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Emerging Pathogens:
What Are the Sources
and How Can They Be Spotted Quickly?
According to the National Institutes of Health’s National
Institute of Allergy and Infectious Diseases (NIHNIAID),
more than 30 newly recognized infectious diseases
and syndromes have been identified in the last 20 years.
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DOI: 10.1309/NM113VCPD3PGVGCL
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These include AIDS, toxic shock syndrome, Lyme disease,
West Nile virus, hantavirus pulmonary syndrome, and hepatitis C,
to name a few. Several infectious diseases that appeared to be under
control, such as tuberculosis and malaria, have reemerged. Since the
winter of 2001, concerns about anthrax, smallpox, and
bioengineered forms of disease-as-warfare have increased. The
Homeland Security Agency has joined the Centers for Disease Control (CDC), the Environmental Protection Agency (EPA), the Food
and Drug Administration (FDA), and the NIHNIAID in developing
lists of diseases of concern. Most of these agencies have also developed research programs to try to unlock the science describing how
such diseases become threats, and how they may be contained.
In an article published in Emerging Infectious Diseases,1 Ewald
noted that the most dangerous emerging pathogens can be identified
using a checklist that identifies its method of transmission.
쐽 Does it have a tendency for waterborne transmission?
쐽 Is it vector-borne with the ability to use humans as part of
the life cycle?
쐽 If it is directly transmitted, is it durable in the external envi-
ronment?
쐽 Is it attendant-borne?
쐽 Is it needle-borne?
쐽 If it is transmitted sexually, is it mutation-prone with a tro-
pism for critical cell types or does it have invasive or oncogenic tendencies?
Looking at organisms that caused epidemics over the last 5
centuries, they would have been identified as extremely dangerous pathogens using these criteria. Yersinia pestis is durable in
the external environment and is vector-borne. The partial eradication or the vectors—fleas and rats—have controlled plague so
long as those vectors are absent. Yellow fever, whose 1878 epidemic killed 25% of the population of Memphis, TN, is vectorborne through human-mosquito cycles. The United States has
seen the increase of West Nile virus, also vector-borne through
mosquito-wild bird cycles.
In 2001, the NIHNIAID research program was defined as directing research into 3 broad areas, not necessarily targeting American problems alone. The interest of NIHNIAID, described as
deriving from both humanitarian concerns and “enlightened selfinterest,” focuses on the globalization of health problems. The announcement of the program identified 3 broad goals for research:
쐽 Strengthening basic and applied research on the multiple-
host pathogen and environmental factors that influence disease emergence.
쐽 Supporting the development of diagnostics, vaccines, and
therapies needed to detect and control infectious diseases.
쐽 Maintaining and expanding the national and international
scientific expertise required to respond to health needs.
At almost precisely the same time, the Department of
Health and Human Services (HHS) released an action plan to
combat antimicrobial resistance. The action plan was put
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together by a task force that included the CDC, the NIH, the
FDA, the Agency for Healthcare Research and Quality, the
Healthcare Financing Administration, Health Resources and Services Administration, the Departments of Agriculture, Defense,
Veterans Affairs, and the EPA. The plan covered 4 components
and 84 action steps, including 13 priority steps. Top priorities of
the 4 major sections include:
쐽 Surveillance: The CDC with state health departments and
other task force members began planning a coordinated surveillance system, such that all entities would use similar
methodology and develop patterns of use for antimicrobial
drug used in human medicine, agriculture, and other consumer products.
쐽 Prevention and Control: The HHS and others planned the
launch of a national public education campaign to reduce
overuse and misuse of antibiotics. Pilot projects were
already underway to identify effective strategies to promote
appropriate antimicrobial drug use and reduce infection
rates in clinical practice.
쐽 Research: The NIH pledged to provide the research communities with genetic blueprints for various organisms to identify targets for needed new diagnostics, treatments, and
vaccines.
쐽 Maintenance: The action plan pledged to maintain and expand the national and international scientific expertise that
are required to respond to health threats.
Genomics Might Be the Key
Understanding the mechanisms that permit infectious diseases
to move virtually unchecked is a key to defeating them. The
human genome sequencing project, finished considerably before it
was expected, has provided a head-start to this understanding.
