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# Plague
### Overview
*Last updated February 27, 2013* Agent
Key microbiological characteristics of
*Yersinia pestis* include the following (ASM 2013, Sneath 1986):
- Pleomorphic gram-negative bacillus (1.0 to 2.0 mcm x 0.5 mcm); single cells or short chains in direct smears
- Bipolar ("closed safety pin") staining with Giemsa, Wright's, or Wayson stains (may not be visible on Gram stain)
- Facultative anaerobe
- Nonmotile, nonsporulating
- Non–lactose fermenter
- Slow-growing in culture (colonies are pinpoint after 24 hours on sheep blood agar [SBA] and much smaller than other Enterobacteriaceae growing for 24 hours on SBA; colonies may not be visible on MacConkey or eosin methylene blue agar at 24 hours)
- Catalase-positive, oxidase- and urease-negative (rarely, strains may be urease-positive)
- Optimal growth at 28°C
- "Stalactite pattern" in broth culture with clumps of cells from the side of the tube settling to the bottom if disturbed
- At 48 to 72 hours of incubation on solid media, colonies have a raised, irregular, "fried egg" appearance under 4X enlargement, which becomes more pronounced as the culture ages; colonies also have been described as having a "hammered copper" shiny surface
- Alkaline slant/acid butt (K/A) on triple sugar iron agar (TSI) without gas or H
2S
- Generally susceptible to tetracyclines, chloramphenicol, aminoglycosides, sulfonamides (with or without trimethoprim), and fluoroquinolone antibiotics
*Y pestis *is divided into three classic biovariants (biovars) (Dennis 1997).
- Biovar antiqua (Africa, southeastern Russia, central Asia)
- Biovar medievalis (Caspian Sea)
- Biovar orientalis (Asia, Western Hemisphere)
Previously, the three biovars were thought to be responsible for the first, second, and third pandemics, respectively. Limited archeologic evidence suggests that all three pandemics were caused by the orientalis biovar (
[Drancourt 2007](http://wwwnc.cdc.gov/eid/article/13/2/06-0197_article)).
Other classification and diversity information includes:
- A nonvirulent strain, microtus, has been proposed as a fourth biovar (
[Zhou 2004:](http://www.ncbi.nlm.nih.gov/pmc/articles/PMC451627/?tool=pubmed)Genetics of metabolic variations between Yersinia pestis biovars and the proposal of a new biovar, microtus). *Y pestis*is thought to have evolved from *Yersinia pseudotuberculosis*1,500 to 20,000 years ago, and the two species remain closely related ( [Achtman 1999](http://www.pnas.org/cgi/reprint/96/24/14043.pdf)). Whole-genome sequence comparisons have identified 32 chromosomal genes and 2 plasmids in *Y pestis*but not *Y pseudotuberculosis*( [Chain 2004](http://www.pnas.org/cgi/content/full/101/38/13826)).
- The complete genomes of several strains have been sequenced and are available online (
[National Center for Biotechnology Information](http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=Genome), [Parkhill 2001](http://www.nature.com/nature/journal/v413/n6858/full/413848a0.html), [Song 2004](http://dnaresearch.oxfordjournals.org/cgi/reprint/11/3/179), [Zhou 2002](http://aem.asm.org/cgi/content/full/68/12/6321?view=long&pmid=12450857)). Pathogenesis
#### Virulence Factors
Virulence factors for
*Y pestis* are primarily encoded on the chromosome and on three plasmids (the *Pst* plasmid, the *Lcr* plasmid, and the *pFra* plasmid) (Dennis 1997).
The major virulence factors for
*Y pestis* are responsible for the following activities (Dennis 1997, [McGovern 1997](http://www.globalsecurity.org/wmd/library/report/1997/cwbw/Ch23.pdf), [Perry 1997](http://cmr.asm.org/cgi/reprint/10/1/35.pdf), [Titball 2003](http://www.biochemsoctrans.org/bst/031/0104/bst0310104.htm)):
- The ability of
*Y pestis*organisms to adhere to cell surfaces is a key step in pathogenesis. Irreversible binding to host cell receptors via adhesins allows the organisms to then penetrate the cell surfaces ( [Zhou 2006](http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16182593&query_hl=11)).
- The F1 antigen is antiphagocytic, elicits a humoral response, and is a target for immunologic-based diagnostic tests. Most pathogenic
*Y pestis*strains isolated from humans contain the F1 antigen.
- Plasminogen activator (Pla) is a protease that appears to degrade fibrin and other extracellular proteins and to facilitate systemic spread from the inoculation site. Expression of Pla allows
*Y pestis*to replicate rapidly in the airways. Pla is essential for *Y pestis*to cause primary pneumonic plague but is less important for dissemination during pneumonic than bubonic plague ( [Lathem 2007](http://www.sciencemag.org/cgi/content/abstract/315/5811/509)).
- The V and W antigens (produced at 37°C) cause the organisms to be resistant to phagocytosis; the V antigen is important for survival of
*Y pestis*in macrophages. *Yersinia*outer proteins (Yops) have a variety of activities, including inhibiting phagocytosis, inhibiting platelet aggregation, and preventing an effective inflammatory response.
- The outer membrane protein A (OmpA) enhances intracellular survival of
*Y pestis*( [Bartra 2012](http://www.sciencedirect.com/science/article/pii/S0882401011001719)).
- Lipopolysaccharide (LPS) endotoxin (encoded on the chromosome) causes the classic features of endotoxic shock. LPS consists of three domains: the hydrophobic membrane anchor (lipid A), the surface-exposed O-antigen polysaccharide, and the core sugar region connecting the other two. Most of the effects of LPS are caused by lipid A (LPS-lipid A) (
[Zhou 2006](http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16182593&query_hl=11)).
- Effectors secreted by the type 3 secretion system enable immunosuppression in the lungs, allowing for rapid, uninhibited growth of
*Y pestis*during the early preinflammatory phase of infection. These effectors alone, however, are not sufficient for this immune suppression to occur ( [Price 2012](http://eutils.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&id=22308352&retmode=ref&cmd=prlinks)).
- Phospholipase D (PLD) allows the bacilli to survive in the flea midgut.
*Yersinia*murine toxin (Ymt) is one of the factors required for maintaining *Y pestis*in fleas. Ymt is highly toxic for mice and rats but less active in other animals ( [Zhou 2006](http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16182593&query_hl=11)).
#### Bubonic Plague
- After a flea initially ingests
*Y pestis*, the organisms elaborate a coagulase that clots ingested blood in the proventriculus (an organ between the esophagus and stomach) of the flea, thus blocking passage of the next blood meal into the flea's stomach. Fleas with this blockage regurgitate *Y pestis*into the bite wound while attempting to feed ( [Perry 1997](http://cmr.asm.org/cgi/reprint/10/1/35.pdf)).
- From 25,000 to 100,000
*Y pestis*organisms are inoculated into the skin via the bite of an infected flea ( [Reed 1970](http://journals.lww.com/md-journal/Citation/1970/11000/Bubonic_Plague_in_the_Southwestern_United_States_.2.aspx)).
- As few as 1 to 10 organisms are sufficient to cause infection via the subcutaneous, intradermal, oral, or intravenous routes (
[Worsham 2007](https://www.hsdl.org/?view&did=19901)).
- A papule, vesicle, pustule, or furuncle may occur at the site of the fleabite but is noted in less than 10% of patients (Dennis 1997).
- The organisms migrate through the cutaneous lymphatics to regional lymph nodes. Comparative studies in mice reveal that
*Y pestis*virulence is associated with a distinct ability to massively infiltrate the draining lymph node without inducing an organized polymorphonuclear cell reaction ( [Guinet 2008](http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=18301765)).
- Once in the lymph nodes, they are phagocytized by polymorphonuclear neutrophils (PMNs) and mononuclear phagocytes. Organisms that are phagocytized by PMNs generally are destroyed, whereas those phagocytized by mononuclear cells proliferate intracellularly and develop resistance to further phagocytosis (
[Perry 1997](http://cmr.asm.org/cgi/reprint/10/1/35.pdf)). These organisms are released when cell lysis occurs.
- Initially, a thick, proteinaceous exudate that includes plague bacilli, PMNs, lymphocytes, and fewer macrophages can be found in affected nodes (Dennis 1997).
- Subsequently, the exudative pattern gives way to lakes of hemorrhagic necrosis, which obliterate the underlying lymph node architecture. A ground-glass amphophilic material that represents masses of bacilli may be present (
[CDC 2004](http://www.cdc.gov/mmwr/preview/mmwrhtml/rr5308a1.htm)).
- The inflammatory process creates swollen painful buboes and surrounding edematous tissues that are characteristic of bubonic plague. Bubo location is a function of the site of inoculation of plague bacilli by the infected flea (
[Worsham 2007](https://www.hsdl.org/?view&did=19901)).
- The organisms often enter the bloodstream, causing hemorrhagic lesions in other lymph nodes and in organs throughout the body (initially the liver and spleen). Findings from a study using a mouse model suggest that the organisms replicate in splenic macrophages during the later stages of infection (
[Lukaszewski 2005](http://iai.asm.org/cgi/content/full/73/11/7142)).
- Septicemia, disseminated intravascular coagulation (DIC), and shock can ensue.
- Unless treated promptly with appropriate antibiotic therapy, death usually results from overwhelming sepsis.
- A bioluminescence imaging study in mice found that
*Y pestis*bacteria initially multiply at the site of inoculation before colonizing the draining inguinal lymph nodes and the associated ipsilateral axillary lymph node. A mild bacteremia then develops and is cleared by the liver and spleen. Once the liver and spleen reach their filtering capacity, terminal septicemia develops. The study also showed that the primary location of multiplication of *Y pestis*is the secondary lymph nodes and that disease progression after colonization of the secondary lymph nodes is rapid ( [Nham 2012](http://dx.plos.org/10.1371/journal.pone.0034714)).
#### Septicemic Plague
- Primary septicemic plague is defined as systemic toxicity caused by
*Y pestis*infection but without apparent preceding lymph node involvement. Secondary septicemic plague occurs commonly with either bubonic or primary pneumonic plague.
- In primary septicemic plague,
*Y pestis*organisms can disseminate from a fleabitesite through thelymphatic system (but without clinically apparent involvement of the lymph nodes), directly through the circulatory system, orboth ( [Sebbane 2006](http://www.pnas.org/cgi/content/full/103/31/11766)).
- Septicemic plague causes sepsis syndrome with multiorgan involvement, DIC, and shock. In the late stages of infection, high-density bacteremia often occurs, leading to identification of organisms on peripheral blood smears (Butler 1991).
- The spleen, liver, kidneys, skin, and brain are the most commonly affected organs. Meningitis can occur and is characterized by a thick, yellow, fibrinous-purulent exudate. Foci of necrosis with hemorrhage are common, as are characteristic lesions of DIC (such as fibrin thrombi in glomerular capillaries or purpuric skin lesions) (Dennis 1997).
#### Pneumonic Plague
*Y pestis*can enter the lungs either through direct inhalation (primary pneumonic plague) or through hematogenous spread as a complication of bubonic or septicemic plague (secondary pneumonic plague).
- Primary pneumonic plague is acquired naturally by inhaling respiratory droplets from infected humans or animals (such as cats).
- The infectious dose by inhalation is estimated to be 100 to 500 organisms (
[Franz 1997](http://www.ncbi.nlm.nih.gov/pubmed/9244332)).
- Marked intra-alveolar edema and congestion of the lungs are common (
[CDC 2004](http://www.cdc.gov/mmwr/preview/mmwrhtml/rr5308a1.htm)). Pulmonary lesions include areas of central exudate with peripheral congestion. This pattern initially is lobular, but usually progresses to lobar consolidation (Dennis 1997).
- Distinguishing primary pneumonic plague from secondary hematogenous spread to the lungs can be difficult. Features that occur more commonly with primary pneumonic plague include the following (Dennis 1997):
- Tracheal and bronchial mucosal hemorrhages
- Fibrinous pleuritis and subpleural hemorrhages overlying areas of exudative pneumonia
- Less inflammation and necrosis and more exudation in lobular foci of the parenchyma
- Foci of pneumonia along medium and large bronchi
- More involvement of hilar lymph nodes
- Less severe evidence of disease in organs other than the lungs, if such evidence is present
- In primary pneumonic plague, as with bubonic plague, organisms often enter the bloodstream and cause multiorgan involvement, DIC, and shock.
- In the absence of early antibiotic therapy (ie, within the first 24 hours), death occurs from overwhelming sepsis (usually within several days after illness onset). Without therapy, mortality approaches 100%.
*Y pestis* may persist in necrotic tissues after antibiotic treatment despite negative blood cultures. Presumably, *Y pestis* becomes trapped in hypoperfused tissues and is able to persist because of: (1) inadequate delivery of antibiotics to affected areas and (2) the ability of the organisms to overcome local host defenses ( [Guarner 2005](http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16084958)). [Reservoirs](#reservoirs) [Vectors](#vectors) [Modes of Transmission](#modes) [Historical Perspective](#historical) [Naturally Occurring Plague in the US](#us) [Naturally Occurring Plague Worldwide](#worldwide) [Prevention](#prevention) Reservoirs
Animals (predominantly wild rodents) are considered to be the primary natural reservoirs for
*Y pestis*. More than 200 mammalian species have been shown to be infected with *Y pestis*.
