Pneumonic Plague Deaths

Plague is a disease of animals, mostly rodents and their fleas, that spills over into people. The usual route is a flea bite, which produces the swollen lymph nodes called buboes; the bacterium then persists between outbreaks in wild rodent populations and contaminated soil rather than in humans.

The Gram-negative bacterium Yersinia pestis is responsible for deadly plague, a zoonotic disease established in stable foci in the Americas, Africa, and Eurasia. [...] Transmission from one host to another relies mainly on infected flea bites, inducing typical painful, enlarged lymph nodes referred to as buboes, followed by septicemic dissemination of the pathogen. (Abstract)

Barbieri, R., Signoli, M., Chevé, D., Costedoat, C., Tzortzis, S., Aboudharam, G., Raoult, D., & Drancourt, M. (2020). Yersinia pestis: The natural history of plague. Clinical Microbiology Reviews, 34(1), e00044-19. https://doi.org/10.1128/CMR.00044-19

10.1128/CMR.00044-19 ↗ (opens in a new tab)

The same bacterium causes two very different illnesses depending on where it multiplies: in the lymph nodes it causes bubonic plague, and in the lungs it causes pneumonic plague. The lung form kills far faster, which is why diagnosis has to be quick to be of any use.

A complex set of virulence determinants [...] play critical roles in the molecular strategies that Y. pestis employs to subvert the human immune system, allowing unrestricted bacterial replication in lymph nodes (bubonic plague) and in lungs (pneumonic plague). [...] which are critical in the context of the rapid onset of death in the absence of antibiotic treatment (less than a week for bubonic plague and <48 h for pneumonic plague). (Abstract)

Demeure, C. E., Dussurget, O., Mas Fiol, G., Le Guern, A.-S., Savin, C., & Pizarro-Cerdá, J. (2019). Yersinia pestis and plague: An updated view on evolution, virulence determinants, immune subversion, vaccination, and diagnostics. Genes & Immunity, 20(5), 357-370. https://doi.org/10.1038/s41435-019-0065-0

10.1038/s41435-019-0065-0 ↗ (opens in a new tab) Open-access PDF ↗ (opens in a new tab)

A current expert review of what is and is not settled about the plague bacterium, written by many of the researchers who study it. It is useful partly because it is explicit that large parts of the biology remain unknown, and it includes a section on the biosafety and biosecurity rules that govern work with the organism.

Although we now have some understanding of the pathogen's physiology, genetics, genomics, evolution, gene regulation, pathogenesis and immunity, there are many unknown aspects of the pathogen and its disease development. [...] Lastly, we present some biosafety and biosecurity information related to Y. pestis and plague. (Abstract)

Yang, R., Atkinson, S., Chen, Z., Cui, Y., Du, Z., Han, Y., Sebbane, F., Slavin, P., Song, Y., Yan, Y., Wu, Y., Xu, L., Zhang, C., Zhang, Y., Hinnebusch, B. J., Stenseth, N. C., & Motin, V. L. (2023). Yersinia pestis and plague: Some knowns and unknowns. Zoonoses, 3(1). https://doi.org/10.15212/ZOONOSES-2022-0040

10.15212/ZOONOSES-2022-0040 ↗ (opens in a new tab) Open licence, no PDF link verified

The single most useful corrective to how pneumonic plague is usually described. Reviewing the historical record, the author concludes the disease is much less contagious than its reputation suggests: people generally pass it on only in the final stage of illness, when they are coughing bloody sputum, and only to people who are physically close to them.

Historical accounts and contemporary experience show that pneumonic plague is not as contagious as it is commonly believed to be. Persons with plague usually only transmit the infection when the disease is in the endstage, when infected persons cough copious amounts of bloody sputum, and only by means of close contact. Before antibiotics were available for postexposure prophylaxis for contacts, simple protective measures, such as wearing masks and avoiding close contact, were sufficient to interrupt transmission during pneumonic plague outbreaks. (Abstract)

Kool, J. L. (2005). Risk of person-to-person transmission of pneumonic plague. Clinical Infectious Diseases, 40(8), 1166-1172. https://doi.org/10.1086/428617

10.1086/428617 ↗ (opens in a new tab)

A real outbreak where investigators measured how many close contacts actually caught the disease. Each of the two sick people infected exactly one caregiver, while 23 other untreated close contacts stayed well, giving an attack rate of 8 percent. The pattern fits spread by large respiratory droplets at close range, not by airborne aerosols that travel across a room.

