4
Clinical Microbiology Newsletter I Vol. 16, No. 10 May 15, 1994 Emerging Infections: Hantavirus Disease Outbreak James L. Beebe, Ph.D., ABMM Chief Microbiologist Division of Laboratories Colorado Department of Health Denver, CO 80220 In 1991, the Institute of Medicine of the National Academy of Sciences con- vened a multi-disciplinary committee to study emerging microbial threats to health. Charged with the identification of significant emerging infectious dis- eases as well as defining courses of ac- tion now and in the future, the committee conducted an 18-mo study culminating in the publication of a re- port (1). In part, the report cited the po- tential for zoonotic infections in the future, slating, "It is likely that emerg- ing pathogens generally are not newly evolved. Rather, it appears that they al- ready exist in nature. The significance of zoonoses in the emergence of human infectious cannot be overstated. The in- troduction of viruses into human popu- lations...is often the result of human activities...." This prophetic narrative was published in October 1992. Seven mouths later, in May 1993, the New Mexico Department of Health began to receive reports of deaths of in- dividuals due to severe pulmonary dis- ease. Many affected individuals were residents of the Navajo reservation lo- cated near the Four Corners area of New Mexico, Arizona, Colorado, and Utah. This outbreak of severe pulmo- nary disease, relxra~l widely as a mys- tery disease in the national media, was characterized by fever, myalgias, head- ache, and cough and, for some patients, an extremely rapid onset of severe pul- monary symptoms leading to death within hours (2). The epidemiologic in- vestigation that followed found an asso- ciation of rodent infestation with the residences of some victims. This led the investigators at the Centers for Disease Control and Prevention (CDC) to sub- mit serum specimens to the CDC labo- ratories for assays designed to detect the presence of antibodies to known ro- dent viruses. In less than a month from the initial reports received by the New Mexico Department of Health, evidence suggesting the etiologic role of a hanta- virus was obtained (3). The clinical case def'mition employed for the investi- gation was quite similar to the descrip- tion of acute respiratory distress syndrome (ARDS), of which approxi- mately 3500 cases are reported annu- ally in the United States. The application of the case definition began to yield possible cases at disparate sites throughout the counlry with no history of travel or association with the initial outbreak area. The operational name for the syndmme progressed from "anspeci- fled acute resphatmy distress syndrome" (UARDS), to "hantavims-related acute resp~ distresssyndrome" ~S), to hantavirus pulmonary syndrome(HPS). Identification of the Agent With the rapid institution of a series of laboratory analyses to confirm whether the clinical cases were truly hantavirus infections, the CDC began to analyze thousands of specimens. The methods employed by CDC scientists included enzyme immanoassay and indirect fluorescent antibody assays employing antigens from known hanta- viruses, immunohistochemical staining of autopsied tissues, and polymerase chain reaction testing. The clinical fea- tures of the disease pointed strongly to a previously unrecognized hantaviras agent that reacted to serologic reagents prepared against other members of that group including Hantaan virus, the pro- totype member of this virus group (4- 7). The legacy of more than two decades of research conducted by sev- eral investigative groups into the nature of this once-obscure group of viruses was already lxoviding dividends in the rapid identification of the etiologic agent. Table 1 illustrates the principle fea- tures of the known hantaviruses in com- parison with the new agent, first called the Four Corners agent but recently named Muerto Canyon virus. During the Korean war, Western physicians at- In This Issue Hantavirus Disease Outbreak .... 73 Description of the Four Corners out- break and how the agent was rapidly identified Hospital Infection Control ....... 76 The authors suggest some novel approaches for controlling hospital infections Unexpected aect~ Carriage of an Amiuoglycoside- and Van- comycin .Resistant Enterococcus faecium ........... 79 A case report 16(10)73---80,1994 Elsevier 01~-4399/94/$0.00+ 07.00

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Page 1: Emerging infections: Hantavirus disease outbreak

Clinical Microbiology Newsletter

I

Vol. 16, No. 10 May 15, 1994

Emerging Infections: Hantavirus Disease Outbreak James L. Beebe, Ph.D., ABMM Chief Microbiologist Division of Laboratories Colorado Department of Health Denver, CO 80220

