INTERNATIONAL THREATS IN INFECTIOUS DISEASES
From Interactive Update in Medicine, presented by the Keck School of Medicine of the University of Southern California
John M. Leedom, MD, Professor Emeritus, Department of Medicine, Division of Infectious Diseases, Keck School of
Medicine of the University of Southern California, Los Angeles
| Presentation: some West Nile infections have typical influenzalike symptoms with or without rash (West Nile fever);
<1% of West Nile infections affect central nervous system (CNS), with altered mental status and stiff neck (meningitis
or encephalitis)
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| Characteristics: arbovirus (arthropod-borne); spread by mosquito; single-stranded RNA virus (Flavivirus); related to
Japanese encephalitis and St. Louis encephalitis; has protein that mediates virus-host cell binding; in 2000, most prominent
in Africa, areas just north of Africa, and few in east coast of United States; virus lives in birds; some infected birds
get sick, and die, but some do not die; all live long enough to have high-grade viremia and infect mosquitoes, which
then bite other hosts (eg, horses, humans); horses and humans are dead-end hosts because viremia not sufficient to infect
mosquito
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| Spread of virus to United States: possibilities include—infected mosquito carried to United States by air or boat,
eg, type of mosquito not considered important vector for West Nile virus (Aedes albopictus; Asian tiger mosquito) entered
United States in shipment of used tires; infected birds imported to United States (legally or illegally); migrating
infected birds or infected person (less likely because human viremia not sufficiently infectious for mosquitoes); bioterrorism;
and other imported animals; geographic spread—in first year in United States, cases all in New York City and
environs; first 8 cases in borough of Queens in summer of 1999; all human cases within 75-mile radius of New York
City; however, other states (Connecticut, Delaware, New Jersey, and Maryland) already had cases in birds, animals, and
mosquitoes
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| Transmission: mosquito vectors numerous and involve multiple species with different host preferences, behaviors,
and ecologic habitats; for transmission to humans, need mosquito that bites birds and humans; many atypical host species,
including mammals; however, very few of these animals get sick and very few have high-grade viremia; sickness
from virus almost exclusively limited to humans and horses; atypical methods of transmission include organ transplantation,
breast-feeding, and blood transfusion
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| West Nile virus activity: in 2000, more states had human cases and even more with bird or animal cases; in 2002,
864 documented cases in Illinois and 1 case in California (no West Nile virus activity in humans in Western states, although
some infected animals and mosquitoes found); in 2003, almost all states had human and animal cases, except
Oregon and Washington; in 2004, 779 cases in California (some states spared human cases but still had avian, animal,
and mosquito infections); virus spread to Central America; in 2005, >800 cases in California but no human cases in
Washington; as virus moves across country, more cases in following year than previous year in “virgin” states and
fewer cases in following year in previously hard-hit states (because virus immunizing); most people infected get minor
illness or do not get sick, so following year, when virus circulates in birds and mosquitoes, no large susceptible population;
virus can be in blood at low level, with patient having no symptoms; if asymptomatic person donates blood, infection
passed to recipient; all donated blood being tested for West Nile virus
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| Clinical disease: until recently, trivial; since 1996, in Africa and Middle East, more frequent outbreaks, more reports
of severe CNS disease, infection, and fatalities, particularly in Israel; incubation period 2 to 15 days; most illness self-
limited, with fever, rash, headache, and some nausea and vomiting; rarely, complications other than meningitis or encephalitis
can occur, including pancreatitis, hepatitis, and myocarditis; classic neurologic syndromes include meningitis,
encephalitis, and meningoencephalitis; number of cases of acute flaccid paralysis and anterior horn cell disease
that mimics poliomyelitis; <1% have CNS disease, ≈20% have West Nile fever, and remainder asymptomatic
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| Treatment and vaccination: 2 licensed vaccines for horses; none for humans (one in phase 1 clinical trial); trials
with antivirals in humans, but none promising; in United States, most important bird involved in lifecycle American
crow (39% of all positive birds); blue jay, Western scrub jay, magpie, and house sparrow also involved
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| SEVERE ACUTE RESPIRATORY SYNDROME (SARS)