The function of the estimated 60,000 to 100,000 human
genes will have an enormous impact on all areas of medicine,
including our understanding of the host response to microbial
pathogens. Microbial pathogens are being sequenced; therefore,
the interaction between microorganisms and the human genome
can shortcut the development process for diagnostics, therapeutics, and vaccines. The first microbial sequencing project,
Haemophilus influenzae, was completed in July 1995 with extraordinary speed.2 The early use of a newly developed technique known as the shotgun approach sequenced thousands of
fragments of the bacterium’s genome. By comparing overlapping sequences, a complete DNA sequence was designed that
contained all of the genetic information of the bacterium. The
NIHNIAID has funded projects to sequence the complete
genomes of the bacteria that cause tuberculosis, gonorrhea,
chlamydia, and cholera, as well as individual chromosomes of
important organisms such as the malaria parasite Plasmodium
falciparum (http://www.niaid.nih.gov/dmid/genomes). Many of
these microbes have been completely sequenced and are now
being annotated and analyzed. The NIHNIAID researchers and
grantees are required to deposit the sequence data in specialized
and public databases such as GenBank, which is run by the
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National Center for Biotechnology Information (http://www.
ncbi.nlm.nih.gov/Genbank/). Access to the sequence data is
available to anyone with Internet connections, and the data is
available even prior to publication in peer-reviewed journals.
Multi-Drug Resistance
While there are advances in understanding and treating a variety of pathogens, the appearance of a well-understood pathogen
that changes its characteristics can be disconcerting. Unlike an
outbreak of a completely unknown organism, an organism that
fails to respond to recommended treatment triggers other problems. A case in point was published in the March 2003 issue of
Emerging Infectious Diseases as a letter to the editor, describing a
multi-drug resistant Shigella dysenteriae type 1 organism, first
seen in India in 1984, where it was sensitive to nalidixic acid. A
few cases of dysentery emerged in the years after 1984, and a
low-level resistance to fluoroquinolones was seen. Then in the
spring of 2002, clusters of patients with acute bacillary dysentery
were seen in eastern India. A total of 1,124 cases were seen and
were found to be unresponsive to the newer fluoroquinolones but
were found to be sensitive to ofloxacin. The authors of the letter,
from the National Institute of Cholera and Enteric Diseases,
Kolkata, India and other institutions, noted that the drug-resistant
Shiga bacillus could spread further without an appropriate awareness programs, alternate drugs, and an effective vaccine.3
Staphlococcus aureus and Psuedomonas aeruginosa developed single mutations that caused multi-drug resistance to the
broad use of fluoroquinolones. These agents were quickly followed by multi-drug resistance of Campylobacter jejuni,
Escherichia coli, and Neisseria gonorrhoeae. For these organisms, multiple mutations are required to generate clinically important resistance. According to David C. Hooper (Massachusetts
General Hospital, Harvard Medical School, Boston, MA), writing
in a special issue of Emerging Pathogens (Mar-April, 2001), drug
resistance in Streptococcus pneumoniae, which is currently low,
will require close monitoring as fluoroquinolones are used more
extensively for treating respiratory tract infections.
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Food-Based Organisms Triggered by Changes
In Diet
As consumers become more interest in healthy eating, a
number of pathogens emerged quickly. Fresh and minimally
processed foods offer additional nutrients as well as fresh taste
and a feeling of doing something good for your body. However,
as a result, food-borne organisms have found it easier to survive
and thrive. For instance, the addition of sprouts to everything
from salads to sandwiches has increased produce-associated bacterial illness. Although sprout-associated outbreaks have been
reported since the early 1970s, gastroenteritis with Salmonella
enterica serotypes Newport and Stanley in 1995 and 19964,5 and
the 1996 Sakai city outbreak of enterohemorrhagic Escherichia
coli O157:H7 in >5,000 Japanese schoolchildren have refocused
attention on the public health hazard posed by seed sprouts.6
The risk for disease from sprouts is connected to seed production, distribution factors, and the sprouting process itself.
Seeds may be reared, harvested, milled, and sprouted locally or
shipped globally to sprout growers; bacterial contamination may
occur at any point in this chain. During germination, seeds are
presoaked in water and then germinated in a warm, moist, aerated
environment for 3 to 7 days. Replication of pathogens by 3 to 5
orders of magnitude may occur during sprouting, resulting in high
pathogen levels on mature sprouts, despite the fact that initial densities are low and the pathogens dispersed irregularly throughout
the seeds.6 In an experimental model of seed contamination, Salmonella serotype Stanley added to alfalfa seeds increased from
approximately 2 x 103 bacteria per gram of mature sprouts to 107
bacteria per gram after 48 to 72 hours incubation, without affecting the appearance, smell, or taste of the sprouts.
Most Recent Outbreak
In the spring of 2003, the outbreak of Severe Acute Respiratory Syndrome (SARS) resulted in the issuing of a clinical description and preliminary information about diagnosis and cause. The
incubation period is generally 2 to 7 days, although some isolated
reports suggests that incubation may require 10 days. Illness begins
with fever (100.4°F) that may be associated with chills and rigors,
and possibly accompanied by headache, malaise, and myalgia.
