, hypotension, and renal failure. Ironically, although this syndrome was initially unrecognized by Western medicine, it had been described over 1,000 years previously in China. Furthermore, recent episodes of the illness had also been noted in the 1930s by both Japanese physicians in Manchuria and by Russian physicians in Siberia. After its "official" recognition in Korea, the syndrome eventually became known as "Korean Hemorrhagic Fever." The collective name, hemorrhagic fever with renal syndrome (HFRS), designates this and other similar illnesses caused by a number of closely related viruses-the Hantaviruses.

Etiology and Epidemiology The etiology of HFRS remained elusive until 1976 when an enveloped virus was isolated from lung specimens harvested from infected Korean field mice. This agent, named after the Hantaan River in Korea, is a rodent-borne RNA virus belonging to the Bunyaviridae family. It is anti-

genically related to viruses subsequently isolated from humans and rodents. Four distinct hantaviruses have been identified thus far: Hantaan, Seoul, Puumala, and Prospect Hill. The known Hantavirus group is the exception to the rule that members of the Bunyaviridae require arthropod vectors to spread. All of the Hantaviruses are maintained in nature as asymptomatic chronic infection in rodent hosts. Infection results in a short-lived viremia with dissemination to various tissues, especially the lung, salivary gland, and kidney. Despite the development of a neutralizing antibody, antigen expression and viral excretion is often persistent. The virus from infected animals is shed in urine, feces, and saliva with transmission to humans occuring through direct contact or by inhalation of infected rodent excretions. Vertical transmission does not occur in Hanta-virus-infected rodents. Hantaan virus, the prototype for agents causing HFRS, is the cause of the most severe form of the disease and is geographically clustered in Korea, China, and Southeastern Siberia. The striped field mouse, Apodemus agrarius, is the rodent host for this agent. Two epidemic peaks of human disease are observed, with one beginning in the spring, and the other © 1991 Elsevier Science Publishing Co., Inc. 0278-2316/91/$0.00 + 2.20

commencing in the fall. At the time of these outbreaks, the mice are reproductively active and spend more time outside of their burrows, exposing farmers who are working in the fields. Dry summer weather enhances the aerosol transmission of virus. During the winter months, mice seek shelter in houses and barns. This increased proximity to humans probably increases the opportunity for viral transmission by contact. In general, disease caused by the Hantaan strain affects individuals 20-50 years of age. Although the disease occurs in both sexes, there is a higher incidence in males. Individuals in close contact with infected rodents in urban, rural, and laboratory environments are at particular risk. The Seoul strain of the virus is responsible for urban cases of HFRS in Asia and laboratory-acquired illness worldwide. It has been isolated from domestic rats, both Rattus rattus and R. norvegicus, and is the cause of a generally less severe form of HFRS. These rats are globally distributed but apparently they spread disease only in limited areas of Asia in which the virus is endemic. The reason for this is unclear. The virus isolated from the bank vole, Clethrionomys glareolus, is now

52 Infectious Diseases NewsLetter I()(0) June 1991

known as Puumala virus. Nephropathia epidemica, a mild form of HFRS endemic in Europe, Scandinavia, and the western Soviet Union, is seemingly caused by this pathogen. Usually patients with nephropathia epidemica have visited a summer cabin in which voles have nested, or cite a history of exposure to infested barns or basements. The peak incidence of illness in Scandinavia correlates with increased human-rodent contact; this occurs in late fall and early winter, when voles invade man-made structures, and in mid-to-late summer, when human outdoor activity increases. Prospect Hill virus was first isolated from a meadow vole, Microtus pennsylvanicus, in Maryland. It is not known to cause human illness, although some surveys have found serologic evidence of human exposure to this agent. Clinical Manifestations The hallmark of Hantaan (murine) infection, the most virulent hantavirus, is a characteristic clinical triad of fever, hemorrhage, and renal insufficiency. The incubation period ranges from 9 to 35 days. In severe forms, the illness typically progresses through five phases; febrile, hypotensive, oliguric, diuretic, and convalescent. The initial symptoms are those of a nondescript, acute, febrile illness with fever, chills, headache, myalgias, and general malaise. After several days of these complaints, hypotension develops abruptly and oliguria ensues with varying degrees of renal insufficiency. Severe proteinuria commonly occurs at this time. Hemorrhagic manifestations are most prominent during the hypotensive and oliguric phases and include conjunctival injection, palatal petechiae, epistaxis, hematemesis, and persistent bleeding from venipuncture sites. Clinically, significant bleeding, such as central nervous system hemorrhage, occurs in about 10% of severely ill patients. The onset of recovery is heralded by the diuretic