In addition, soil may be an important reservoir. In one model, soil serves as the ultimate reservoir, with burrowing animals as the first link in the chain of transmission, followed by spread to other animals and humans through ectoparasites (via fleaborne transmission) (
[Drancourt 2006](http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?orig_db=PubMed&db=PubMed&cmd=Search&term=%22The+Lancet+infectious+diseases%22%5bJour%5d+AND+6%5bvolume%5d+AND+4%5bissue%5d+AND+234%5bpage%5d+AND+2006%5bpdat%5d+AND+Drancourt%5bauthor%5d)). Experimental studies document survival of *Y pestis *in soil from 24 days ( [Eisen 2008](http://wwwnc.cdc.gov/eid/article/14/6/08-0029_article): Persistence of Yersinia pestis in soil under natural conditions) to 40 weeks ( [Ayyadurai 2008](http://mic.sgmjournals.org/cgi/content/full/154/9/2865)); however, further study is needed to asses the role of soil in maintaining *Y pestis* in the natural environment ( [Drancourt 2006](http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?orig_db=PubMed&db=PubMed&cmd=Search&term=%22The+Lancet+infectious+diseases%22%5bJour%5d+AND+6%5bvolume%5d+AND+4%5bissue%5d+AND+234%5bpage%5d+AND+2006%5bpdat%5d+AND+Drancourt%5bauthor%5d)).
Some animal populations, such as mammalian carnivores, are relatively resistant to the effects of
*Y pestis* infection and serve as enzootic reservoirs (Dennis 1997). Although carnivores routinely are surveyed as sentinels of local plague activity, a 2009 study suggested this may be unreliable in some ecologic systems ( [Brinkerhoff 2009](http://www.ncbi.nlm.nih.gov/pubmed/18973449)). Plague-resistant mammalian carnivores may aid the spread of plague by feeding on and removing infected prairie dog carcasses to other areas ( [Boone 200](http://www.ncbi.nlm.nih.gov/pubmed/18945188?ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DefaultReportPanel.Pubmed_RVDocSum)9, [Salkeld 2007](http://www.jwildlifedis.org/doi/abs/10.7589/0090-3558-43.3.425)).
Other animal species, particularly rodents, are more susceptible to disease caused by
*Y pestis* and serve as epizootic hosts (Butler 1991, Gage 1998). Examples of susceptible rodents include the following (Dennis 1997, [Gabastou 2000](http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11127240&dopt=Abstract), [Reed 1970](http://journals.lww.com/md-journal/Citation/1970/11000/Bubonic_Plague_in_the_Southwestern_United_States_.2.aspx)):
- Urban and domestic rats
- Ground squirrels
- Rock squirrels
- Prairie dogs
- Deer mice
- Field mice
- Gerbils
- Voles
- Chipmunks
- Marmots
- Guinea pigs
- Kangaroo rats
Like humans, mammalian species other than rodents generally are incidental hosts for
*Y pestis*. However, such animals also can serve as sources of human exposure (either through direct contact or through flea vectors). Examples of animals other than rodents that are susceptible to plague include the following ( [Bevins 2009](http://wwwnc.cdc.gov/eid/article/15/12/09-0526_article), [Christie 1980](http://www.ncbi.nlm.nih.gov/pubmed/7391614), Dennis 1997, [Gage 2000](http://www.journals.uchicago.edu/doi/full/10.1086/313804), [Palmer 1971](http://jid.oxfordjournals.org/content/124/4/367.abstract), [Reed 1970](http://journals.lww.com/md-journal/Citation/1970/11000/Bubonic_Plague_in_the_Southwestern_United_States_.2.aspx), [von Reyn 1976](http://www.ncbi.nlm.nih.gov/pubmed/961983), [Wild 2006](http://www.jwildlifedis.org/doi/abs/10.7589/0090-3558-42.3.646)):
- Domestic and feral cats
- Wild cats
- Dogs
- Lagomorphs (rabbits and hares)
- Coyotes
- Camels
- Goats
- Deer
- Antelope
Humans are incidental hosts for
*Y pestis* and are not part of the natural life cycle of the organisms. The risk of spread of plague from rodents to humans is related to the density of rodents, the number of fleas per animal (flea index), and the rate of *Y pestis* infection in the rodents and fleas (Dennis 2010). Disease occurrence in humans also depends on the degree of contact between rodents and humans. Most human exposures to plague occur in the peridomestic environment, and free-roaming pets that bring infected rodent fleas into the home are considered to be a potential source of infection as well ( [CDC 2006](http://www.cdc.gov/mmwr/preview/mmwrhtml/mm55d825a1.htm)).
- Human outbreaks usually are preceded by epizootics with increased deaths in susceptible animal hosts (Butler 1991,
[Perry 1997](http://cmr.asm.org/cgi/reprint/10/1/35.pdf)).
- Exposure to dogs was found to be a significant risk factor for plague among infected patients in New Mexico. Patients with plague were more likely to report having a sick dog or having slept in the same bed with a pet dog than were controls (
[Gould 2008](http://www.ncbi.nlm.nih.gov/pubmed/18489541)). Infected cats were the source of 7.7% of the 297 cases of plague in the United States from 1977 through 1998 ( [Gage 2000](http://www.journals.uchicago.edu/doi/full/10.1086/313804)).
- In Africa, a study of fleas that have humans as their host (the "human flea,"
*Pulex irritans*) revealed that they may be an indicator of plague potential in rural areas and may play a role in plague epidemiology ( [Laudisoit 2007](http://wwwnc.cdc.gov/eid/article/13/5/06-1084_article)). Cat fleas may also be secondary vectors for plague in Africa ( [Eisen 2008](http://www.ajtmh.org/cgi/content/full/78/6/949): Early-phase transmission of Yersinia pestis by cat fleas).
- Analysis of serum samples from domestic dogs and cats in an area of China that had recent human plague cases suggests that these animals may serve as sentinels for surveillance (
[Li 2008](http://www.ajtmh.org/cgi/content/full/79/5/799)).
- A study in Arizona found that a 17% or higher seroprevalence of
*Y pestis*in coyotes was predictive of increased risk of human disease, suggesting that such surveillance could be a tool for public health risk assessments ( [Brown 2011](http://www.liebertonline.com/doi/abs/10.1089/vbz.2010.0196)).
- Logistic regression models were used to identify landscape features associated with areas where humans have acquired plague from 1957 to 2004 in the four-corners region of the United States (Arizona, Colorado, New Mexico, and Utah). The overall accuracy of the model was >82%, and the most conservative model predicted that 14.4% of the region represented a high-risk area of peridomestic exposure to
*Y pestis*( [Eisen 2007](http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=ShowDetailView&TermToSearch=17547242&ordinalpos=2&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum): Human plague in the southwestern United States, 1957-2004). Such information can be used to identify target areas for surveillance and control ( [Eisen 2007](http://www.ajtmh.org/cgi/content/full/77/1/121): Residence-linked human plague in New Mexico).
Plague dynamics also appear to be driven by climate variation and seasonal influences.
- Studies of plague movement eastward from California show that factors such as climatic and environmental variables can influence spread (
[Adjemian 2007](http://www.ajtmh.org/cgi/content/full/76/2/365)).
- In the western United States, above-normal numbers of human cases of plague are associated with El Nino weather patterns, which result in a wetter and milder climate. This could be explained by the fact that wetter conditions increase the food supply for rodents, thereby increasing the rodent reservoir for
*Y pestis*( [Ari 2010](http://www.ajtmh.org/content/83/3/624.long)).
- Models of climate change suggest that over the next 50 years geographic shifts of zoonotic diseases such as tularemia and plague will occur. Plague disease ranges in the United States have the potential to expand from a current central focus in New Mexico north into Wyoming and Idaho (
[Nakazawa 2007](http://www.ncbi.nlm.nih.gov/pubmed/18047395)).
- Another study used logistic regression and geographic information system (GIS)–based modeling to identify environmental predictors of elevated risk for plague in the southwestern United States. Results showed that two factors (distance to pinon-juniper ecotones and amount of precipitation) accurately identified case locations as suitable for plague (producer accuracy, 93%) (
[Eisen 2007](http://www.ajtmh.org/cgi/content/full/77/6/999): A spatial model of shared risk for plague and hantavirus pulmonary syndrome in the southwestern United States).
- In the central highlands of Vietnam, a study was conducted to examine the association between plague and ecologic factors from 1997 through 2002 (
[Pham 2009](http://www.ncbi.nlm.nih.gov/pubmed/19584125)). Study data indicated that the risk of plague was increased during dry and hot months when the flea index and rodent density increased.
- A modeling analysis from China that used 114 years of spatial and temporal human plague records with proxy data on climate conditions found that the impact of precipitation on plague cases depended on the regional climate. In northern China(arid climate), above-normal but not extreme levels of precipitation were generally associated with increased plague intensity. In southern China(tropical climate), plague intensity generally decreased when wetness increased (
[Xu 2011](http://www.pnas.org/content/108/25/10214.abstract)). The authors noted that in northern China rodents generally respond positively to increased precipitation, but in southern China rodents generally respond negatively to increased precipitation. Vectors
The organisms most commonly are transmitted between animal reservoirs and to humans via bites of infected fleas. In order to survive in the flea midgut,
*Y pestis* organisms require phospholipase D (PLD; formerly referred to as *Yersinia* murine toxin), which allows the organisms to be resistant to a cytotoxic digestion product of blood plasma in the flea gut. One study demonstrated that the acquisition of the gene, *ymt* (which encodes for PLD) in conjunction with the acquisition of other virulence traits was necessary for *Y pestis* to transform from a rather benign species of gut bacteria to a major global pathogen ( [Hinnebusch 2002](http://www.ncbi.nlm.nih.gov/pubmed/11976454)).
Of the more than 1,500 flea species, about 30 are known to be vectors for
*Y pestis*. Examples include ( [Perry 1997](http://cmr.asm.org/cgi/reprint/10/1/35.pdf)): *Xenopsylla cheopis*(the oriental rat flea; nearly worldwide in moderate climates) *Oropsylla montanus*(United States) *Nosopsyllus fasciatus*(nearly worldwide in temperate climates) *X brasiliensis*(Africa, India, South America) *X astia*(Indonesia and Southeast Asia) *X vexabilis*(Pacific Islands)
The most common and efficient flea vector is
*X cheopis, *and most infected fleas come from the black rat *Rattus rattus* or the brown rat *R norvegicus* ( [Butler 2009](http://www.journals.uchicago.edu/doi/full/10.1086/604718)) *.* Because of the poor vector competence of fleas, plague epizootics require a high flea burden per host, even when the susceptible host population density is high ( [Lorange 2005](http://www.journals.uchicago.edu/doi/full/10.1086/429931)). In North America the ecological requirements of the vector may be more important than the host in sustaining plague niches ( [Maher 2010](http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2946734/)).
Experimental studies of human body lice have demonstrated that lice also can serve as vectors of
*Y pestis. *In one study, infected lice were able to transmit two virulent strains of plague to uninfected rabbits that subsequently became septicemic and died of plague. Infections were transmitted to naïve lice that fed on infected rabbits ( [Houhamdi 2006](http://www.journals.uchicago.edu/doi/full/10.1086/508995)). This experiment has been replicated with success, raising questions regarding the role body lice played in transmission of *Y pestis *during the Black Death (a medieval plague epidemic) ( [Ayyadurai 2010](http://wwwnc.cdc.gov/eid/article/16/5/09-1280_article.htm)). Modes of Transmission
Bubonic plague is transmitted from animal reservoirs via:
- Bites from flea vectors
- Bites or scratches from infected animals, such as cats (
[Gage 2000](http://www.journals.uchicago.edu/doi/full/10.1086/313804))
- Direct contact with infected animal carcasses, such as rodents (especially marmots), rabbits, hares, carnivores (eg, wild cats, coyotes), and goats (
[Christie 1980](http://www.ncbi.nlm.nih.gov/pubmed/7391614), [Reed 1970](http://journals.lww.com/md-journal/Citation/1970/11000/Bubonic_Plague_in_the_Southwestern_United_States_.2.aspx), [von Reyn 1976](http://www.ncbi.nlm.nih.gov/pubmed/961983))
Pneumonic plague is transmitted via:
- Inhalation of respiratory droplets (ie, large droplets [>5 microns]) from infected animals such as cats (
[Gage 2000](http://www.journals.uchicago.edu/doi/full/10.1086/313804))
- Inhalation of respiratory droplets from a person with primary or secondary pneumonic plague
- Inhalation of aerosols generated from procedures involving infected human or animal tissues, such as autopsies or necropsies (
[Wong 2009](http://www.journals.uchicago.edu/doi/full/10.1086/600818))
- Handling
*Y pestis*cultures in the laboratory ( [Burmeister 1962](http://annals.org/article.aspx?volume=56&page=789))
Plague also can be transmitted via ingestion of contaminated meat.
- One report identified 5 patients with plague who acquired infection after eating raw camel liver; 4 developed severe pharyngitis and 1 developed submandibular lymphadenitis (
[Bin Saeed 2005](http://wwwnc.cdc.gov/eid/article/11/9/05-0081_article)).
- In another report from Jordan, pharyngeal plague developed in 12 people after they consumed contaminated camel meat; 11 ate the meat raw and 1 ate cooked meat (
[Arbaji 2005](http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?orig_db=PubMed&db=PubMed&cmd=Search&term=Ann+Trop+Med+Parasitol+%5bJour%5d+AND+99%5bvolume%5d+AND+8%5bissue%5d+AND+789%5bpage%5d+AND+2005%5bpdat%5d)).
- A recent outbreak in Afghanistan involved 83 patients who developed severe gastroenteritis after consuming contaminated camel meat (
[Leslie 2011](http://journals.cambridge.org/action/displayAbstract?fromPage=online&aid=8246077)).
The risk of infection among contacts of cases of pneumonic plague varies with intensity of exposure and possibly with environmental factors.