After 3 to 7 days, a lower respiratory phase produces a dry, unproductive cough or dyspnea, and may progress to hypoxemia. The
case fatality rate among patients that meet the World Health Organization (WHO) definition of SARS is about 3%.
Initial diagnostic tests should include chest radiograph,
pulse oximetry, blood cultures, sputum Gram’s stain and culture,
and testing for viral respiratory organisms. As of March 22,
2003, the case number of SARS suspected in the United States
stood at 37, while the WHO reported 456 cases worldwide, including a number of deaths.
Recently, WHO reported finding a test that appears to identify the virus that may cause the disease. By isolating the organism from a patient and inoculating it with blood from a
recovered patient, the virus was killed presumably because the
recovered patient’s blood included antigens to the virus. The
WHO scientist who developed the test is not yet certain what
type of virus he isolated. The paramyxovirus family—which
includes measles, mumps, and canine distemper—remained a
leading suspect. A new form of influenza, once the most feared
scenario, is now low on WHO’s suspect list. Also recently, CDC
announced that a previously unrecognized virus from the Coronavirus family is the leading hypothesis for the cause of SARS.
Two Coronaviruses that are known to infect humans cause onethird of common colds and are also a common cause of health
care-associated upper respiratory infections in premature infants.
Additional steps needed to confirm this hypothesis include further
culturing of the virus from appropriate specimens, sequencing
the viral genome, and examining specimens from patients at different stages of their illness. According to a CDC spokesperson,
in one patient, a virus was seen in kidney specimens very clearly
on the electron microscope. The CDC spokesperson said, “We
also have done PCR, which is a way of probing for the genetic
material of the virus, and we’re finding virus PCR, very specific
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evidence of that, in lung tissue, as well as the kidney in this individual patient. This patient, when tested with an antibody, in an
antibody test to the virus, had a negative antibody test at the very
beginning of the illness, and by the end of the illness that antibody test had become positive. It appears that, the patient seroconverted using a very specific assay for this new Coronavirus.
This is very strong evidence supporting Coronavirus as an etiology, but we know from sequencing pieces of the virus DNA that
it is a virus unlike those that have been identified. . . . it’s very
premature to assign a cause or to make dogmatic statements
about the etiology. We’re still learning as we go, and we will
maintain that spirit of collaboration.”
At the time that a distinct disease required identification, the
disease outbreak was only about 2 weeks old. It was first spotted
in Guangdong Province, China. During the short time since the
outbreak was first reported, the CDC acted decisively.7 The
agency activated the Emergency Operations Center; alerted public
health partners in cities and states by issuing electronic messages.
It also prepared and distributed more than 60,000 health alert
cards to travelers returning from Southeast Asia; provided guidance to public health departments, health care facilities, and clinicians in monitoring and identifying potential cases; provided
safe specimen-handling guidelines to laboratories; deployed
more than a dozen CDC staff members, including medical officers, epidemiologists, infection control specialists, and patholo-
gists to support the WHO in the global investigation; and provided
regular media briefings to report on progress of the investigation.
The new tools for identifying new viruses and bacteria have
shortened the time needed for identification and genome
sequencing. Other tools make it possible to develop medications
that may ease the problems with new pathogens. The difficulty
is often recognizing that a new disease is present before it has
become epidemic.
1. Guarding against the most dangerous emerging pathogens: Insights from
evolutionary biology. Emerging Infect Dis. 1996;2:4.
2. Brosius J, Robison K, Church GM, et al. More haemophilus and mycoplasma
genes. Science. 1996;271:1302-1304.
3. Sur D, Niyogi SK, Datta KK, et al. Multi-drug resistant Shigella dysenteriae
type 1, forerunners of a new epidemic strain in Eastern India? Emerg Infect Dis.
Available at: http://www.cdc.gov.ncidod/EUD/vol9no3/0203542.htm. Accessed
on March 28, 2003.
4. Mahon BE, Ponka A, Hall WN, et al. An international outbreak of Salmonella
infections caused by alfalfa sprouts grown from contaminated seeds. J Infect
Dis. 1997;175:876-882.
5. Van Beneden CA, Keene WE, Strang RA, et al. Multinational outbreak of
Salmonella enterica serotype Newport infections due to contaminated alfalfa
sprouts. JAMA. 1999;281:158-162.
6. Fukushima H, Hashizume T, Morita Y, et al. Clinical experiences in Sakai City
Hospital during the massive outbreak of enterohemorrhagic Escherichia coli
O157 infections in Sakai City, 1996. Pediatr Int. 1999;41:213-217.
7. Severe Acute Respiratory Syndrome (SARS). Available at:
http://www.cdc.gov/ncidod/sars. Accessed on March 28, 2003.
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