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| Incidence: no documented case of community transmission of SARS since July 2003; since July 2003—11 cases diagnosed
by means acceptable to World Health Organization (WHO); 11 of cases associated with laboratory work in 3
laboratories; one isolated case in Guangdong province in nonlaboratory worker; 2 community suspect cases in same
place in November and December 2003 (did not cause sustained community transmission); thought to have potential
to cause worldwide pandemic; requirements for pandemic—must have new organism to which general population has
little or no immunity; new organism must be able to replicate in humans and cause serious illness and be transmissible
efficiently from one human to another; when first detected, SARS had pandemic potential
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| Response to SARS: within 5 mo, virus identified, diagnostic tests developed, infection control practices established,
and effective international public health response mounted; surveillance programs established; in July 2003, WHO removed
last region from list of places with recent local transmission; good international cooperation (including China) in
attempts to control agent; WHO summary—≈8000 people worldwide sick with SARS; >24 countries involved; case fatality
rate ≈10%; 774 deaths; in United States only 8 laboratory-confirmed cases and no indigenous transmission (all
cases in travelers)
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| Identification and source: coronavirus; before SARS virus isolated, common cold only coronaviruses known to infect
humans; in March or April 2003, SARS-like coronavirus isolated, with 99.8% homology to virus isolated from
humans and from palm civets in wet markets in Guangdong, China; during epidemic, 2 cases in restaurant workers in
Guangdong who handled wild animals, including civets; restaurant workers had higher frequency of seropositivity to
SARS virus than rest of people in area, as did wild-animal traders in market; virus also found in ferret badgers and raccoon
dogs; question of whether these animals reservoirs or infected like humans; meat from these animals often eaten
rare (possible mode of transmission)
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| Mode of transmission: virus transmitted most of time by contact; for airborne infection, virus must be coughed out
on particles small enough for suspension in Brownian motion (hyperspreading; not common); virus not transmissible
before onset of fever and symptoms; asymptomatic cases rare (unlike influenza); if SARS virus truly airborne
and asymptomatic infection occurred, pandemic would have occurred
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 | Horseshoe bats: probably ultimate source of and reservoir for SARS virus; in China, polymerase chain reaction (PCR)
showed virus in bat stool, and ≈80% of bats have antibodies to virus; bats sold live in markets for food and medicine
and may have had contact with civets, but bats not sick; viruses not identical among bats, civets, and humans (differ
in sequences governing receptor sites)
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Influenza (general)
| Clinical features: may include CNS symptoms and internal bleeding (unusual for human influenza viruses); controversy
as to whether they ever cause encephalitis; incubation period 1 to 4 days (average 2 days); infectious by droplets
24 hr before symptoms and ≈5 days later; part of time, probably infectious by airborne route; abrupt onset of
constitutional and respiratory signs and symptoms (eg, fever, myalgia, headaches, malaise, nonproductive cough,
sore throat, rhinitis); usually resolves after several days; can exacerbate underlying medical conditions (eg, pulmonary
disease, cardiac disease) and can lead to viral or bacterial pneumonia; also may be spread by feces (animal to
animal and probably in humans)
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| Hospitalizations and deaths from influenza: common even in nonpandemic years; 0 to 4 yr of age—500 per 100,000
for those with high-risk conditions to 100 per 100,000 for healthy people; generally true that the older or younger
patient is, more likely to have severe disease or death from influenza in any given year
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| Types of influenza viruses: type A—zoonosis; infects wild birds (usually not sick from virus); gastrointestinal (GI)
virus in birds; comes out in bird’s fecal material; mutates and passed on to humans and other animals; subtypes based
on hemagglutinin (H) and neuraminidase (N) antigens; new subtypes arise frequently by point mutations; cause regular
epidemics and few pandemics; types B and C—infect only humans; type B occurs in epidemics every 2 to 3 yr and
causes influenza syndrome, with few complications and little mortality; type C seldom seen and usually causes only
common cold syndrome; all known subtypes of influenza A found in birds; 144 possible combinations from 16 known
H antigens and 9 N antigens; H5 and H7 pathogenic at times for birds and cause severe outbreaks; human disease