- During an outbreak of pneumonic plague in Madagascar, investigators measured serum F1 antibodies among contacts and estimated that the secondary infection rate was 8.4% (
[Ratsitorahina 2000](http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=10675169&query_hl=1)).
- Another report reviewed eight documented outbreaks of pneumonic plague and found that the average number of secondary transmissions per primary transmission ranged from 0.8 to 3.0 (mean, 1.5; median, 1.3) (
[Gani 2004](http://wwwnc.cdc.gov/eid/article/10/4/03-0509_article)).
- A third study involved one definite and three probable plague cases (two concurrent index patient-caregiver pairs) (
[Begier 2006](http://wwwnc.cdc.gov/eid/article/12/3/05-1051_article)). Each index case transmitted infection to one caregiver, although there were 23 additional close contacts for the two index cases (yielding a secondary infection rate of 8%). Transmission was consistent with large-droplet spread.
- Several experimental studies have been conducted to determine how far
*Y pestis*organisms will spread from patients with pneumonic plague. These studies involved placing agar plates at various distances from the mouths of infected patients. The greatest distance of spread was 3.7 feet, indicating that close contact is necessary for transmission ( [Kool 2005](http://www.journals.uchicago.edu/doi/full/10.1086/428617)).
- An analysis of 1,001 US plague cases occurring over 109 years demonstrated that most pneumonic plague cases fail to transmit infection to others and do not result in secondary cases. However, there appears to be a high variability in individual transmission potential, and super spreading events can occur (
[Hinckley 201](http://www.ncbi.nlm.nih.gov/pubmed/21733272)2). Historical Perspective
Plague is one of the oldest identifiable diseases known to man (
[WHO](http://www.who.int/csr/resources/publications/plague/WHO_CDS_CSR_EDC_99_2_EN/en/): Plague manual). Three plague pandemics have been recorded throughout history ( [WHO 2000](http://www.who.int/csr/resources/publications/surveillance/plague.pdf)), with an estimated 200 million deaths ( [Perry 1997](http://cmr.asm.org/cgi/reprint/10/1/35.pdf)). Brief descriptions of the three pandemics follow.
- The first pandemic started in Egypt in 542 AD and continued for more than a century. Outbreaks in Europe, Central and Southern Asia, and Africa killed an estimated 100 million people.
- The second pandemic began in Italy in 1347 and rapidly spread throughout Europe over the next several years, killing an estimated one third of the European population. Paleodemographic studies suggest that mortality was partially determined by relative health of those infected (
[DeWitte 2008](http://www.pnas.org/content/105/5/1436.full)). During that time, plague became known as the Black Death. Outbreaks of plague continued to occur sporadically in Europe over the next several centuries. Recent genetic analysis suggests that the Black Death was caused by a variant of *Y pestis*biovar *Medievalis*that no longer exists ( [Schuenemann 2011](http://www.pnas.org/content/108/38/E746)).
- The third pandemic began in 1894 in China and spread around the world over a 10-year period, predominantly by infected rats and their fleas aboard steamships. An estimated 12 million deaths occurred, mostly in India.
Although bubonic plague historically has been the most common form of disease, large outbreaks of pneumonic plague (with person-to-person transmission as the primary mode of spread) also have been reported (
[Kool 2005](http://www.journals.uchicago.edu/doi/full/10.1086/428617), [Meyer 1961](http://www.ncbi.nlm.nih.gov/pmc/articles/PMC441101/pdf/bactrev00130-0086.pdf)).
- Two large outbreaks of pneumonic plague occurred in Manchuriain the early 20th century (1910-1911 and 1920-1921). An estimated 60,000 deaths occurred in the former and an estimated 9,300 in the latter.
- Two pneumonic plague outbreaks occurred in the United States in the early 1900s (
[Anderson 1978](http://canarydatabase.org/record/2552), [Kool 2005](http://www.journals.uchicago.edu/doi/full/10.1086/428617)). The first occurred in 1919 in Oakland,California. The index case was a hunter who contracted bubonic plague from an infected squirrel. He subsequently developed plague pneumonia and transmitted the disease to 12 or 13 other persons. A second outbreak occurred in Los Angeles in 1924 and involved 39 cases of pneumonic plague. Naturally Occurring Plague in the United States
- Plague was first introduced into the United States in 1900 from China; the first plague epidemic occurred in San Francisco from 1900 to 1904 (
[Caten 1968](http://jama.ama-assn.org/content/205/6/333.abstract)).
- Up through 1926, plague occurred most commonly in urban settings (particularly in California) and was associated with infections in urban rat populations (
[Kaufmann 1980](http://www.jstor.org/stable/30081738)).
- After 1926, plague gradually became endemic in wild animal populations in the western United States (generally in wild rodents), and human cases continued to occur in persons with exposure to such populations.
- Cases also have occurred following exposure to infected cats (
[Eidson 1988](http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1349433/?tool=pubmed), [Gage 2000](http://www.journals.uchicago.edu/doi/full/10.1086/313804)). In the western United States from 1977 through 1998, 23 cases of cat-associated plague were reported; 5 were cases of primary pneumonic plague ( [Gage 2000](http://www.journals.uchicago.edu/doi/full/10.1086/313804)).
- From 1947 through 1996, 390 cases of plague were reported to the Centers for Disease Control and Prevention (CDC) (
[CDC 1997](http://www.cdc.gov/mmwr/preview/mmwrhtml/00048352.htm): Fatal human plague—Arizona and Colorado, 1996):
- The overall case-fatality rate was 15.4%.
- Bubonic plague accounted for 327 (83.8%) cases.
- Primary septicemic plague accounted for 49 (12.6%) cases.
- Primary pneumonic plague accounted for 7 (1.8%) cases.
- Seven cases were unclassified.
- From 1990 through 2005, 107 cases of plague were reported to the CDC, with a median of 7 cases per year (
[CDC 2006](http://www.cdc.gov/mmwr/preview/mmwrhtml/mm55d825a1.htm)).
- Since the 1920s, most human plague cases in the United States have occurred in California, New Mexico, Arizona, and Colorado (
[CDC 1994](http://www.cdc.gov/mmwr/preview/mmwrhtml/00026077.htm)).
- Most human cases in the United States occur in two regions: (1) northern New Mexico, northern Arizona, and southern Colorado and (2) California, southern Oregon, and far western Nevada(
[CDC](http://www.cdc.gov/ncidod/dvbid/plague/epi.htm): Plague: epidemiology). In April 2006, Los Angeles County health officials confirmed a case of bubonic plague in a local resident; this was the first human case of plague in a Los Angeles County resident since 1984 ( [County of Los Angeles Department of Health Services](http://lapublichealth.org/phcommon/public/media/mediapubdetail.cfm?unit=media&ou=dhs&prog=media&cur=cur&prid=384&row=25&start=1)).
- Between February and July 2006, 13 human cases of plague were reported among residents of four states: New Mexico, 7; Colorado, 3; California, 2; and Texas, 1. This total is the largest number of cases reported in a single year in the United States since 1994.
- The increased number of cases during this time frame is consistent with the predicted relationship between climate and frequency of human plague in the southwestern United States.
- Two consecutive February-March periods with high precipitation and an intervening cool summer favor an increased number of cases of plague the following summer. The net effect is increased reproduction and survival rates among rodents and fleas (
[CDC 2006](http://www.cdc.gov/mmwr/preview/mmwrhtml/mm55d825a1.htm), [Enscore 2002](http://www.ajtmh.org/cgi/reprint/66/2/186)).
- In the 1980s, individuals of lower socioeconomic status tended to live in the highest risk areas for plague in New Mexico; however, that trend had changed by the 2000s. More recent information indicates that those who live in affluent areas of Santa Fe and Albuquerque tend to be at greater risk for plague (
[Schotthoefer 2012](http://eutils.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&id=22709463&retmode=ref&cmd=prlinks)).
- Plague in the United States generally is seasonal, with a higher incidence in the summer months (
[Caten 1968](http://jama.ama-assn.org/content/205/6/333.abstract), [Kaufmann 1980](http://www.jstor.org/stable/30081738)).
- In the United States, males and females are affected nearly equally by plague. More than half of plague cases occur in persons younger than 20 years old. Although most cases occur in whites, Native Americans and Hispanics have the highest incidence rates in the endemic Southwest (Dennis 2010).
- A fatal laboratory-acquired case of septicemic plague was identified in September 2009 in Chicago. This was the first fatal infection from an attenuated strain of
*Y pestis*and the first laboratory-associated infection since 1959. The route of exposure was not determined, and this strain of *Y pestis*was not a select agent and thus was handled under biosafety level 2 (BSL-2) conditions ( [Frank 2011](http://www.nejm.org/doi/full/10.1056/NEJMc1010939), [Ritger 2011](http://www.cdc.gov/mmwr/preview/mmwrhtml/mm6007a1.htm)). Naturally Occurring Plague Worldwide
The worldwide numbers of human plague may be significantly underestimated. Plague is underdiagnosed and misdiagnosed because the clinical presentation often is nonspecific and the means for laboratory confirmation often are absent. Additionally, countries may fail to report plague cases, and many countries have dismantled their plague surveillance systems. The reliability of country-specific plague incidence and mortality data varies for these same reasons (
[WHO 2010](http://www.who.int/wer/2010/wer8506.pdf)).
Natural enzootic foci of plague (and therefore areas with the highest incidence of human disease) include the following countries or regions (
[Bertherat 2007](http://wwwnc.cdc.gov/eid/article/13/10/07-0284_article), [CDC](http://www.cdc.gov/ncidod/dvbid/plague/info.htm): Plague: information on plague, [WHO 2000](http://www.who.int/csr/resources/publications/surveillance/plague.pdf)):
- Madagascar
- Eastern and southern Africa (eg, Democratic Republic of the Congo [DRC], Tanzania, Uganda, Kenya, Mozambique, Botswana)
- Algeria
- Southeast Asia (particularly Vietnam and Myanmar)
- Pockets in South America (including areas in the Andean regions ofPeru, Bolivia, and Ecuador and in northeastern Brazil)
- The western United States
- Mongolia and northern China
- Russia (the area of the Caucasus Mountains) and central Asia into the Middle East
Between 1954 and 1997, 38 countries reported cases of human plague to the WHO (
[WHO 2000](http://www.who.int/csr/resources/publications/surveillance/plague.pdf)). No plague cases have been reported from Europe since shortly after World War II, and no cases have been reported from Australia. Overall, 80,613 cases were reported, with a mean of 1,832 cases per year (range, 200 to 6,004 cases).
- The overall case-fatality rate was 11.8%.
- Seven countries reported cases of plague for each of the 44 years: Brazil, DRC, Madagascar, Myanmar, Peru, the United States, and Vietnam.
- Large outbreaks occurred in Vietnam (from 1966 through 1972), India (1954, 1963, and 1994), Tanzania (1990 through 1992), and Madagascar (1994 through 1996).
- The 1994 outbreak in India included cases of pneumonic plague and raised concerns about the spread of pneumonic plague to other areas of the world through airline travel (
[Campbell 1995](http://www.annals.org/content/122/2/151.long), [Titball 1998](http://bmb.oxfordjournals.org/cgi/reprint/54/3/625)).
- In 1997, a localized outbreak of pneumonic plague involving 18 patients occurred in Madagascar; most of the patients had exposure to a traditional healer who died of the disease after treating the index patient (
[Ratsitorahina 2000](http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=10675169&query_hl=1)).
The average annual global incidence of human plague has not changed markedly since 1998; however, there has been a general upward trend in incidence since 2005. In 2009, a large decrease in incidence was recorded. From 2004 to 2009, a total of 12,548 cases of plague, including 845 deaths, were reported to the WHO by 16 countries in Africa, Asia, and the Americas(
[WHO 2010](http://www.who.int/wer/2010/wer8506.pdf)).
- The global case-fatality rate was 7%.
- Four countries reported cases of plague each year during this period (DRC, Madagascar, Peru, and the United States).
- Africa reported the vast majority of worldwide cases (98%) and deaths (97%). Historical data on plague occurrence in Africa was compiled in a centralized database (
[Neerinckx 2010](http://www.ncbi.nlm.nih.gov/pubmed/19716148)). From 1877 through 2008, hundreds of thousands of human plague infections were reported in nearly half of Africa's countries. Data from the 20th century show that the number of African plague cases peaked in 1929 and then rapidly declined, although sporadic outbreaks occurred. During the last 30 years, reported cases of plague have increased dramatically in Africa, a trend that may be continuing. This upward trend in cases may represent a real increase or an improvement in reporting to the WHO.
Examples of major outbreaks around the globe include the following:
- During 2003, plague reemerged in Algeria after an absence of more than 50 years. Eighteen bubonic plague cases and one death were observed (
[Bertherat 2007](http://wwwnc.cdc.gov/eid/article/13/10/07-0284_article)). In 2008, 4 more cases of plague were identified (3 bubonic and 1 pneumonic, which was fatal) in a remote region of Algeria ( [Bitam 2010](http://www.ncbi.nlm.nih.gov/pubmed/20875302)). Previously, no natural focus of plague had been described in Algeria.
- An outbreak of pneumonic plague was reported in the DRC in early 2005. Cases occurred between December 2004 and March 2005 in employees of a diamond mine where about 7,000 people worked under crowded conditions with poor sanitation. The WHO reported 130 cases with 57 deaths in its last bulletin on the subject (
[WHO](http://www.who.int/csr/don/archive/disease/plague/en/): Plague in the Democratic Republic of the Congo). It is likely that the index case acquired Y pestis infection through a fleabite and then developed the pneumonic form of the disease and subsequently transmitted infection to other workers through the respiratory route. Additional outbreaks of pneumonic plague occurred in 2006 in the Oriental province of the DRC ( [WHO](http://www.who.int/csr/don/archive/disease/plague/en/): Plague in the Democratic Republic of the Congo). More than 620 cases, including 42 deaths, were reported from the end of July to mid-October; however, investigators suspect that the total may be overestimated because of the low fatality rate observed among cases.