phase, with peak urine volumes that reach 3-6 L/day. Convalescence may take several months and renal function usually returns to normal. The fatality rate in Hantaan HFRS averages about 6%, with one-third occuring during the shock phase and two-thirds occuring during the renal phases of illness when stroke and congestive heart failure are common. Unlike Hantaan infection, less severe forms of the illness are seen with Seoul or Puumala infection. These infections demonstrate less tendency toward hemorrhage, shock, and renal failure with correspondingly lower rates of fatality. Most studies have found < 1% mortality in patients infected with these other agents.

Pathophysioiogy Vascular damage leading to vascular dilatation and increased permeability appears to be the primary pathologic lesion in HFRS. This permeability with subsequent loss of plasma from the vascular space results in hypotension. The same mechanism presumably acts on the renal vasculature thereby reducing concentrating ability. The marked reductions in renal plasma flow and decreased glomerular filtration rate associated with systemic hypotension further aggravate the renal insult. Hemorrhage occurs both as a result of the vascular abnormality and on occasion from uremic platelet dysfunction. The process producing the vascular lesion is not understood at this time. Some have postulated immune-complex-mediated injury to the vasculature but direct viral infection of endothelial cells is also a possibility.

Diagnosis Because of the diverse spectrum of signs and symptoms, the diagnosis of hemorrhagic fever with renal syndrome is usually not made on clinical grounds alone. Diagnosis is primarily based upon serologic studies. A fourfold rise in IgG antibody titer to Hantavirus during a l-week interval can be detected by assaying paired © 1991 Elsevier Science Publishing Co., Inc. 0278-2316/91/$0.00 + 2.20

sera specimens with indirect fluorescent antibody technique. Specific lgM antibodies to Hantaan virus in human serum can also be tbund by ELISA. This is of significant clinical value as the IgM can be detected in patients in a single assay early in the course of infection. Both of these methods are simple, rapid, and sensitive for identifying Hantavirus group antibodies. Neither EL1SA nor immunofluorescent methods can distinguish between the different hantaviruses. Specific identification of the hantavirus type involved requires more elaborate studies that are not readily available. Detection of serum IgM Hantavirus antibodies by ELISA is currently the diagnostic method of choice. Nonspecific laboratory abnormalities encountered during the illness include thrombocytopenia, leukocytosis, azotemia, elevated transaminase, hypocalcemia, and prolonged prothrombin and partial thromboplastin times.

Differential Diagnosis Physicians should be alert for HFRS whenever they are confronted with an acute, febrile illness accompanied by renal failure and bleeding tendencies. The mild form of HFRS is especially difficult to recognize. Acute onset, headache, fever, increased serum creatinine, proteinuria, and polyuria are signs and symptoms associated with the mild nonmurine form of HFRS. Awareness of the clinical manifestations and geographic distribution of the virus is important, it is unlikely that symptoms of fever, myalgia, and backache in a patient from western Europe would be immediately attributed to Hantavirus disease. The development of conjunctival infection is more likely to raise the suspicion of leptospirosis, especially when renal failure or hepatic dysfunction is encountered where there is a history of exposure to rat habitats. The following diseases should be included in the differential diagnosis of the HFRS syndrome in nonendemic areas: idio-

53 Infectious Diseases Newsletter 10(6) June 1991 pathic acute renal failure, hemorrhagic scarlet fever, leptospirosis, scrub typhus, murine typhus, spotted fevers, Colorado Tick fever, Dengue fever, and heatstroke.