mostly due to H1, H2, H3, N1, and N2; H and N surface proteins targets of antibodies; 2 ways flu viruses change—1)
point mutations; 2) reassortment, ie, 2 different flu viruses infecting same cell swap genetic segments; virus coming
out of person or animal different from either of viruses that entered; one of traditional ways influenza viruses change
thought to occur in pigs; respiratory mucosa of pigs contains receptors for avian influenza viruses, human influenza
viruses, and pig viruses
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Pandemics
| Influenza pandemic: prerequisites include replication, efficient transmission, and population with little or no immunity;
seasonal influenza—occurs every year, mostly in winter; most recover without treatment; very young and old
most at risk for serious illness and death; pandemic influenza—occurs 3 to 4 times per century; occurs any time of
year; some may not recover, even with therapy; people of all ages at risk; H1N1 virus caused first pandemic of 20th
century; direct bird-to-human transmission; thought that all 8 genetic segments originated directly from avian influenza;
in 1957 Asian flu pandemic, avian and human virus genes reassorted, resulting in new virus to which population
had little immunity; same thing occurred in 1968 pandemic, resulting in H3N2 disease; from lessons of history, only
question of time before next influenza pandemic occurs; how bird and human influenza viruses differ—mainly in
structure of H antigen; viruses preferentially attach to different forms of sialic acid in respiratory tract; for pandemic to
occur, avian virus has to change enough to transmit efficiently to humans by this attachment
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| 1918 Spanish influenza pandemic: killed 20 to 50 million people worldwide and at least half-million people in
United States; RNA recovered from preserved specimens of soldiers who died in 1918 and from lung tissue from
permafrost graves in Alaska where mass deaths occurred; RNA fragments from these sources enabled reconstruction
of 8 essential genes; tissue culture of this genetic material yielded replication-competent virus thought to be
identical to virus of 1918 pandemic; 39,000 more virus particles found on mouse lung with experimental infection
than with modern type A strains infected at same multiplicity; all mice died within 6 days of infection with 1918 virus,
while none died with Texas A strain used for comparison; in tissue culture, 50 times more virus particles released
day after infection than with control virus; reconstruction yields potential bioweapon now being studied in
laboratories; potential for researcher to become inadvertently infected and carry virus home to infect family; 1918
virus also called swine flu; disease in swine not seen by veterinarians before; thought now that swine probably incidental
victims, because all genes avian type
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| Virulence patterns: younger people had high mortality; some increased mortality in old; mortality began to increase at
age 15 yr, peaked at age 25 yr, and went down at age 40 yr; people killed in most productive years; young pregnant
women also particularly affected and killed; case fatality rate for pregnant women 23% to 71%; why young people
died—good immune system; cytokine storm, particularly tumor necrosis factor (TNF)-α, which destroys lining of
lungs and ability of lungs to transmit O2 ; older people and babies die of superimposed bacterial pneumonia; most of
young people died within 24 to 72 hr; pathology in lung similar to overwhelming viral pneumonia; even in 2006, no
good treatment for cytokine storm; clinical picture of people who died of H5N1 virus in Southeast Asia suggests
similar cytokine storm phenomenon
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| Fatality rates: case fatality rate in 1918 ≈2%; of >200 cases of H5N1 influenza that have occurred recently in humans,
>50% died; if H5N1 virus becomes able to be transmitted efficiently in humans without becoming less virulent, results
potentially disastrous
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Avian (H5N1) influenza
| Epidemiology: first appeared in humans in Hong Kong in 1997; 18 cases, ranging from 1 to 60 yr of age (6 fatal);
found elevated neutralization titers in few patients; not efficiently transmitted; epidemic averted by slaughtering all
poultry, putting in lye, and burying within 3 days
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| Clinical features: influenza-like symptoms, eye infections, encephalitis, meningitis, severe pneumonia, and internal
bleeding and hemorrhages; in 1999, 2 children with respiratory disease due to H9N2, with no spread to family members;
prevalence of infection 30% in poultry workers in Hong Kong; poultry culled and disease failed to spread
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| Preventive measures: poultry killed and buried; vaccination of poultry; H5N1 influenza now in poultry and wild birds