- During 2006 in northwestern Uganda, an outbreak of 127 plague cases and 28 deaths occurred (
[CDC 2009](http://www.cdc.gov/mmwr/preview/mmwrhtml/mm5828a3.htm)). Clinical criteria were used for identifying plague cases because of limited laboratory capacity. Among the 102 patients with documented symptoms, 90 (88%) had bubonic plague and 12 (12%) had pneumonic plague. Case-fatality rates were 10% and 92% for the bubonic and pneumonic forms, respectively. Interviews of surviving patients and villagers revealed recent exposure to dead rats in or near homes.
- Two outbreaks of pneumonic plague occurred in Himachal Pradesh, India, during 2002. The first outbreak was started by a hunter who killed and skinned a sick wild cat. Before he died, he infected 13 relatives and 2 hospital patients. Overall, the case-fatality rate for this outbreak was 25% (4/16) (
[Gupta 2007](http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2725948/)). The second outbreak was first suspected when 4 members of the same family were hospitalized with similar respiratory symptoms. Active surveillance was initiated, and 30 cases were identified, including 5 fatalities (case-fatality rate, 17%) ( [Joshi 2009](http://www.ncbi.nlm.nih.gov/pubmed/19211117)).
- In December 2007, an outbreak of severe gastroenteritis caused by
*Y pestis*was reported in southern Afghanistan. This represents the first reported outbreak of plague in Afghanistan. There were 83 probable cases and 17 deaths, for a case-fatality rate of 20.5%. An infected symptomatic camel was butchered and the meat was widely distributed between two villages. Initially this outbreak was attributed to *Bacillus anthracis*, but testing several months after the outbreak was over confirmed *Y pestis*as the causative agent ( [Leslie 2011](http://journals.cambridge.org/action/displayAbstract?fromPage=online&aid=8246077)).
- In August 2009, China Experienced an outbreak of pneumonic plague in the remote town of Ziketan, Qinghai province (
[WHO](http://www.who.int/csr/don/2009_08_11/en/index.html): Plague in China). The index case was a herdsman; he was referred to a hospital but died en route. Subsequently, 11 people who had close contact with the herdsman developed symptoms and were hospitalized. Two of these patients also died. Specimens taken from all 12 people tested positive for plague. An epidemiologic investigation of the outbreak revealed the source was a marmot, which had contact with the index case's dog.
- In June 2009, Libya experienced its first outbreak of plague in decades. The index case was a young male in a nomadic family, who later died. Five cases were identified, including two additional family members and two individuals who were not epidemiologically linked to the other cases. Genetic analysis of the involved strain showed that it was not similar to the strain that caused a plague outbreak in neighboring Algeria, suggesting that the outbreak resulted from reactivation of a dormant focus of disease (
[Cabanel 2013](http://wwwnc.cdc.gov/eid/article/19/2/12-1031_article.htm)). Prevention
Most plague cases occur in impoverished, unsanitary environments with close proximity to large commensal or wild rodent populations (
[Butler 2009](http://www.journals.uchicago.edu/doi/full/10.1086/604718)). In endemic areas, plague prevention involves providing public health education, rodent-proofing dwellings and workplaces, removing food and shelter for rodents, using insecticides and repellants in areas frequented by rodents, and controlling fleas on pets (Dennis 2010). Insecticides must be used to kill fleas before rodenticides are employed (Oyston 2009). Indoor residual spraying in plague-endemic areas appears to be effective in mitigating flea transmission ( [Borchert 2012](http://www.bioone.org/doi/abs/10.1603/ME11230)).
Experience with plague as a biological weapon is limited; however, the following information supports the perspective that plague deserves serious consideration as a bioterrorist agent:
- Plague was used as a biological weapon in the Middle Ages when armies catapulted dead plague victims into cities under siege in order to spread the disease (Osterholm 2000).
- Japan used plague as a biological weapon against the Chinese during World War II by dropping plague-infected fleas over populated areas and causing outbreaks of the disease (
[McGovern 1997](http://www.globalsecurity.org/wmd/library/report/1997/cwbw/Ch23.pdf), Osterholm 2000).
- In the years following World War II, biological weapons programs in the United States and the Soviet Union developed techniques for aerosolizing
*Y pestis*, thus enhancing the effectiveness of this agent as a potential biological weapon ( [Inglesby 2000](http://jamanetwork.com/journals/jama/fullarticle/192665)).
- A 1970 WHO report estimated that an aerosol release of 50 kg of dried powder containing 6 x 10
15 *Y pestis*bacteria over a city of 5 million people in an economically developed country (such as the United States) would produce 150,000 incapacitating illnesses and up to 36,000 deaths ( [WHO](http://www.who.int/csr/delibepidemics/biochem1stenglish/en/): Health aspects of chemical and biological weapons). These estimates did not take into consideration secondary cases that would occur through subsequent person-to-person contact.
- Plague is a suitable pathogen for use as a biological weapon because:
*Y pestis*is readily available and may be produced in large quantities.
- The organisms can be delivered in an aerosol form.
- Pneumonic plague causes a serious illness with a high case-fatality rate.
- Pneumonic plague is communicable, and large outbreaks have occurred in the past.
- A bioterrorist attack involving pneumonic plague would cause widespread fear and panic that would be difficult to contain, partly because of the communicable nature of the disease (
[Campbell 1995](http://www.annals.org/content/122/2/151.long), [Inglesby 2001](http://www.journals.uchicago.edu/doi/full/10.1086/318513)). *Y pestis*could potentially be genetically altered to enhance virulence or create antibiotic-resistant strains ( [Gilsdorf 2005](http://www.journals.uchicago.edu/doi/full/10.1086/428843)).
- Plague used as a bioterrorist weapon would be expected to have the following features:
- Previously healthy patients would present with a severe and rapidly progressive pneumonia.
- An acute multilobar pneumonia accompanied by hemoptysis, associated gastrointestinal symptoms, and a fulminant clinical course would be very suspicious for pneumonic plague.
- Many similar cases would present over several days.
- Illness onsets would generally occur 2 to 4 days after release but could occur as soon as 1 day and up to 6 days later.
- Buboes characteristic of bubonic plague would not be present.
- Illness would likely occur in an urban area and patients would not have a history of recent travel to a plague-endemic region (ie, southwestern United States).
- Patients would not necessarily have risk factors for plague exposure (eg, outdoor field work, veterinary work, recent outdoor recreational activity).
- There would be no indication of a prior recent plague epizootic with rodent deaths in the affected community.
- Antibiotic resistance may be present.
- Investigators used univariate and multivariate modeling to assess key parameters for controlling a pneumonic plague outbreak (
[Massin 2007](http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=17121692&query_hl=43&itool=pubmed_docsum)). Using a hypothetical reference scenario of 1,000 index cases of plague pneumonia in Paris, if interventions were taken 10 days after an attack, an estimated 2,500 deaths would occur. Rapidity of implementing interventions offered the greatest effect on final epidemic size. Other measures, in order, were wearing masks, treating contacts preventively, and quarantine. Limiting inter-regional mixing confined casualties to the region but did not reduce casualties in the model.
- A new model focused on human risks and the uncertainties of an intentional airborne release of category A agents has been developed. This model can be used to refine risk assessments and response plans (
[Hong 2012](http://dx.plos.org/10.1371/journal.pone.0032732)).
[Overview](#over) [Clinical Features](#clinical) [Pediatric Considerations](#pediatric) [Differential Diagnosis](#differential) [Images](#images) Overview *Y pestis* infection can cause the following clinical syndromes:
- Bubonic plague
- Primary septicemic plague
- Primary pneumonic plague
- Plague meningitis
- Plague pharyngitis
- Gastroenteritis
- Pestis minor
- Subclinical infection
The classic forms of plague are bubonic plague, septicemic plague, and pneumonic plague; these are outlined in the tables below. Septicemic plague can be either primary or secondary to bubonic plague. Similarly, pneumonic plague can be either primary or secondary to septicemic plague or bubonic plague (ie, following hematogenous spread).
Brief information about other syndromes caused by
*Y pestis* infection follows:
- Plague meningitis occurs as a complication of bacteremia and may be the presenting clinical syndrome for some cases. Symptoms are typical of meningitis from other causes and include fever, headache, meningismus, and mental status changes. If meningitis occurs as a complication of bubonic plague, some data suggest that a bubo in the axillary region is a predisposing factor (Butler 1976). The cerebrospinal fluid demonstrates PMNs; characteristic gram-negative organisms usually can be seen on Gram stain (Butler 1991).
- Plague pharyngitis occurs as a result of inhaling or ingesting
*Y pestis*organisms. The clinical illness is similar to severe pharyngitis or acute tonsillitis from other causes (eg, streptococcal infection); inflamed cervical nodes usually are present (and usually have the features of a characteristic bubo or buboes). As with bubonic plague, septicemia can occur. Asymptomatic pharyngeal colonization with *Y pestis*has been noted among healthy contacts of pneumonic plague cases (Dennis 2010).
- A report from Afghanistan describes an outbreak of severe gastroenteritis associated with consumption of camel meat. Patients presented with fever, vomiting, and diarrhea; some also had pharyngeal lesions and lymphadenopathy. The case-fatality rate was 20.5% (
[Leslie 2011](http://journals.cambridge.org/action/displayAbstract?fromPage=online&aid=8246077)).
- Pestis minor is a milder form of bubonic plague. Patients usually have a febrile illness with localized lymphadenopathy. The nodes drain and patients recover without therapy. Patients with this form of plague are more likely to have some preexisting immunity to
*Y pestis*( [Legters 1970](http://www.ajtmh.org/cgi/content/abstract/19/4/639)).
- Subclinical infections can occur as evidenced by cross-sectional surveys of serum antibody titers in populations living in endemic areas (
[Ratsitorahina 2000](http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=10675169&query_hl=1)). Clinical Features
## Clinical Features of Bubonic Plague
## Feature
## Characteristics
Incubation period
1-7 days
Presenting features
—Sudden onset of fever, chills, weakness
Laboratory features
—Laboratory features for case series of 40 Vietnamese patients
Complications
—Secondary septicemia (can lead to DIC, shock, multisystem involvement)
Case-fatality rate
—Over 50% without antibiotic therapy
## Clinical Features of Primary Septicemic Plague
## Feature
## Characteristics
Incubation period
1-4 days
Presenting features
—10%-25% of US plague cases present with primary septicemic plague
Laboratory features
—Laboratory features consistent with severe bacterial infection and sepsis syndrome (as often seen with bubonic plague and secondary septicemia)
Complications
—Illness rapidly progresses to sepsis syndrome, often with DIC, shock, and multisystem involvement
Case-fatality rate
—Overall 30%-50%
## Clinical Features of Primary Pneumonic Plague
## Feature
## Characteristics
Incubation period
1-4 days
Presenting features
—Symptoms of primary plague pneumonia
Laboratory features
—Findings consistent with severe bacterial infection and sepsis syndrome (as often seen with bubonic and primary septicemic plague)
Complications
—Septicemia with sepsis syndrome
Case-fatality rate
—Close to 100% without appropriate antibiotic therapy (generally, fatality rates are high if antibiotic therapy is not instituted soon after symptom onset [ie, within 24 hr]; however, patients may survive even if appropriate therapy is instituted beyond 24 hr)
A review of the medical literature on pneumonic plague was undertaken to characterize its early clinical course and presentation (
[Babin 2010](http://journals.cambridge.org/action/displayFulltext?type=1&fid=6701184&jid=&volumeId=&issueId=01&aid=6701176&bodyId=&membershipNumber=&societyETOCSession=)). Gastrointestinal symptoms (ie, nausea, vomiting, abdominal pain, and diarrhea) dominate in the early stages of pneumonic plague and are presumed to be due to central nervous system effects rather than direct gastrointestinal inflammation. Initially, minimal, if any, respiratory symptoms are present; a dry cough and increased respiration rate may occur. When respiratory symptoms do develop, they typically are much worse than the pulmonary signs would indicate, but the disease then progresses rapidly. These findings reveal that early diagnosis of pneumonic plague resulting from either natural or bioterrorist origins, as well as detection of this disease in syndromic surveillance systems, requires recognition of specific gastrointestinal symptoms followed by particular respiratory symptoms and signs. Pediatric Considerations
The clinical presentation of plague in children is similar to that in adults. Several studies have made the following observations about pediatric plague:
- Children with bubonic plague may have a slightly increased risk for development of secondary pneumonic plague or meningitis. In one study of 38 pediatric patients with plague, 16% developed pneumonia and 11% developed meningitis (
[Mann 1982](http://www.ncbi.nlm.nih.gov/pubmed/7079041)). In two other case series, most of the meningitis cases occurred among children ( [Crook 1992](http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?orig_db=PubMed&db=PubMed&cmd=Search&defaultField=Title+Word&term=%22Archives+of+internal+medicine%22%5bJour%5d+AND+152%5bvolume%5d+AND+6%5bissue%5d+AND+1253%5bpage%5d+AND+1992%5bpdat%5d+AND+Crook%5bauthor%5d+AN), Reed 1970).
- Vomiting may be more common in children at the time of presentation of illness than in adults (about 50% and 30%, respectively) (Burkle 1973,
[Mann 1982](http://www.ncbi.nlm.nih.gov/pubmed/7079041)).
- In cases of bubonic plague, node pain is more common in children than lymph node swelling or a bubo; this may manifest as limb immobility (such as from painful axillary nodes).