In 1991, the Institute of Medicine of the National Academy of Sciences con- vened a multi-disciplinary committee to study emerging microbial threats to health. Charged with the identification of significant emerging infectious dis- eases as well as defining courses of ac- tion now and in the future, the committee conducted an 18-mo study culminating in the publication of a re- port (1). In part, the report cited the po- tential for zoonotic infections in the future, slating, "It is likely that emerg- ing pathogens generally are not newly evolved. Rather, it appears that they al- ready exist in nature. The significance of zoonoses in the emergence of human infectious cannot be overstated. The in- troduction of viruses into human popu- lations...is often the result of human activities...." This prophetic narrative was published in October 1992.

Seven mouths later, in May 1993, the New Mexico Department of Health began to receive reports of deaths of in- dividuals due to severe pulmonary dis- ease. Many affected individuals were residents of the Navajo reservation lo- cated near the Four Corners area of New Mexico, Arizona, Colorado, and Utah. This outbreak of severe pulmo- nary disease, relxra~l widely as a mys- tery disease in the national media, was characterized by fever, myalgias, head- ache, and cough and, for some patients, an extremely rapid onset of severe pul-

monary symptoms leading to death within hours (2). The epidemiologic in- vestigation that followed found an asso- ciation of rodent infestation with the residences of some victims. This led the investigators at the Centers for Disease Control and Prevention (CDC) to sub- mit serum specimens to the CDC labo- ratories for assays designed to detect the presence of antibodies to known ro- dent viruses. In less than a month from the initial reports received by the New Mexico Department of Health, evidence suggesting the etiologic role of a hanta- virus was obtained (3). The clinical case def'mition employed for the investi- gation was quite similar to the descrip- tion of acute respiratory distress syndrome (ARDS), of which approxi- mately 3500 cases are reported annu- ally in the United States. The application of the case definition began to yield possible cases at disparate sites throughout the counlry with no history of travel or association with the initial outbreak area. The operational name for the syndmme progressed from "anspeci- fled acute resphatmy distress syndrome" (UARDS), to "hantavims-related acute r e s p ~ distress syndrome" ~ S ) , to hantavirus pulmonary syndrome (HPS).

Identification of the Agent With the rapid institution of a series

of laboratory analyses to confirm whether the clinical cases were truly hantavirus infections, the CDC began to analyze thousands of specimens. The methods employed by CDC scientists included enzyme immanoassay and indirect fluorescent antibody assays employing antigens from known hanta-

viruses, immunohistochemical staining of autopsied tissues, and polymerase chain reaction testing. The clinical fea- tures of the disease pointed strongly to a previously unrecognized hantaviras agent that reacted to serologic reagents prepared against other members of that group including Hantaan virus, the pro- totype member of this virus group (4- 7). The legacy of more than two decades of research conducted by sev- eral investigative groups into the nature of this once-obscure group of viruses was already lxoviding dividends in the rapid identification of the etiologic agent.

Table 1 illustrates the principle fea- tures of the known hantaviruses in com- parison with the new agent, first called the Four Corners agent but recently named Muerto Canyon virus. During the Korean war, Western physicians at-

In This Issue

Hantavirus Disease Outbreak . . . . 73 Description of the Four Corners out- break and how the agent was rapidly identified

Hospital Infection Control . . . . . . . 76 The authors suggest some novel approaches for controlling hospital infections

Unexpected aect~ Carriage of an Amiuoglycoside- and Van- comycin .Resistant E n t e r o c o c c u s f a e c i u m . . . . . . . . . . . 79 A case report

16(10)73---80,1994 Elsevier 01~-4399/94/$0.00 + 07.00

Page 2: Emerging infections: Hantavirus disease outbreak

Table 1. Characteristics of Imntaviruses

Virus Principle rodent host Disease Distribution Hantaan Field mouse (Apodemus agraricus) HFRS a Seoul Black rat (Rattus rattus), "Mild" HFRS