Both index patients transmitted pneumonic plague to only 1 caregiver each, despite 23 additional untreated close contacts (attack rate 8%). Person-to-person transmission was compatible with transmission by respiratory droplets, rather than aerosols, and only a few close contacts, all within droplet range, became ill. (Abstract)

Begier, E. M., Asiki, G., Anywaine, Z., Yockey, B., Schriefer, M. E., Aleti, P., Ogen-Odoi, A., Staples, J. E., Sexton, C., Bearden, S. W., & Kool, J. L. (2006). Pneumonic plague cluster, Uganda, 2004. Emerging Infectious Diseases, 12(3), 460-467. https://doi.org/10.3201/eid1203.051051

10.3201/eid1203.051051 ↗ (opens in a new tab) Open-access PDF ↗ (opens in a new tab)

Using every US case from 1900 to 2009 rather than only the famous large outbreaks, the authors found that most people with pneumonic plague infect nobody at all, even without antibiotics. The risk of a sustained outbreak comes from rare superspreading events, not from average transmission.

Efforts to quantify its transmission potential have relied on published data from large outbreaks, an approach that artificially inflates the basic reproductive number (R(0)) and skews the distribution of individual infectiousness. Using data for all primary pneumonic plague cases reported in the USA from 1900 to 2009, we determined that the majority of cases will fail to transmit, even in the absence of antimicrobial treatment or prophylaxis. Nevertheless, potential for sustained outbreaks still exists due to superspreading events. These findings challenge current concepts regarding primary pneumonic plague transmission. (Abstract)

Hinckley, A. F., Biggerstaff, B. J., Griffith, K. S., & Mead, P. S. (2012). Transmission dynamics of primary pneumonic plague in the USA. Epidemiology and Infection, 140(3), 554-560. https://doi.org/10.1017/S0950268811001245

10.1017/S0950268811001245 ↗ (opens in a new tab)

The high end of published estimates. Reconstructing who infected whom in two historical outbreaks, the authors estimated that each case produced about 2.8 to 3.5 further cases before control measures began, and that this number fell below one once measures were in place. This is the figure often quoted to argue pneumonic plague is dangerous, and it should be read alongside the US-wide analyses that give much lower averages.

According to the estimates, the basic reproduction number, R(0), was on the order of 2.8 to 3.5, which is higher than previous estimates. The lower 95% confidence intervals of R(0) exceeded unity. The effective reproduction number declined below unity after control measures were introduced in Mukden, and before the official implementation in Madagascar. (Abstract, Results)

Nishiura, H., Schwehm, M., Kakehashi, M., & Eichner, M. (2006). Transmission potential of primary pneumonic plague: Time inhomogeneous evaluation based on historical documents of the transmission network. Journal of Epidemiology and Community Health, 60(7), 640-645. https://doi.org/10.1136/jech.2005.042424

10.1136/jech.2005.042424 ↗ (opens in a new tab)

A small Madagascar outbreak of 14 cases where transmission among close contacts was high, each case producing about 1.44 further cases, and 71 percent of patients died. It shows that although average transmission is usually low, among people caring for the sick at close quarters it can sustain an outbreak.