- Retroperitoneal adenopathy may be responsible for vomiting and/or abdominal pain.
- Children may be more likely to have seizures as part of the presenting symptom complex (Butler 1991). Most often these are febrile seizures, although they may be caused by plague meningitis, which may be more common in children.
- The diagnosis often is not considered at time of initial presentation for pediatric cases, even in a plague-endemic area (
[Mann 1982](http://www.ncbi.nlm.nih.gov/pubmed/7079041)).
Presenting symptoms for 38 pediatric patients with bubonic or septicemic plague diagnosed in New Mexico between 1970 and 1980 are shown in the table below. The overall case-fatality rate was 15.8%.
## Presenting Symptoms for 38 Pediatric Patients With Bubonic or Septicemic Plague
## Symptom
## Patients With Bubonic Plague (n=31)
## Patients With Septicemic Plague (n=7)
Fever
30 (97%)
6 (86%)
In the pre-antibiotic era, pregnant women with plague usually either died or had an adverse outcome of pregnancy (eg, spontaneous abortion, stillbirth). However, more recent reports have demonstrated successful outcomes with antibiotic therapy, including normal gestational periods and delivery of healthy infants (
[Mann 1977](http://jama.ama-assn.org/content/237/17/1854.extract), [Welty 1985](http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1306131/?tool=pubmed)). Differential Diagnosis
## Differential Diagnosis for Bubonic, Septicemic, and Pneumonic Plague
## Condition
## Distinguishing Features
Streptococcal or staphylococcal adenitis (
—Purulent or inflamed lesion often noted distal to involved nodes (eg pustule, infected traumatic lesion)
Tularemia (
—Ulcer or pustule often present distal to involved nodes
Cat-scratch disease (
—History of contact with cats; usually history of cat scratch
Mycobacterial infection, including scrofula (
—With scrofula, adenitis occurs in cervical region
Lymphogranuloma venereum (
—Adenitis occurs in the inguinal region
Chancroid (
—Adenitis occurs in the inguinal region
Primary genital herpes
—Herpes lesions present in genital area
Primary or secondary syphilis (
—Enlarged lymph nodes in the inguinal region
Strangulated inguinal hernias
Evidence of bowel involvement
Meningococcemia
More likely to have evidence of meningitis (but not always present)
Septicemia caused by other gram-negative bacteria
Underlying illness usually present
Inhalational anthrax (
—Widened mediastinum and pleural effusions seen on CXR or chest CT
Tularemia (
Clinical course not as fulminant as pneumonic plague
Community-acquired bacterial pneumonia
—Rarely as fulminant as pneumonic plague
Viral pneumonia
—Influenza generally seasonal (October-March in United States) or involves history of recent cruise ship travel or travel to tropics
Q fever (
—Exposure to infected parturient cats, cattle, sheep, goats
Images
Images of
*Y pestis* organisms, characteristic buboes, skin lesions, and chest films can be found at the following CDC Web site: [CDC: Public Health Image Library](http://phil.cdc.gov/Phil/home.asp) [Specimen Collection and Transport](#specimen) [Laboratory Biosafety](#biosafety) [Biosecurity Information](#biosecurity) [Laboratory Response Network](#lrn) [Standard Tests for Detection of Y Pestis](#standard) [Additional Tests for Detection, Confirmation, and Characterization of](#tests) *Y pestis* [Antimicrobial Susceptibility Studies](#antimicrobial) Specimen Collection and Transport
## Collection and Transport of Clinical Laboratory Specimens for Diagnosis of Plague
## Condition
## Collection and Transport
Pneumonia
Sputum:
Bronchial wash (>1.0 mL):
Blood:
Serum:
Septicemia
Blood:
Serum:
Bubonic plague
Bubo aspirate:
Tissues:
Blood:
Serum:
Meningitis
CSF:
Blood:
Autopsy
Blood, tissue from buboes, liver, spleen, lungs, and bone marrow:
Guidelines have been published for packing and shipping of infectious substances, diagnostic specimens, and biological agents from suspected acts of bioterrorism (
[ASM 2012](http://www.asm.org/images/PSAB/PackAndShip.pdf)). Laboratory Biosafety
- Laboratory-acquired
*Y pestis*infections have been reported, although rarely. In September 2009, a researcher at the University of Chicago died after working with an altered strain of *Y pestis*that does not normally cause disease in humans ( [Steenhuysen 2009](http://www.reuters.com/article/idUSTRE58K3J120090921)). Nonetheless, the laboratory strain was found in the researcher's blood, and he may have had the septicemic form of plague.
- Hazards to laboratory personnel include:
- Direct contact with cultures and infectious materials from humans or animals
- Infectious aerosols or droplets generated during manipulation of cultures and infected tissues
- Accidental autoinoculation, ingestion, or bites from infected fleas during necropsy of rodents
- Procedures for ruling out
*Y pestis*should be performed in microbiology laboratories that use BSL-2 practices, which at a minimum have a biological safety cabinet. The CDC recommends that all manipulations be performed within a biological safety cabinet. Because of the infectious nature of this organism, the state public health laboratory should be consulted immediately if *Y pestis*is suspected (ASM 2013).
- BSL-2 conditions are recommended in the following situations (
[CDC 2007](http://www.cdc.gov/od/ohs/biosfty/bmbl5/BMBL_5th_Edition.pdf)):
- Culture of specimens
- Handling of cultures that may contain
*Y pestis*
- Necropsy of potentially infected animals
- Once the organism has been identified, it is prudent to work in a higher-level containment environment (Aleksic 1999).
- BSL-3 practices are required for the following activities (
[CDC 2007](http://www.cdc.gov/od/ohs/biosfty/bmbl5/BMBL_5th_Edition.pdf)):
- Those with high potential for droplet or aerosol production
- Those involving work with antibiotic-resistant strains
- Those involving production quantities or concentrations of infectious materials
- Vaccination is not recommended for clinical laboratory personnel (CDC: Emergency Preparedness and Response > Preparedness for All Hazards > Labs > Biosafety > Vaccines).
- Laboratory safety practices associated with
*Y pestis*and other potential agents of bioterrorism have been reviewed elsewhere ( [Sewell 2003](http://www.ncbi.nlm.nih.gov/pmc/articles/PMC165388/)). Biosecurity Information *Y pestis*is classified under WHO risk group 4. Cultures of *Y pestis*must be transported as "category A infectious substances." The US Department of Transportation regulations and International Air Transport Association (IATA) rules require training of all individuals involved in the transport of dangerous goods, including infectious substances ( [DOT](http://phmsa.dot.gov/portal/site/PHMSA/menuitem.ebdc7a8a7e39f2e55cf2031050248a0c/?vgnextoid=e4439f5cf6f57110VgnVCM1000009ed07898RCRD&vgnextchannel=a45a764e4da7e010VgnVCM1000008055a8c0RCRD&vgnextfmt=print#page3)and [IATA 2012](https://www.iataonline.com/Store/default.htm?NRMODE=Published&NRORIGINALURL=%2fStore%2fProducts%2fProduct%2bDetail.htm%3fcs_id%3d9660-30%26cs_catalog%3dPublications&NRNODEGUID=%7b16F5587B-8B15-4B8B-8EB5-498DFA3C1136%7d&NRCACHEHINT=NoModifyGuest&cookie_test=1&cs_id=9065-51&cs_catalog=Publications)). Chain of custody should be documented for material that may constitute evidence of criminal activity. *Y pestis*is classified as a select agent and therefore is regulated under 42 CFR part 73 (Possession, Use, and Transfer of Select Agents and Toxins), which was published in final form in the *Federal Register*in March 2005 and amended in October 2012 ( [HHS 2012](http://www.ecfr.gov/cgi-bin/text-idx?tpl=/ecfrbrowse/Title42/42cfr73_main_02.tpl)). As specified in the Public Health Security and Bioterrorism Preparedness and Response Act of 2002, 42 CFR part 73 provides requirements for laboratories that handle select agents (including registration, security risk assessments, safety plans, security plans, emergency response plans, training, transfers, record keeping, inspections, and notifications). These requirements went into effect on February 7, 2003, and override earlier government requirements regarding possession and transfer of select agents. Effective April 3, 2013, *Y pestis*will be considered a Tier 1 agent and subject to additional security requirements ( [HHS 2012](http://www.ecfr.gov/cgi-bin/text-idx?tpl=/ecfrbrowse/Title42/42cfr73_main_02.tpl)). Select agents are biological agents designated by the US government to be major threats to public health and safety. A current list of select agents is published on the CDC Web site under information about the Select Agent Program ( [CDC/APHIS 2008](http://www.selectagents.gov/SelectAgentsandToxinsList.html)). In addition, the CDC has published additional guidelines for enhancing laboratory security for laboratories working with select agents ( [CDC 2002](http://www.cdc.gov/mmwr/PDF/rr/rr5119.pdf)). Laboratory Response Network
The Laboratory Response Network (LRN) is a national network of approximately 150 laboratories. The network includes the following types of labs: federal, state and local public health, military, food testing, environmental, veterinary, and international (located in Canada, the United Kingdom, and Australia) (
[CDC](https://emergency.cdc.gov/lrn/factsheet.asp): Facts about the Laboratory Response Network; [CDC](http://emergency.cdc.gov/lrn/ppt/lrn-overview-presentation.ppt): The Laboratory Response Network). The LRN structure for bioterrorism designates laboratories as sentinel, reference, or national. Designation depends on the types of tests a laboratory can perform and how it handles infectious agents to protect workers and the public. *Sentinel laboratories,*formally called "level A laboratories,"represent an estimated 25,000 hospital-based laboratories that have direct contact with patients. In an unannounced or covert terrorist attack, sentinel laboratories could be the first facilities to encounter suspicious specimens. These laboratories generally have at least BSL-2 containment capabilities. Sentinel laboratories use the *ASM Sentinel Level Clinical Microbiology Laboratory Guidelines*to rule out microorganisms that might be suspected as agents of bioterrorism ( [ASM](http://www.asm.org/index.php/guidelines/sentinel-guidelines)). *Reference laboratories,*sometimes referred to as "confirmatory reference," can perform tests to detect and confirm the presence of a threat agent. These laboratories ensure a timely local response in the event of a terrorist incident. Rather than having to rely on confirmation from laboratories at the CDC, reference laboratories are capable of producing conclusive results; this allows local authorities to respond quickly to emergencies. These are mostly state or local public health laboratories but also include military, international, veterinary, agriculture, and food- and water-testing laboratories. Reference laboratories operate with BSL-3 containment facilities that have been given access to nonpublic testing protocols and reagents. One of the roles of the LRN reference laboratories is to provide guidance, training, outreach, and communications to the sentinel laboratories in their jurisdictions. *National laboratories*have unique resources to handle highly infectious agents and the ability to identify specific agent strains through molecular characterization methods. These laboratories also are responsible for methods development, bioforensics, and select-agent activity. Standard Tests for Detection of *Y pestis*
#### Direct Stains for Bacterial Micromorphology
- Approved for LRN sentinel laboratories.
- Gram stain:
*Y pestis*organisms in direct specimens or in specimen cultures appear as single cells or short chains of plump, gram-negative rods (1.0 to 2.0 mcm x 0.5 mcm).
- Specimen types in order of likely positive smear results are:bubo aspirates, tissue, blood, sputum.
- In direct smears, bacterial cells may be inside or outside of leukocytes.
- The Gram smear morphology is suggestive but not specific for
*Y pestis*. *Streptococcus pneumoniae*may be visualized on the Gram stain (gram-positive lancet-shaped diplococci) in pneumonic plague cases with secondary infection (ASM 2013).
- Polychromic stain:
*Y pestis*stains as a bipolar "closed safety pin" with Giemsa, Wright's, or Wayson stains. Bipolar morphology may not be evident on Gram stain.
- Bipolar staining is not exclusive to
*Y pestis*and therefore is considered only suggestive of the diagnosis (ASM 2013).Limited information is available on the sensitivity of direct staining for detecting *Y pestis*organisms in clinical specimens. The following findings have been reported:
- Investigation of an outbreak of pneumonic plague in Madagascar demonstrated that a sputum Gram stain was positive in only 1 (14%) of 7 patients tested; of these, all except 1 (not the patient with the positive stain) had been receiving streptomycin for 48 hours prior to specimen collection (
[Ratsitorahina 2000](http://www.ncbi.nlm.nih.gov/pubmed/10675169?dopt=Abstract)).
- A study in New Mexico found that gram-negative bacteria were seen on direct examination of peripheral smears from 3 (17.6%) of 17 patients with septicemic plague and 4 (9.5%) of 42 patients with bubonic plague (
[Hull 1987](http://www.ncbi.nlm.nih.gov/pubmed/3794395)).
- In 22 Vietnamese patients with bubonic plague, Wayson staining of bubo aspirates demonstrated characteristic organisms in 13 (59%) of the patients (
[Butler 1974](http://jid.oxfordjournals.org/content/129/Supplement_1/S78.abstract)).
- Another Vietnamese study found that plague bacilli were visible in blood smears from plague patients with blood concentrations of more than 10
6colony-forming units per milliliter. The authors concluded that patients with high concentrations of bacilli in the blood, whose specimens are most likely to be positive upon direct examination, have a poorer prognosis than patients with lower concentrations ( [Butler 1976](http://www.ncbi.nlm.nih.gov/pubmed/1262715)).
- Although aspiration of buboes is more difficult early in the course of disease, early samples are more likely to yield characteristic gram-negative bacilli that to exhibit bipolar staining with polychromic stains (Goldenberg 1968).
#### Bacteriologic Culture
- Approved for LRN sentinel laboratories.
- Standard procedures for culture are as follows (ASM 2013):
- Culture setup procedure: Use standard protocol for specimen type.