in Europe and Africa; human cases in Asia, Africa, and Middle East (Turkey); from WHO tabulation of documented
cases, 148 of 252 cases fatal; some family clusters noted; among 15 families studied (41 cases), 3 husbands or wives, 2
aunts (genetic relationship not stated), and 39 genetic relatives; strongly suggests genetic susceptibility to infection because
blood relative of case seems at much greater risk than spouse
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| Summary: H5N1 virus endemic in Asian birds, with spread to Middle East, Europe, and Africa; disease serious, with
high case fatality rate; human population has no immunity to virus; question of whether virus will acquire ability to
transmit from person to person efficiently; virus can infect other animals, eg, large carnivores fed chickens in zoo;
big problem with smuggling exotic animals for pets; virus sensitive to neuraminidase inhibitors (eg, oseltamivir
[Tamiflu], zanamivir [Relenza]) but not to amantadines; virus spread mostly by big droplets and probably can be
airborne
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| Health care issues: handwashing recommended; difference in opinion as to whether airborne isolation necessary;
health care problem of surge capacity and ability to make vaccines; with current technology, takes 6 mo to produce
vaccine for new strain; spending money on preparedness for theoretic event not popular
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Suggested Reading
Abroug F et al: A cluster study of predictors of severe West Nile virus infection. Mayo Clin Proc 81:12, 2006;
Blumberg-Kason S et al: Avian flu: what to tell your patients. J Am Diet Assoc 107:194, 196, 2007; Coombes R:
Hunting down the H5N1 virus. BMJ 334:342, 2007; Fauci AS: Emerging and reemerging infectious diseases: the perpetual
challenge. Acad Med 80:1079, 2005; Goicoechea M: Human H5N1 influenza. N Engl J Med 356:1375; author
reply 1376, 2007; Gorsche R et al: The rash of West Nile virus infection. CMAJ 172:1440, 2005; Hampton T: Bats
may be SARS reservoir. JAMA 294:2291, 2005; Hampton T: Drug, vaccine research target avian flu. JAMA
297:1179, 2007; Kondro W: West Nile virus still a threat. CMAJ 175:570, 2006; Lim MK: Bird flu: pandemic flu
preparation: an unheeded lesson from SARS. BMJ 332:913, 2006; Lo B et al: Clinical decision making during public
health emergencies: ethical considerations. Ann Intern Med 143:493, 2005; Ma MH et al: A clinical prediction rule
for the severe acute respiratory syndrome. Ann Intern Med 142:225; author reply 225, 2005; Mack TM: The ghost of
pandemics past. Lancet 365:1370, 2005; McKenna M: Anatomy of a pandemic: emergency departments woefully unprepared
for bird flu outbreak. Ann Emerg Med 48:312, 2006; Murray S et al: West Nile virus. CMAJ 173:484, 2005;
Shuchman M: Improving global health--Margaret Chan at the WHO. N Engl J Med 356:653, 2007; Tong TR: Airborne
severe acute respiratory syndrome coronavirus and its implications. J Infect Dis 191:1401, 2005; Tyler KL:
West Nile virus infection in the United States. Arch Neurol 61:1190, 2004; Zhong N et al: What we have learnt from
SARS epidemics in China. BMJ 333:389, 2006
Educational Objectives
| The goal of this program is to increase awareness of and preparedness for international threats from the West Nile virus,
severe acute respiratory syndrome (SARS), and avian influenza. After hearing and assimilating this program, the
clinician will be better able to:
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| 1. Discuss the epidemiology of West Nile virus and recognize the clinical disease caused by this virus.
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| 2. Review the prerequisites for a pandemic and describe the differences between seasonal influenza and pandemic
influenza.
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| 3. Discuss the epidemiology of SARS.
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| 4. Identify and characterize the various types of influenza viruses in relation to previous epidemics and pandemics.
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| 5. Summarize what is known about the avian influenza virus (H5N1) and discuss preventive measures and health
care issues related to this virus.
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Faculty Disclosure
In adherence to ACCME Standards for Commercial Support, Audio-Digest requires all faculty members to disclose relevant
financial relationships within the past 12 months that might create any personal conflicts of interest. Any identified
conflicts were resolved to ensure that this educational activity promotes quality in health care and not a proprietary business
or commercial interest. For this program, the faculty reported nothing to disclose.
Acknowledgements
Dr. Leedom was recorded at Interactive Update in Medicine: 2006, presented October 21, 2006, in Los Angeles, CA.
The Audio-Digest Foundation thanks Dr. Leedom and the Keck School of Medicine of the University of Southern California
for their cooperation in the production of this program.
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