Norway rat (Rattus norvegicus) Bank vole ( Ciethrionomys glareolus) Yellow-necked mouse (Apodemusflavicolis)

Puumala

"Porogia" "Four Comers Agent"

(Mu~to Canyon) Tchonpitonlas Prospect Hill

Deer mouse ( P e rom y sc us manic ulatus ) Norway rat (Rattus norvegicus) Meadow vole (Microtus pennsytvanicus)

Nephropathia epidemica "Severe" HFRS

Korea, Manchuria, China Worldwide

Europe, East Asia Balkan peninsula

Hantavirus Pulmonary Syndrome Uncertain Uncertain Uncertain None Uncertain

a Hemon~c fever with renal syndrome.

tended to more than 3,000 cases of an illness called Korean hemmrhagic fever among United Nations soldiers. The ill- ness, recognized by Asian physicians for decades lxior to the Korean war, was marked by hemonhagic phenom- ena and renal involvement with high mortality. Althongh the virus, which came to he known as Hantaan vires, was not isolated until 1976 (8), Gajdusek discerned similarities between this syn- drome and a milder illness with renal in- volvement common to Scandinavian nations called nepleolmthia epidemica (9). This illness, as well as similar syn- dromes, has come to be classified as "hemorrhagic fever with renal syn- drome" (HFRS). Subsequent research revealed the etiologic agents---a group of viruses that parasitize rodents, ex- hibit broad serologic cross-reactivity, and axe transmilted by aerosols of ro- dent excreta.

Transmission Currently classified with the Bun-

yaviridae, a family of spherical, mem- brane-bound RNA viruses, the hantavimses are transmitted by a means that differs from the arthrolmd (mosqui- toes and ticks) mode of transmission of the other viruses of the Bunya group (10). Research has shown that each of the recognized hantaviruses Ferasitize a single or a group of closely related ro-

dent species. Infected animals become chronically infected even after mount- ing an immune response, shedding in- fectious viral particles in saliva, urine, and presumably dmpl~gS for weeks and months. Humans become infected after contact with rodent excreta. Some laboratory outbreaks have shown that even a brief exposure of a susceptible human to caged, infected rodents is suf- ficient to effect transmission with sub- sequent infection and illness. Clinical illness, which can occur in less than 10% of infected individuals for some hantavirus types, usually appears after an incubation period of 9 to 35 d.

Other Rodent Hantaviruses In the last decade, studies of rodent

populations have resulted in descrip- tions of rodent hantavim.~ that have not yet been shown to cause human dis- ease, including the Prospect Hill virus, which infects the meadow vole. In 1984, LeDuc et al. (11) reported that do- mestic rats were infected with a virus re- sembling the prototype Hantaan virus. Their study showed that some groups of rats captured in the urban settings had very high rates of infection while other groups in the same city were totally un- infected; i.e., that diac~te foci of infec- tion existed in a field of non-infection. In 1985, Tsai and coworkers reported the isolation of a rat hantavims desig-

nated Tchoupitoulas and provided sero- logic survey aa_~ that indicated that han- tavimses infect urban rats and several species of rodents, including the deer mouse (Peromyscus manicutatus), which are widely distributed in the western United States (12). In 1987, Childs et al. (13) reported the isolation of a strain of Seonl virus from the Nor- way rat (Rattus norvegicus) recovered from a site in Baltimore, Md., and pre- sented evidence that the v~as had ex- isted in rat populations for a considerable period of time and that hu- mans were being infected by this en- demic virus. This report and subsequent studies (14,15) showed that the Seoul virus was infecting humans in Balti- more. ~ t l y , Glass et al. implicated hantavirus infection with hypertensive renal disease, reporting that 6.5% of pa- tients with end-stage renal disease due to hypertension were seropositive for a hanmvirus (16). A picture had emerged that indicated that hantaviruses infect humans in diverse geographic locations throughout the United States and the world. The human target organ was usu- ally the kidney.