- Tape plates shut if plague is suspected.
- Add media for 28
oC incubation (optimal growth temperature of *Y pestis*) if plague is suspected. Media incubated at standard 35 oto 37 oC incubation is necessary for development of the F1 antigen of *Y pestis*and for recovery of other pathogens that may be present.
- Atmosphere: ambient or 5% CO
2
- Incubation time: 5 days; 7 days if the patient has been treated with a bacteriostatic antibiotic
- Colony morphology, 24 hours (SBA): gray-white, pinpoint
- Colony morphology, 48 hours (SBA): 1- to 2-mm gray-white to pale yellow nonhemolytic, described as having a "fried-egg" or "hammered-copper" appearance
- Broth culture colonial morphology, 24 hours: "flocculant" or "stalactite" clumps
- Broth culture colonial morphology, 48 hours: "white fluff" on bottom of tube
#### Preliminary Identification
- Approved for LRN sentinel laboratories (ASM 2013).
- Isolates identified as
*Y pestis*(or isolates that cannot be ruled out as *Y pestis*) should be forwarded to LRN reference or higher laboratories for confirmatory testing.
- Biochemical screening tests:
- TSI K/A (no gas or H
2S)
- Oxidase-negative
- Catalase-positive
- Urea-negative
- Indole-negative
- Commercial identification tests:
- As
*Y pestis*is relatively nonreactive, commercial tests may identify it as *Shigella*species, H 2S-negative *Salmonella*, *Acinetobacter*species, or *Y pseudotuberculosis*[ **THIS IS EXTREMELY IMPORTANT TO CONSIDER].** *Note:*
- Many automated commercial identification systems do not include
*Y pestis*in the data bank. Additional Tests for Detection, Confirmation, and Characterization of *Y pestis*
Some of the tests outlined below are available through LRN reference and national laboratories.
- Direct fluorescent antibody stain (DFA):
- Based on the F1 antigen.
- Offers presumptive identification of
*Y pestis*in patient samples and for cultures.
- Specimens can be falsely negative if refrigerated for more than 30 hours.
- Since the antigen is only expressed at temperatures above 35
oC, DFA tests performed on cultures incubated at lower temperatures may be falsely negative ( [WHO](http://www.who.int/csr/resources/publications/plague/WHO_CDS_CSR_EDC_99_2_EN/en/): Plague manual).
- The test may not work directly on fleas (
[Perry 1997](http://cmr.asm.org/cgi/reprint/10/1/35.pdf)).
- Bacteriophage lysis:
- Used for culture confirmation.
- Unlike F1 antigen expression,
*Y pestis*is susceptible to phage lysis at both 25 oC and 37 oC ( [CDC](http://www.cdc.gov/plague/diagnosis/index.html): Plague: diagnosis).
- Antimicrobial susceptibility tests
- Standard biochemical identification
- Serology:
- Paired sera (collected 4 to 6 weeks apart) can be used for retrospective diagnosis (
[WHO](http://www.who.int/csr/resources/publications/plague/WHO_CDS_CSR_EDC_99_2_EN/en/): Plague manual).
- Single titer of more than 1:10 is considered presumptively positive for plague if the patient has not been vaccinated previously or has a history of infection.
- Single titer of more than 1:128 or a fourfold increase in paired sera is considered confirmatory (
[CDC](http://www.cdc.gov/plague/diagnosis/index.html): Plague: diagnosis).
- An F1 antigen-capture enzyme-linked immunsorbent assay (ELISA) (
[Chanteau 2000](http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10959730&dopt=Abstract), [Seramun Diagnostica](http://www.seramun.de/), [Splettstoesser 2004](http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15145459))
- Polymerase chain reaction (PCR)-based assays (
[Loiez 2003](http://jcm.asm.org/cgi/content/full/41/10/4873?view=long&pmid=14532247), [McAvin 2003](http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=14620654&dopt=Abstract), [Norkina 1994](http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=8157543), [Tomaso 2003](http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=13129646&dopt=Abstract), [Zhou 2004](http://www.ncbi.nlm.nih.gov/pubmed/15107536): Identification of signature genes for rapid and specific characterization of Yersinia pestis)
- A simultaneous real-time PCR assay can detect
*Bacillus anthracis*(anthrax), *Francisella tularensis*(tularemia), and *Y pestis*( [Skottman 2007](http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=17294160&query_hl=4&itool=pubmed_docsum)).
- A new multiplex real-time PCR assay proved sensitive and specific, with a lower detection limit of 10 to 100 fg of extracted
*Y pestis*DNA ( [Matero 2009](http://www.ncbi.nlm.nih.gov/pubmed/19161535)).
- Mouse inoculation is used to increase recovery of
*Y pestis*with contaminated specimens ( [CDC](http://www.cdc.gov/plague/diagnosis/index.html): Plague: diagnosis).
- Molecular-based subtyping tests (
[Ciammaruconi 2008](http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=18230125), [Drancourt 2004](http://wwwnc.cdc.gov/eid/article/10/9/03-0933_article), [Huang 2002](http://jcm.asm.org/cgi/content/full/40/4/1164?view=full&pmid=11923326), [Klevytska 2001](http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=11526147), [Lowell 2005](http://www.ncbi.nlm.nih.gov/pmc/articles/PMC548095/?tool=pubmed), [Pourcel 2004](http://www.biomedcentral.com/1471-2180/4/22), [Torrea 2006](http://jcm.asm.org/cgi/content/full/44/6/2084)):
- Multilocus variable-number tandem-repeat analysis (MLVA/VNTR)
- Restriction length polymorphism (RFLP)
- Pulsed-field gel electrophoresis (PFGE)
- Multiple spacer typing (MST)
- IS100 typing
- Genome-wide synonymous single nucleotide polymorphisms (SNPs)
- Immunohistochemistry (IHC):
- IHC can be performed on formalin-fixed tissues.
- One assay utilizing anti-F1 antibody has been described (
[Guarner 2002](http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11863216&dopt=Abstract)). Antimicrobial Susceptibility Studies
Four studies (
[Frean 1996](http://aac.asm.org/cgi/reprint/40/11/2646.pdf), [Frean 2003](http://jac.oxfordjournals.org/cgi/content/full/52/2/294), [Smith 1995](http://aac.asm.org/cgi/reprint/39/9/2153.pdf), [Wong 2000](http://aac.asm.org/cgi/content/full/44/7/1995)) have examined antimicrobial susceptibilities of *Y pestis* strains to various antibiotics. Data from these studies are shown in the table below.
The major conclusions from each of the studies are as follows:
*Frean 2003*: Cefditoren and new fluoroquinolones were the most active, and macrolides the least active, in vitro *.* *Wong 2000*: Low minimal inhibitory concentrations (MICs) were found for ampicillin, cefixime, ceftazidime, ceftriaxone, chloramphenicol, doxycycline, gentamicin, streptomycin, trimethoprim-sulfamethoxazole, and trovafloxacin. Significant resistance to imipenem and rifampin was noted. *Frean 1996*: The most active agents in vitro were cefotaxime, levofloxacin, and ofloxacin. All isolates were susceptible to chloramphenicol, trimethoprim-sulfamethoxazole, tetracycline, doxycycline, streptomycin, and amoxicillin. *Smith 1995*: Antibiotics used as traditional treatment options (eg, streptomycin, tetracycline, chloramphenicol) were less active than ceftriaxone, ciprofloxacin, ofloxacin, and ampicillin. Azithromycin showed poor activity against all strains.
## MICs of Various Antibiotics for
## Study
a b c d
ABT
0.008-0.016
0.016
—
—
—
—
—
—
Amoxicillin
—
—
—
—
<0.03-0.25
0.12
—
—
Ampicillin
—
—
0.094-0.38
0.38
—
—
0.125-0.5
0.5
Azithromycin
—
—
—
—
—
—
4.0-32.0
32.0
Cefdinir
0.063-0.125
0.125
—
—
—
—
—
—
Cefditoren
0.031-0.063
0.063
—
—
—
—
—
—
Cefotaxime
—
—
—
—
<0.03
<0.03
—
—
Cefixime
—
—
0.006-0.032
0.023
—
—
—
—
Ceftazidime
—
—
0.016-0.19
0.125
—
—
—
—
Ceftriaxone
—
—
0.006-0.032
0.023
—
—
0.008-0.031
0.031
Cethromycin
2-4
4
—
—
—
—
—
—
Chloramphenicol
—
—
0.25-4.0
2.0
0.06-2.0
1.0
0.5-4.0
4.0
Ciprofloxacin
0.016-0.031
0.031
—
—
—
—
0.008-0.062
0.062
Clarithromycin
4->32
>32
—
—
—
—
—
—
Doxycycline
0.25-0.5
0.5
0.125-2.0
1.5
<0.03-4.0
1.0
0.25-1.0
1.0
Erythromycin
16-32
32
—
—
<0.03->16.0
16.0
—
—
Gentamicin
—
—
0.19-1.0
0.75
—
—
0.25-1.0
1.0
Imipenem
—
—
0.094->32
>32
—
—
—
—
Levofloxacin
—
—
—
—
<0.03-0.06
<0.03
—
—
Ofloxacin
—
—
—
—
<0.03-0.12
<0.03
0.031-0.25
0.25
Olamufloxacin
0.008
0.016
—
—
—
—
—
—
Penicillin
—
—
—
—
—
—
0.25-2.0
2.0
Rifampin
—
—
2.0-32
16
<0.03-8.0
8.0
2.0-8.0
8.0
Streptomycin
—
—
1.5-4.0
3.0
<0.03-2.0
0.5
4.0-8.0
4.0
Temafloxacin
0.016-0.031
0.031
—
—
—
—
—
—
Tetracycline
—
—
—
—
<0.03-2.0
2.0
0.5-4.0
4.0
TMP-SMX
—
—
0.012-0.047
0.032
<0.03/
0.06/1.18
0.5/2.0-1.0/32.0
1.0/16.0
Tosufloxacin
0.004-0.008
0.008
—
—
—
—
—
—
Trovafloxacin
—
—
0.006-0.047
0.032
—
—
—
—
Additional antimicrobial susceptibility studies include the following:
- Studies in the Russian literature have found that alternative aminoglycosides (eg, tobramycin and amikacin) are effective against
*Y pestis*using in vitro and animal models ( [Romanov 2001](http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11871319&dopt=Abstract): Evaluation of the effectiveness, [Romanov 2001](http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11550501&dopt=Abstract): Effect of antibacterial therapy; [Ryzhko 1998](http://www.ncbi.nlm.nih.gov/pubmed/9791683), [Shcherbaniuk 1992](http://www.ncbi.nlm.nih.gov/pubmed/1417325)).
- Two strains of
*Y pestis*isolated from patients in Madagascar were found to have plasmid-mediated drug resistance. The first isolate was resistant to ampicillin, chloramphenicol, kanamycin, minocycline, streptomycin, spectinomycin, sulfonamides, and tetracycline, and was susceptible to cephalosporins, other aminoglycosides, quinolones, and trimethoprim ( [Galimand 1997](http://content.nejm.org/cgi/content/full/337/10/677)). Investigators have shown that this strain contains a self-transmissible plasmid (pIP1202) that confers resistance to many of the antimicrobials recommended for plague treatment and prophylaxis ( [Galimand 2006](http://aac.asm.org/cgi/content/full/50/10/3233?view=long&pmid=17005799), [Welch 2007](http://www.plosone.org/article/fetchArticle.action?articleURI=info:doi/10.1371/journal.pone.0000309)). The second isolate was resistant to streptomycin but remained susceptible to other antimicrobial agents used against plague. Resistance of this strain was due to a different plasmid (pIP1203) ( [Galimand 2006](http://aac.asm.org/cgi/content/full/50/10/3233?view=long&pmid=17005799)).
- Antibiotic resistance plasmids were not detected in 713 isolates of
*Y pestis*from humans, small mammals, and fleas in plague-endemic western states. The plasmid conferring multidrug resistance that was noted in *Y pestis*strains isolated in Madagascar in 1995 is similar to the multidrug-resistant plasmid commonly found in enterobacterial pathogens. *Salmonella*species would be the most likely source of naturally acquired multidrug resistance in *Y pestis*in the United States, owing to similar plasmids between the organisms and frequent co-infection in the flea gut ( [Wagner 2010](http://wwwnc.cdc.gov/eid/article/16/5/09-0892_article.htm)).
- Researchers evaluated 392 isolates of
*Y pestis*from 19 countries to determine the MICs against *Y pestis*for eight primary antibiotics. These isolates included clinical samples from 32 patients who died from plague, of which 10 were treated with antibiotics. No resistant strains of *Y pestis*were identified ( [Urich 201](http://aac.asm.org/cgi/doi/10.1128/AAC.05043-11)2).
- Gatifloxacin and moxifloxacin appeared efficacious against experimental plague in a mouse model (
[Steward 2004](http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15555886)).
- Cethromycin appears to be as effective as levofloxacin in preventing pneumonic plague in rats (
[Rosenzweig 2011](http://aac.asm.org/cgi/doi/10.1128/AAC.00632-11)).
- Environmental testing generally is not considered necessary, since
*Y pestis*does not sporulate and the organisms generally do not persist in the environment for prolonged periods. In one study, *Y pestis*cells were viable for up to 6 hours after drying on steel, 7 hours on glass, 24 hours on polyethylene, and up to 5 days on paper under controlled conditions ( [Rose 2003](http://aem.asm.org/cgi/content/full/69/4/2166)).
- If environmental testing is considered, samples should be tested at LRN reference or higher laboratories (ASM 2013).