Treatment The treatment of HFRS is supportive. Meticulous attention to fluid and electrolyte balance is critical to effective patient management. Hypotension should initially be treated with plasma expanders followed by vasopressors, if necessary. In patients with severe renal impairment, hemodialysis may be used to correct electrolyte and acid-base derangements as well as to improve fluid balance. Hemorrhagic tendencies potentiated by uremia may be improved by hemodialysis. More specific therapy may be afforded by the antiviral agent ribavirin. This agent has been shown effective in in vitro studies, and recent trials in China have shown that patient

mortality can be reduced with the use of this drug. Presently, there is no effective vaccine available.

sensitive method for diagnosis. The treatment of HFRS is thus far supportive, but ribavirin does show promise.

Summary HFRS is an acute, infectious illness characterized by a triad of fever, hemorrhage, and renal failure. The causative agent belongs to a group of RNA viruses in the Bunyaviridae family known as the Hantaviruses. Three distinct viruses in this group are known to cause human disease: Hantaan, Seoul, and Puumala, which are transmitted respectively by mice, rats, and voles. Although these viruses have become more widely recognized, their protean clinical manifestations continue to make hantavirus disease a difficult diagnosis. HFRS should be suspected in any patient who presents with an acute, febrile illness or renal failure of unknown origin, especially when a history of rodent exposure or travel to an endemic area is present. Serologic studies provide a simple and

Bibliography Bruno P, et al: The protein manifestations of hemorrhagic fever with renal syndrome. Ann Intern Med 113:385-391, 1990. Cosgriff TM: Hemorrhagic fever with renal syndrome: Four decades of research. Ann Intern Med 110:313-315, 1989. Editorial: Hantavirus disease. Lancet 336:407-408, t990. Johnson KM: California encephalitis and bunyaviral hemorrhagic fevers, in Mandell G, Douglas R, Bennett J (eds): Principles and Practice of Infectious Diseases, ed 3. New York, Churchill Livingstone, pp 1326-1329. Lee HW, et al: Hemorrhagic fever with renal syndrome. Prog Med Viral 36:62102, 1989. Yangihara R: Hantavirus infection in the United States: Epizootiology and epidemiology. Rev Infect Dis 12:449-455, 1990.

Extrapulmonary Pneumocystosis in AIDS Mario C. Raviglione, MD Beth Israel Hospital, Harvard Medical School, Boston, Massachusetts

Pneumocystis carinii has been known since the 1960s as a cause of pneumonitis in immunocompromised patients. Despite awareness of this disease, only 16 cases of extrapulmonary infection were reported prior to 1985. With the advent of the acquired immunodeficiency syndrome (AIDS) epidemic, Pneurnocystis carinii pneumonia (PCP) has become a very prevalent disease in certain areas of the United States, and currently represents the most common AIDSrelated opportunistic infection. By December 1990, over 70 cases of extrapulmonary pneumocystosis had been described in patients with HIV infection. Naturally, the interest is increasing and many investigators have tried to accumulate data that may help define the hallmarks of extrapul-

monary Pneumocystis carinii infection. The true frequency of extrapulmonary pneumocystosis in AIDS is not well established. At Cabrini Medical Center in lower Manhattan, we detected five cases out of 940 episodes of PCP in a 31-month period. This gives a figure of approximately one case for every 200 cases of PCP. However, a much higher incidence of dissemination has been reported: Four (2.5%) of 161 autopsies produced evidence of extrapulmonary spread at Memorial Sloan-Kettering Cancer Center in New York City, whereas dissemination was detected in 3% of all patients with AIDS and 5% of those with prior PCP in another hospital. Therefore, it is likely that many cases remain undiagnosed unless an © 1991 Elsevier Science Publishing Co., Inc. 0278-2316/91/$0.00 + 2.20

autopsy is performed, while many others may just be treated unwittingly by systemic antipneumocystis agents used to treat a concomitant PCP. The clinical significance and pathologic importance of extrapulmonary pneumocystosis remain controversial. Out of 16 cases reported in patients without human immunodeficiency virus (HIV) infection, four (25%) could be considered as clinically significant with evidence of hepatic damage and hypoplastic bone marrow. On the other hand, patients with HIV infection and extrapulmonary P. carinii infection had more evidence for a pathogenic role of the organism in extrapulmonary sites. There are examples of hearing loss due to otitis, liver dysfunction due to hepatitis, severe splenomegaly, thy-