Distribution The broad antigenic cross-reactivity

of the hantavims group ~ sero- logic surveys using the Wototype strain of Hantann virus among other hanta-

NOT~ No mqxm*ibility is Imnmd by the PubliMmr for may injury mad/or dmml~ to ~ or ~ -- a nm~r of im~t~,~ li,bility, ne41ligmce or otlmrwi~, or fnma may use or opcut/on of may midlands, pmducl, immuctiem or idms mntained in *lw nmtmi*l htmdn. No ~ t~t or ~ - --- '~ should be carrkd out unl~8, in the rmdor's ~ : ~ ~ ~ jmtifi~L Became o~ rapid ~ hl moglicM sc~wga*, we reccmmmad th~ flw ~ veriftcxt/cn of d~gnoees and dmS dosages should be made. Discumdom, views, and recotmnendati~s w to medical preceding, choice of drags, and drug dosages are the responsibility of the authors.

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Page 3: Emerging infections: Hantavirus disease outbreak

vinmes and demonstrated the wide dis- tribution of hantavimses. This attribute allowed the rapid implication of the han- tavims group with the Four Cornets out- break.

Virtually every collection of deer- mouse sera recovered in the outbreak arena shows evidence of infection by the Four Corners agent, with rates as high as 56%. The broad distribution of the Four Corners virus contrasts with the discrete foci of infection previously demonstrated with rat hantaviruses (11, 12). Other species of rodents have shown lesser or "spill-over" rates of in- fection.

With the progression of the outbreak investigation, the fine net of the clinical ease definition began to yield candidate cases from states outside the Four Cor- ners area. Several of these cases were shown to be caused by hantaviruses, in- chiding those in indivi0nals from Cali- fornia, Louisiana, Idaho, Nev~a~ Oregon, Texas, Montana, North Da- kota, and South Dakota (5-7). More re- cently, cases have been idenfif'~l in Minnesota, Kansas, and IHinois. Three different serologic variants of the Four Comers agent have been identified so far.

At this writing, the CDC has success- fully isolated the Four Comers virus. Nearly simultaneously, the U.S. Army Medical Research Institute of Infectious Disease (USAMRIID) in Fort Detrick, Md., has also successfully grown the vi- rus in cell culture.

While isolation of hantavirus is the definitive method for diagnosis, it is not a routine laboratory exercise, but is typi- cally a laborious trial involving multi- ple passages in laboratory animals before cultivation in cell culture mono- layers such as Vero cells. I-lantaviruses typically exert subtle cytopathic effects in susceptible cell monolayers and usu- ally must he demonstrated by im- munofluorescent techniques.

Hantavi rus Diseases Hantaan, Puumula, Seoul, and

Porogia viruses caese ttFRS, charac- terized by fever, t h r o m ~ and acute renal insufficiency. Puumula and Seoul viruses cause a milder illness; the former is the agent of a mild form of the kidney disorder called nephropathia

epidemica found principally in Scandi- navian countries. Disease caused by Hantaan and Porogia viruses is usually severe. Porogia virus is a partially char- acterized hantavirus that is responsible for cases of disease in the Bnlkaq penin- sula, with mortality rates as high as 30%. A single case report (17) has indi- cated that the mouse hantavims, Leakey virus, can also cause HFRS. Recent studies have indicated that this is not a new virus, but represents contamination of cultures by two known hantavimses.

Other agents of the Bunyavirus group primarily attack the meninges (e.g., LaCrosse, Jamestown Canyon) or liver (Phleboviruses, such as Rift Val- ley fever virus, and Nairoviruses, such as Congo-Crimean Hemorrhagic fever virus). In conlrast, the Four Corners agent primarily attacks the lungs. The severity of symptoms and the rapidity with which the virus deslroys lung tis- sue are hallmarks that are singularly di- vergent from the pathogenetic features of other hantaviruses and other Bun- yaviridae. Mortality for the more than 60 cases implicated in the Four Comers outbreak is approximately 70%.

When the institution of the HPS case definition began to yield possible cases from many locations outside the Four Comers area, the obvious question arose: Did the outbreak spread from the Four Comers area or is the virus en- demic to many areas of the country? The report on emerging infections pre- dicts that this "new" virus has long been present. Future studies will deter- mine if this is true.