- An autonomous pathogen detection system (APDS) has been described for
*Y pestis*. It consists of an aerosol collector, an immunoassay subsystem, a flow-through PCR subsystem with sequential injection analysis, and a multianalyte flow-cytometry subsystem for PCR product detection ( [Hindson 2004](http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15228315), [Hindson 2005](http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15623307), [LLNL 2002](http://www.llnl.gov/str/JanFeb02/pdfs/01_02.4.pdf), [McBride 2003](http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=14710805)).
- The handheld advanced nucleic acid analyzer (HANAA) is a real-time PCR analyzer utilizing a miniaturized thermal cycling process. It has been developed for anthrax and plague (
[LLNL 2002](http://www.llnl.gov/str/JanFeb02/pdfs/01_02.4.pdf)).
- A variety of other systems are available for detection and identification of
*Y pestis*in the environment, but the practical applications of these systems are not always clear ( [Alexeter Technologies](http://www.alexeter.com/biow/index.asp), [Defense Advanced Research Projects Agency](http://www.darpa.mil/), [Kenny 2008](http://www.ncbi.nlm.nih.gov/pubmed/18655809), [New Horizons Diagnostics Inc](http://www.nhdiag.com/), [Research International](http://www.resrchintl.com/), [Rider 2003](http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=12855808)).
[Treatment](#treatment) [Postexposure Prophylaxis](#postexposure) [Vaccines](#vaccines)
Safe and effective medical countermeasures (MCMs) (drugs, vaccines, diagnostics, and other products) are needed for plague and other threats. A report described the status of MCM development, acquisition, stockpiling, and distribution in the United States as follows (
[National Biodefense Science Board 2010](http://www.liebertonline.com/doi/abs/10.1089/bsp.2010.0016)): *Diagnostics*: MCMs are neither licensed by the US Food and Drug Administration (FDA) nor stocked by the Strategic National Stockpile (SNS); however, they are national priorities and are being pursued. Specifically, the US Department of Defense has developed an integrated system for rapid identification and diagnostic confirmation of biological agent exposure or infection (the Joint Biological Agent Identification and Diagnostic System). *Vaccines*: Candidate MCMs are not yet licensed by the FDA. *Antibiotics*: MCMs are licensed or approved by the FDA and are stocked by the SNS; additionally, products that have been licensed or approved for other uses are eligible for use as MCMs under emergency use authorization. Treatment
Traditionally, streptomycin, tetracycline, and doxycycline have been used for the treatment of plague and are approved by the FDA for this indication. In April 2012, the FDA approved Levaquin (levofloxacin) as an additional antibiotic for treating plague (
[FDA 2012](http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm302220.htm), [Janssen Pharmaceuticals 2012](http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/020634s061,020635s067,021721s028lbl.pdf)). Gentamicin also has been shown to be efficacious for plague treatment, although it is not currently approved by the FDA ( [Boulanger 2004](http://www.journals.uchicago.edu/doi/abs/10.1086/381545), [Crook 1992](http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?orig_db=PubMed&db=PubMed&cmd=Search&defaultField=Title+Word&term=%22Archives+of+internal+medicine%22%5bJour%5d+AND+152%5bvolume%5d+AND+6%5bissue%5d+AND+1253%5bpage%5d+AND+1992%5bpdat%5d+AND+Crook%5bauthor%5d+AN), [Welty 1985](http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1306131/?tool=pubmed)). In the United States, supplies of streptomycin are limited, and it is rarely used for plague treatment ( [Worsham 2007](https://www.hsdl.org/?view&did=19901)).
Doxycycline and gentamicin regimens have been compared in mice receiving aerosolized
*Y pestis*. Survival was similar with both drugs, although because doxycylcine behaved in vivo as a bacteriostatic drug, it required an intact immune system for clearance of infection after challenge ( [Heine 2007](http://www.journals.uchicago.edu/doi/full/10.1086/520547)).
Clinical experience with the fluoroquinolones in treating plague is limited; however, animal studies have suggested efficacy in this setting (
[Russell 1996](http://jac.oxfordjournals.org/cgi/reprint/37/4/769?view=long&pmid=8722542)).
- An in vitro pharmacodynamic infection model showed that a regimen of levofloxacin was superior to a regimen of streptomycin (
[Louie 2007](http://aac.asm.org/cgi/content/full/51/8/2661)). Streptomycin therapy caused a reductionin the number of bacteria over 24 hours, followed by regrowth withstreptomycin-resistant mutants. Levofloxacin resulted in a greater reduction in the number of bacteria within 12 hours and ultimatelysterilized the culture without resistance selection.
A randomized, comparative, open-label clinical trial involving monotherapy with gentamicin or doxycycline found that both antibiotics were effective in treatment of plague (
[Mwengee 2006](http://www.journals.uchicago.edu/doi/full/10.1086/500137)). The patients studied had bubonic, septicemic, or pneumonic plague; 35 patients were randomized to receive gentamicin and 30 to receive doxycycline. Three patients died (two were treated with gentamicin and one with doxycycline); all had advanced disease or complications at the start of therapy. The overall effectiveness of treatment was 94% for gentamicin and 97% for doxycycline.
Rifampin, aztreonam, ceftazidime, cefotetan, and cefazolin have been shown to not be efficacious and should not be used to treat plague.
Some investigators have suggested alternative therapies for treatment of plague, such as immunotherapy, non-pathogen-specific immunomodulatory therapy, bacteriocin therapy, treatment with inhibitors of virulence factors, and phage therapy (
[Anisimov 2006](http://jmm.sgmjournals.org/cgi/content/full/55/11/1461)).
Potential adverse effects to the fetus are governed by the time of antibiotic therapy; however, during outbreaks and bioterrorism emergencies, treatment benefits for the mother outweigh fetal risk (
[Cono 2006](http://wwwnc.cdc.gov/eid/article/12/11/06-0618_article)). Antibiotics should be administered to infants born to infected mothers ( [Welty 1985](http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1306131/?tool=pubmed)).
Breast-feeding women and their infants should be treated with the same antibiotic. The medication that is safest for the infant generally should be considered the first choice (ie, gentamicin in the contained casualty setting and doxycycline in the mass- casualty setting). Fluoroquinolone antibiotics would be the recommended alternative in both settings (
[Inglesby 2000](http://jamanetwork.com/journals/jama/fullarticle/192665)).
#### Treatment for Bubonic Plague
The initial cases in a bioterrorist attack would be expected to be pneumonic plague from exposure to the initial aerosol release and the occurrence of secondary cases with respiratory droplet transmission. It is also conceivable that, as the epidemic progressed, some cases of bubonic plague might occur from contact with infected animals in the area (ie, bites, scratches) or even from subsequent flea bites (
[McGovern 1999](http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10086453&dopt=Abstract)).
Antibiotic treatment of bubonic plague is the same as therapy for pneumonic plague (see below). Usually buboes will recede without intervention, but if they become fluctuant or secondarily infected, they made need incision and drainage.
#### Treatment for Pneumonic Plague
The Working Group on Civilian Biodefense has developed consensus-based recommendations for treatment of pneumonic plague during a bioterrorist attack (
[Inglesby 2000](http://jamanetwork.com/journals/jama/fullarticle/192665)). The working group made the following recommendations:
- In a contained casualty setting where the medical care delivery system can effectively manage the number of patients, parenteral antibiotics should be administered to all patients whenever possible, according to the table below.
- In a mass-casualty setting where the medical care delivery system is not able to meet the demands for patient care, use of oral antibiotics may be necessary. In such a situation, the medications listed below in the table on antibiotic postexposure prophylaxis should be used, except that treatment should be given for 10 days instead of 7 days.
- Supportive care of patients also is critical, including fluid management and hemodynamic monitoring. Many patients would require intensive care with respiratory support owing to complications of gram-negative sepsis (eg, shock, adult respiratory distress syndrome, multisystem failure, DIC).
- Bioterrorist use of a
*Y pestis*strain resistant to conventional antibiotic therapy is of concern and should be considered, particularly if patients deteriorate despite early initiation of antibiotic therapy. Clinical isolates of *Y pestis*with plasmid-mediated drug resistance have been identified in Madagascar ( [Galimand 1997](http://content.nejm.org/cgi/content/full/337/10/677), [Galimand 2006](http://aac.asm.org/cgi/content/full/50/10/3233?view=long&pmid=17005799)).
## Recommendations From the Working Group on Civilian Biodefense for Treatment of Pneumonic Plague During a Bioterrorism Event
## Choices by Patient Category
## Therapy Recommendations
Adults: Preferred choices
Streptomycin: 1 g IM twice daily for 10 days
or
c,d
Adults: Alternative choices
Doxycycline: 100 mg IV twice daily or 200 mg IV once daily for 10 days
or
d ,f Chloramphenicol: 25 mg/kg IV 4 times daily for 10 days
or
g
Children: Preferred choices
Streptomycin: 15 mg/kg IM twice daily (maximum daily dose, 2 g)
or
c
Children: Alternative choices
Doxycycline:
or
f Chloramphenicol: 25 mg/kg IV 4 times daily for 10 days (maximum daily dose, 4 g)
or
g,h Postexposure Prophylaxis
Antibiotic prophylaxis (with tetracycline, doxycycline, or trimethoprim-sulfamethoxazole) following exposure to a person with primary or secondary pneumonic plague has been recommended as a public health control measure (
[ACIP/CDC 1996](http://www.cdc.gov/mmwr/preview/mmwrhtml/00044836.htm)). Prophylaxsis also is recommended for laboratory workers who may have been exposed to an infectious aerosol via a laboratory accident ( [Worsham 2007](https://www.hsdl.org/?view&did=19901)). Tetracycline and doxycycline are approved by the FDA for this indication. Clinical experience with the fluoroquinolones for prophylaxis against pneumonic plague is limited; however, animal studies have suggested efficacy in this setting ( [Russell 1996](http://jac.oxfordjournals.org/cgi/reprint/37/4/769?view=long&pmid=8722542)).
Few data are available on the efficacy of postexposure prophylaxis in this setting; however, according to a CDC report published in 1984, more than 2,000 persons had been placed on prophylactic antibiotics, and no cases of person-to-person transmission had been reported (
[CDC 1984](http://www.cdc.gov/mmwr/preview/mmwrhtml/00000394.htm)). In fact, the CDC has not received any reports of person-to-person *Y pestis* transmission in the United States since the last US outbreak of pneumonic plague in Los Angeles in the 1920s.
The Working Group on Civilian Biodefense developed consensus-based recommendations in 2000 for treatment and postexposure prophylaxis of pneumonic plague during a bioterrorist attack (
[Inglesby 2000](http://jama.ama-assn.org/cgi/content/full/283/17/2281)). The working group made the following recommendations:
- Any potentially exposed persons in the affected community in whom a temperature of 38.5°C or higher or a new cough develops should be evaluated and placed on appropriate parenteral therapy (if available) for presumptive pneumonic plague. (
*Note*: the working group did not recommend mass use of antibiotic prophylaxis for the entire population in the affected community in response to a release of *Y pestis*organisms.)
- Persons who have close contact with a patient with pneumonic plague who has not received at least 48 hours of appropriate antibiotic therapy should receive antibiotic postexposure prophylaxis, as outlined in the table below. Since transmission occurs through respiratory droplets, close contact is defined as contact at less than 2 meters.
- Persons who develop fever or cough while receiving antibiotic prophylaxis should be evaluated immediately for pneumonic plague and treated appropriately if plague is suspected.
## Recommendations from the Working Group on Civilian Biodefense for Antibiotic Postexposure Prophylaxis During an Outbreak of Pneumonic Plague Following a Bioterrorism Event
## Choices by Patient Category
## Therapy Recommendations
Adults: Preferred choices
Doxycycline: 100 mg PO twice daily for 7 days
c,d
Adults: Alternative choice
Chloramphenicol: 25 mg/kg PO 4 times daily for 7 days
Children: Preferred choices
Doxycycline:
d
Children: Alternative choice
Chloramphenicol: 25 mg/kg PO 4 times daily for 7 days (maximum daily dose, 4 g)
The success of mass postexposure prophylaxis and other interventions depends on public cooperation. A telephone survey of a sample of the adult population of Great Britain was conducted to assess perceptions about pneumonic plague and likely actions in response to hypothetical outbreak scenarios (
[Rubin 2010](http://wwwnc.cdc.gov/eid/article/16/1/08-1604_article)). In general, participants who perceived pneumonic plague to be more severe, more communicable, or more persistent in the environment were more likely to engage in spontaneous precautionary behavior; however, perceptions were not as associated with willingness to follow explicit public health advice. Intended compliance with public health recommendations varied: 98% would take antimicrobial drugs, 92% would stay home for 7 days, and 75% would visit a mass-treatment center. Vaccines
Plague vaccines at one time were widely used, but their efficacy has not been proven. Vaccines are not recommended for immediate protection in outbreak situations due to the short plague incubation period (days) and the long interval (months) required to produce an immune response (
[HPA 2007](http://webarchive.nationalarchives.gov.uk/20140714084352/http://www.hpa.org.uk/webc/HPAwebFile/HPAweb_C/1194947396073), Oyston 2009). Recently, trials of plague vaccines were reviewed, and the authors concluded that not enough evidence exists to evaluate the effectiveness of any plague vaccine, the relative effectiveness between vaccines, or vaccine tolerability. However, findings from observational studies suggest that killed vaccines may have the best combination of efficacy and side effects (Jefferson 2009). The different vaccine types are briefly described below.
#### Killed Whole-Cell Vaccine
A licensed vaccine against plague was available in the United States until 1999 (
[ACIP/CDC 1996](http://www.cdc.gov/mmwr/preview/mmwrhtml/00044836.htm)), when the sole manufacturer discontinued production.