Epidemiology The initiation of the Four Corners

outbreak may have stemmed from an in- crease in the Four Comers rodent popu- lation fueled by a bumper crop of pinon nuts--a principle food of the deer mouse--following heavy winter precipi- tation. The greatly increased numbers of rodents and their invasion of housing structures, especially those with poor defenses against rodent infestation, ap- parently resulted in increased rodent- human contact and exposure of humans to aerosofized rodent excreta containing the virus. The value of interventions de- signed to avert these infestations will also be determined,

O 1994 El~.vier Scimee Inc.

In the 1976 Legionnaires disease out- break investigation, the tedious but eventually fruitful laboratory studies culminated in the isolation of the bacte- rium reapmsible for the infeOJon after many months of effort. In contrast, the fruit of research invested into this group of viruses resulted in not only the identification of the etiologic agent but also the estabfishment of intervention measures and clean-up of the rodent- infested areas. The application of mo- lecular genetic techniques also resulted in immediate gains. Even before the first isolation of this new virus had been performed, Drs. Brian Hjeele and Stanley Jenison of the University of New Mexico School of Medicine suc- cessfully cloned the Four Corners virus genome and produced an antigen suit- able for an immunoassay. The im- munoblot devised by these investigators may become the fwst widely available method for laboratory testing specifically designed to detect antibody to the Four Comers agent (I 8). Routine laboratory identification of hantaviruses as the causative agent of some cases of ARDS, and possibly kidney disease, awaits the availability of reagents to perform testing like that now done in Sp~i~liTJ~d laboratories such as the CDC, USAMRfiD, and se- lected university laboratories.

This outbreak is unlikely to be the last that public health authorities and laboratory scientists deal with in this century. Microbiologists and clinicians are advised to build effective lines of communication with public health authorities to insure that emerging in- fections such as that associated with the Four Comers outbreak are promptly recognized and investigations are initi- ated at the earliest juncture.

R e~erences 1. Lederberg, J., R. E. Shope, and S. C.

Oaks Jr. 1992. Emerging infections: mi- crobial threats to health in the United States. Washington, DC, National Academy Press.

2. Centers for Disease ConUol. 1993. Out- break of acute illness--muthwestem United States, 1993. Morbid. ~ . Weekly Rep. 42:421--424.

3. Centers for Disease Control. 1993. Up- date: outbreak of hantavims infection-- southwestern United States, 1993.

0196-4399~94/$0.00 + 07.00 75 Clinical l~crobiology Newdetter 16:10,1994

Page 4: Emerging infections: Hantavirus disease outbreak

Morbid. Mortal. Weekly Rep. 42:441- 443.

4. Centers for Disease Control. 1993. Up- date: outbreak of hantavirus infection-- southwestern United States, 1993. Morbid. Mortal. Weekly Rep. 42:477- 479.

5. Centers for Disease Control. 1993. Up- date: outbreak of hantavirus infection-- southwestca-n United States, 1993. Morbid. Mortal. Weekly Rep. 42:517- 519.

6. Centers for Disease Control. 1993. Up- date: outbreak of hantavirus infection--- southwestern United States, 1993. Morbid. Mortal. Weekly Rep. 42:570- 571.

7. Centers for Disease Control. 1993. Up- date: hantaviros pulmonary syndrom~--- United States, 1993. Morbid. Mortal. Weekly R¢p. 42:816-820.

8. Le,, H. W., P. W. Lee, and K. M. Johnson. 1978. Isolation of the etiologic agent of Korean hemorrhagic fever. J. Infect. Dis. 137:298--308

9. Gajdusek, D. C. 1953. Acute infectious hemorrhagic fever and mycotoxicoses in the Union of Soviet Socialist Repub- lies. Medical Science Publication No. 2. Army Medical Services Graduate School, Walter Reed Army Medical Center, Washington, DC.

10. McKee, K. T. Jr., J. W. LeDuc, and C. J. Peters. 1991. Hantaviruses, pp. 615- 632. In R. B. Belshe (ed.), Textbook of human virology, 2nd ed. Mosby Year Book, St. Louis.

11. LeDuc, J. W., G. A. Smith, and K. M. Johnson. 1984. Hantaan-like viruses from domestic rats captured in the United States. Am. J. Trop. Med. Hyg. 33:992-998.

12. Tsai, T. F. et al. 1985. Serological and virological evidence of a Hantaan virus- related enzootic in the United States. J. Infect. Dis. 152:126--136.

13. Childs, J. E. et al. 1987. Epizootology of hantavirus infections in Baltimore: isolation of a virus from Norway rats, and characteristics of infected rat popu-

lations. Am. J. Epidemiol. 126:55--68.

14. Childs, J. E. et al. 1988. Evidence of hu- man infection with a rat-associated han- tavirus in Baltimore, Maryland. Am. J Epidemiol. 127:875--878.

15. Childs, J. E. et al. 1991. Human-rodent contact and infection with lymphocytic choriomeningitis and Seoul viruses in an inner-city population. Am. J. Trop. Med. Hyg. 44:117-121.

16. Glass, G. E. et al. 1993. Infection with a ratborne hantavirus in US residents is consistently associated with hyperten- sive renal disease. J. Infect. Dis. 167:614-620.

17. Baek, L. J. et al. 1988. ~ e y virus: a new hantavirus isolated from Mus mus- culus in the United States. J. Gen. Vi- rol. 69:3129-3133.

18. Centers for Disease Control. 1993. Pro- gress in the development of hantavims diagnostic assays---United States, 1993. Morbid. Mortal. Weekly Rep. 42:770- 771.

E d i m f i M

Novel Approaches to Hospital Infection Control

Gaff S. Itokazu, Pharm.D. Department of Pharmacy

Robert A. Weinstein, M.D. Depamnent of Medicine University of Illinois at Chicago Michael Reese Hospital and Medical Center Chicago, IL 60616

Major challenges face infection con- trol--an increasing population of immu- nocompromised patients, increasing use of indwelling devices and procedures, and the increasing presence of antimi- crobial-resistant bacteria, fungi, myco- bacteria, and viruses. Traditional responses to such challenges have in- volved a series of time-honored prac- tices aimed m reducing mi~ 'ob~ resetvo/rs in hospitals and limiting cross-infection (Table 1). However, because of the difficulty in achieving the necessary modifications of he,qth- care-workcx behavior, there has been an ongoing effort to develop behavior-inde-

pendent approaches to infection control. Here we review the more novel of these approaches and their outlook for suc- cess (Table 2).

Given that reducing microbial coloni- zation is one of the major goals for in- fection control, it is no wonder that many infection control approaches have focused on (and often have revisited) ag- gressive use of antibiotics---systemi- cally, topically, or impregnated in indwelling devices. For example, while short courses of systemic antibiotics tra- ditionaUy have been reserved for proce- dures with a high risk for infection, "newer" prophylaxis regimens have been suggested for ~ surgeries that do not meet this critexion---e.g., hernior- rhaphies and breast surgery (1). Sys- temic antibiotics also have been used to prevent device-related infections such as intravascutar catheter infections (2) and urinary tract infections (3). How- ever, the long-term consequences of

more aggressive antimicrobial prophy- laxis need to be carefully evahmled be- fore this approach is considered for general use. For example, in one study, use of oral ciprofloxacin to prevent nosocomial urinary tract irdections al- lowed proliferation of organisms that were intrinsically resistant to fluoroqui- nolones (3).

Because of these concerns about emergence of resistant organisms, local application of antibiotics at the pre- sumed sites of microbial colonization has been advocated to avoid systemic administration. For example, antibiotic mouthwashes plus antibiotic irrigation i n ~ i v e l y may be promising strategies for the prevention of wound infection in patients undergoing head and neck surgery (4). Selective decon- tamination of the digestive tract (SDD), which entails the use of topical antibiot- ics to the stomach and oropharynx, at limes coupled with a short course of sys-

76 0196.4399194/$0.00 + 0%00 @ 1994 Elsevier Science Inc. Clinical Microbiology Newsletter 16:10,1994