- The vaccine was a formalin-inactivated whole-cell vaccine, and a series of injections was required.
- The vaccine primarily induced antibodies to the F1 capsular antigen.
- The vaccine protected against bubonic plague but did not protect against pneumonic plague.
- Data on efficacy are limited; however, US military servicemen were vaccinated during the Vietnam War, and even though plague was prevalent in the local animal and human populations at the time, only eight cases of plague occurred among immunized US servicemen (
[Titball 2001](http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11457543&dopt=Abstract)). The estimated plague incidence in Vietnamese civilians was 333 cases per 10 6population, versus 1 case per 10 6population among US servicemen.
- Administration of a heat-killed vaccine against plague provided long-lasting T-cell responses, comparable to those of conventional vaccines such as pertussis or tetanus-diphtheria, among Gulf War participants. The study was conducted among British soldiers vaccinated at the time of the first Gulf War (1990-1991) (
[Allen 2006](http://www.journals.uchicago.edu/doi/full/10.1086/504806)).
#### The EV76 Live Attenuated Vaccine
The EV76 vaccine was initially developed in the early 1900s and has been used since then in some parts of the world (particularly in the former Soviet Union). However, the vaccine strain is not avirulent, and its safety in humans has been questioned. This vaccine preparation is not available in the United States.
#### New Plague Vaccines
Research is ongoing to develop new and improved plague vaccines, particularly in light of the current bioterrorist threat and concerns about intentional dissemination of aerosolized plague organisms. Approaches for new vaccine development include the following:
- One approach is to create vaccines using live attenuated mutant strains of
*Y pestis*or related organisms (such as *Salmonella*or attenuated *Y pseudotuberculosis*) ( [Blisnick 2008](http://iai.asm.org/cgi/content/full/76/8/3808), [Bubeck 2007](http://cvi.asm.org/cgi/content/abstract/CVI.00137-07v1), [Calhoun 2006](http://www.ncbi.nlm.nih.gov/pubmed/16604240), [Liu 2007](http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2121146/?tool=pubmed), [Yang 2007](http://www.jimmunol.org/cgi/content/full/178/2/1059)).
- Another approach is to create subunit vaccines that selectively target antigens on the surface of the plague bacillus. Most candidate vaccines involve the F1 capsular antigen and the V antigen (also referred to as LcrV [low-calcium-response] antigen) (
[Alvarez 2006](http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=ShowDetailView&TermToSearch=16442673&ordinalpos=7&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum), [Anderson 1998](http://www.ajtmh.org/cgi/reprint/58/6/793), [Chiuchiolo 2006](http://www.journals.uchicago.edu/doi/full/10.1086/507644), [Cornelius 200](http://iai.asm.org/cgi/content/abstract/IAI.00699-08v1)8, [Elvin 2006](http://www.ncbi.nlm.nih.gov/pubmed/16546306), [Jones 2003](http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=12922126), [Palin 2007](http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=16959385&query_hl=37&itool=pubmed_docsum), [Rocke 2008](http://www.jwildlifedis.org/doi/abs/10.7589/0090-3558-44.1.1), [Thomas 2009](http://iai.asm.org/cgi/content/abstract/IAI.01473-08v1), [Titball 2001](http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11457543&dopt=Abstract), [Tripathi 2006](http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=16476510&query_hl=8&itool=pubmed_docsum), [Wang 2007](http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=ShowDetailView&TermToSearch=17879056&ordinalpos=4&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum), [Williamson 2007](http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=17101198&query_hl=1&itool=pubmed_docsum)).
- Combinatorial vaccines involving antigens against more than one bacterial agent may represent the next generation in biodefense vaccines (
[DuBois 2007](http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1929014/?tool=pubmed)).
- A major challenge in developing new vaccines for plague is the identification and validation of an appropriate correlate of protection (
[Williamson 2012](http://jmm.sgmjournals.org/cgi/doi/10.1099/jmm.0.037960-0)). [Isolation Precautions](#isolation) [Decontamination](#decontamination) [Issues Related to Autopsies and Burial](#autopsies) Isolation Precautions
Droplet Precautions plus eye protection, in addition to Standard Precautions, should be implemented for patients with pneumonic plague. Although Droplet Precautions are generally accepted as adequate for protection against pneumonic plague, some experts have questioned whether or not they are sufficient to protect healthcare workers.
Patients are considered infectious for 48 to 72 hours after initiation of appropriate antibiotic therapy with evidence of clinical improvement (
[APIC/CDC 1999](https://emergency.cdc.gov/bioterrorism/pdf/13apr99APIC-CDCBioterrorism.pdf), [Inglesby 2000](http://jama.ama-assn.org/cgi/content/full/283/17/2281), [Weber 2001](http://www.journals.uchicago.edu/doi/full/10.1086/318509)).
Standard Precautions include the following practices related to direct patient care (
[CDC/HICPAC 2007](http://www.cdc.gov/hicpac/2007IP/2007isolationPrecautions.html)):
- Hand washing:
- Wash hands after touching blood, body fluids, secretions, excretions, or contaminated items, whether or not gloves are worn.
- Wash hands immediately after gloves are removed, between patient contacts, and when otherwise indicated to avoid transfer of microorganisms to other patients or environments.
- Gloves:
- Wear gloves when touching blood, body fluids, secretions, excretions, or contaminated items; put on clean gloves just before touching mucous membranes and nonintact skin.
- Change gloves between tasks and procedures on the same patient after contact with material that may contain a high concentration of microorganisms.
- Remove gloves promptly after use, before touching noncontaminated items or environmental surfaces, and before going to another patient, and wash hands immediately to avoid transfer of microorganisms to other patients or environments.
- Masks, eye protection, face shields:
- Wear a mask (ie, standard surgical mask) and eye protection or a face shield to protect mucous membranes of the eyes, nose, and mouth during procedures and patient-care activities that are likely to generate splashes or sprays of blood, body fluids, secretions, or excretions.
- Gowns:
- Wear a gown to protect skin and prevent soiling of clothing during procedures and patient-care activities that are likely to generate splashes or sprays of blood, body fluids, secretions, or excretions.
- Select a gown that is appropriate for the activity and amount of fluid likely to be encountered.
- Remove a soiled gown as promptly as possible and wash hands.
- Patient-care equipment:
- Handle used equipment soiled with blood, body fluids, secretions, or excretions in a manner that prevents skin and mucous membrane exposures, contamination of clothing, and transfer of microorganisms to other patients or environments.
- Ensure that reusable equipment is not used for the care of another patient until it has been appropriately cleaned and reprocessed; single-use items should be appropriately discarded.
Droplet Precautions include the following (
[CDC/HICPAC 2007](http://www.cdc.gov/hicpac/2007IP/2007isolationPrecautions.html)):
- Place the patient in a private room or in a room with other patients who have the same infection (ie, cohort). When a private room is not available and cohorting is not possible, a spatial separation of at least 3 ft should be maintained between the patient and other patients or visitors. (
*Note:*Other sources suggest that contact within 2 m [6.5 ft] can spread the disease.)
- Healthcare workers should wear a mask when working within 3 ft of the patient; a standard surgical mask is considered adequate.
- Patient transportation should be limited to essential purposes only. If transport or movement is necessary, minimize dispersal of droplets from the patient by masking the patient using a standard surgical mask.
- Negative-pressure rooms or other special air-handling measures are not necessary for routine care, and doors may remain open.
Contact and Droplet Precautions should be implemented when buboes are being aspirated or irrigated, owing to the propensity for aerosolization of infectious material. Contact Precautions include the following (
[CDC/HICPAC 2007](http://www.cdc.gov/hicpac/2007IP/2007isolationPrecautions.html)):
- Place the patient in a private room, or, if a private room is not available, place the patient in a room with a patient who has an active infection with the same pathogen (ie, cohort). When a private room is not available and cohorting is not possible, a spatial separation of at least 3 ft should be maintained between the infected patient and other patients and visitors. (
*Note:*Other sources suggest that contact within 2 m [6.5 ft] can spread the disease.)
- Gloves should be worn when entering the room and removed before leaving the room; hands should be washed with an antimicrobial agent or a waterless hand washing agent immediately after removing gloves, and clean hands should not touch potentially contaminated items or environmental surfaces. Gloves should be changed during the course of patient care following contact with infective material that may contain high concentrations of microorganisms.
- Gowns should be worn when entering the room if it is anticipated that clothing will have substantial contact with the patient, environmental surfaces, or items in the room; the gown should be removed before leaving the patient's environment.
- Patient transport should be limited to essential purposes only; if the patient is transported out of the room, precautions should be maintained.
- Noncritical patient-care equipment should be dedicated whenever possible. If equipment cannot be dedicated, then it should be adequately cleaned and disinfected between patients.
Decontamination
In general, environmental decontamination following an aerosol event has not been recommended, since experts have estimated that an aerosol of
*Y pestis* organisms would be infectious for only about 1 hour ( [Inglesby 2000](http://jama.ama-assn.org/cgi/content/full/283/17/2281)).
One study demonstrated that
*Y pestis* can survive on selected environmental surfaces for at least several days, with survival being the longest on paper (cells were still viable after 120 hours) ( [Rose 2003](http://aem.asm.org/cgi/content/full/69/4/2166)), although the potential for re-aerosolization of these organisms was not addressed.
- Commercially available bleach or 0.5% hypochlorite solution (1:10 dilution of household bleach) is considered adequate for cleaning. Experiments show that vapor-phase hydrogen peroxide may be used for decontamination in circumstances in which liquid or heat decontamination may not be suitable (eg, to meet time-sensitive schedules and activities) (
[Rogers 2008](http://www.ncbi.nlm.nih.gov/pubmed/19241520)).
- Organisms are killed by heating at 56°C for 15 minutes or by exposure to sunlight for 4 hours. Survival is prolonged in dried blood and secretions (
[HPA 2007](http://webarchive.nationalarchives.gov.uk/20140714084352/http://www.hpa.org.uk/webc/HPAwebFile/HPAweb_C/1194947396073)). Issues Related to Autopsies and Burial
#### Autopsy Practices
- Guidelines from the CDC indicate that Standard Precautions should be used for postmortem care. These include using a surgical scrub suit, surgical cap, impervious gown or apron with full sleeve coverage, a form of eye protection (eg, goggles or face shield), shoe covers, and double surgical gloves with an interposed layer of cut-proof synthetic mesh (
[CDC 2004](http://www.cdc.gov/mmwr/preview/mmwrhtml/rr5308a1.htm)).
- In addition, autopsy personnel should wear N-95 respirators during all autopsies, regardless of suspected or known pathogens. Powered air-purifying respirators equipped with N-95 or HEPA filters should be considered.
- Other experts have recommended that aerosol-generating procedures (such as bone sawing) should be avoided during autopsies if possible. If such procedures are necessary, then HEPA–filtered masks and negative-pressure rooms should be used (
[Inglesby 2000](http://jama.ama-assn.org/cgi/content/full/283/17/2281), [Weber 2001](http://www.journals.uchicago.edu/doi/full/10.1086/318509)).
#### Burial
- Contact with corpses should be limited to trained personnel, and routine precautions should be implemented when transporting corpses.
- Bodies infected with biological terrorism agents should not be embalmed (
[CDC 2004](http://www.cdc.gov/mmwr/preview/mmwrhtml/rr5308a1.htm)). Bodies infected with *Y pestis*can be directly buried without embalming. [Clinical Description](#clindesc) [Laboratory Criteria for Diagnosis](#labcrit) [Case Classifications](#caseclass)
Plague is a reportable disease. Suspected or confirmed cases must be reported immediately to public health authorities, according to disease-reporting rules within each state or local jurisdiction.
In 1997, the Council of State and Territorial Epidemiologists (CSTE) and the CDC revised the public health case definitions for conditions under public health surveillance (
[CDC 1997](http://www.cdc.gov/mmwr/preview/mmwrhtml/00047449.htm): Case definitions for infectious conditions under public health surveillance). The current public health case definitions for plague include the following. Clinical Description
Plague is transmitted to humans by fleas or by direct exposure to infected tissue or respiratory droplets; the disease is characterized by fever, chills, headache, malaise, prostration, and leukocytosis that manifests in one or more of the following principal clinical forms:
- Regional lymphadenitis (bubonic plague)
- Septicemia without an evident bubo (septicemic plague)
- Plague pneumonia, resulting from hematogenous spread in bubonic or septicemic cases (secondary pneumonic plague) or inhalation of infectious droplets (primary pneumonic plague)
- Pharyngitis and cervical lymphadenitis resulting from exposure to larger infectious droplets or ingestion of infected tissue (pharyngeal plague)
Laboratory Criteria for Diagnosis *Presumptive: *
- Serum antibody titer(s) to
*Y pestis*F1 antigen of 1:10 or more (without documented fourfold or greater change) in a patient with no history of plague vaccination *or*
- Detection of F1 antigen in a clinical specimen by fluorescent assay
*Confirmatory: *
- Isolation of
*Y pestis*from a clinical specimen *or*
- Fourfold or greater change in serum antibody titer to
*Y pestis*F1 antigen Case Classifications *Suspected:* A clinically compatible case without presumptive or confirmatory laboratory results *Probable:* A clinically compatible case with presumptive laboratory results *Confirmed:* A clinically compatible case with confirmatory laboratory results **AAP (American Academy of Pediatrics). **Plague. In: Pickering LK, Baker CJ, Long SS, et al (eds). 2006 Red book: report of the Committee on Infectious Diseases. Ed 27. Elk Grove Village, IL: American Academy of Pediatrics, 2006:523-5 **Achtman M, Zurth K, Morelli G, et al. **Yersinia pestis, the cause of plague, is a recently emerged clone of Yersinia pseudotuberculosis. 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