During a pneumonic plague outbreak in Moramanga, Madagascar, we identified 4 confirmed, 1 presumptive, and 9 suspected plague case-patients. Human-to-human transmission among close contacts was high (reproductive number 1.44) and the case fatality rate was 71%. (Abstract)

Ramasindrazana, B., Andrianaivoarimanana, V., Rakotondramanga, J. M., Birdsell, D. N., Ratsitorahina, M., & Rajerison, M. (2017). Pneumonic plague transmission, Moramanga, Madagascar, 2015. Emerging Infectious Diseases, 23(3), 521-524. https://doi.org/10.3201/eid2303.161406

10.3201/eid2303.161406 ↗ (opens in a new tab) Open-access PDF ↗ (opens in a new tab)

A 2009 outbreak in which one patient infected 11 close contacts and three people died, but 61 other direct contacts and 256 indirect contacts were not infected during two weeks of quarantine. It is one of the clearest demonstrations that proximity, not mere presence, is what transmits the disease.

The index case, a patient with PPP, contaminated 11 close contacts. All the 12 cases, including the index patient, experienced sudden onset of fever, headache, and productive coughing with bloody sputum. Three of them died. Nevertheless, another 61 direct and 256 indirect contacts were not infected during the 2-week quarantine. (Abstract, Results)

Wang, H., Cui, Y., Wang, Z., Wang, X., Guo, Z., Yan, Y., Li, C., Cui, B., Xiao, X., Yang, Y., Qi, Z., Wang, G., Wei, B., Yu, S., He, D., Chen, H., Chen, G., Song, Y., & Yang, R. (2011). A dog-associated primary pneumonic plague in Qinghai Province, China. Clinical Infectious Diseases, 52(2), 185-190. https://doi.org/10.1093/cid/ciq107

10.1093/cid/ciq107 ↗ (opens in a new tab)

A systematic search of seven decades of published pneumonic plague cases, assembling deaths within 28 days of illness onset and separating patients by whether they received antibiotics. It is the standard reference for comparing treated and untreated fatality in the pneumonic form.

We searched references and included articles describing death (within a 28-day period from illness onset) among patients with confirmed, probable, and suspected primary or undifferentiated [...] pneumonic plague, 1999 World Health Organization case definition [...] Data fields extracted included year and country of the outbreak, number of patients who survived and died (stratified by antimicrobial drug status), number of patients receiving different antimicrobial [regimens]. (Methods)

Salam, A. P., Rojek, A., Cai, E., Raberahona, M., & Horby, P. (2020). Deaths associated with pneumonic plague, 1946-2017. Emerging Infectious Diseases, 26(10), 2432-2434. https://doi.org/10.3201/eid2610.191270

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In a remote outbreak of 22 cases, every patient who went untreated died. This is the empirical basis for describing untreated pneumonic plague as essentially always fatal.

This outbreak had a case-fatality rate of 100% for nontreated patients. (Abstract)

Richard, V., Riehm, J. M., Herindrainy, P., Soanandrasana, R., Ratsitoharina, M., Rakotomanana, F., Andrianalimanana, S., Scholz, H. C., & Rajerison, M. (2015). Pneumonic plague outbreak, Northern Madagascar, 2011. Emerging Infectious Diseases, 21(1), 8-15. https://doi.org/10.3201/eid2101.131828

10.3201/eid2101.131828 ↗ (opens in a new tab) Open-access PDF ↗ (opens in a new tab)

The clearest measurement of how narrow the treatment window is. In monkeys whose disease closely tracks the human illness, antibiotics started 10 hours after fever began still saved 90 to 100 percent of animals, but effectiveness fell away after that, with half the animals no longer expected to survive once treatment was delayed about 20 hours for ciprofloxacin or 27 hours for levofloxacin.

When administered 10 hours after fever onset, 10 days of ciprofloxacin and levofloxacin treatment remained very effective (90 or 100%, respectively). The efficacy of both antimicrobials declined as treatment initiation was further delayed. Statistical analyses estimated the treatment delay times at which half of the AGMs were no longer expected to survive as 19.7 hours for ciprofloxacin and 26.5 hours for levofloxacin. (Abstract, Results)

Campbell, J. L., Fay, M. P., Lanning, L. L., & Hewitt, J. A. (2020). Effect of delaying treatment on efficacy of ciprofloxacin and levofloxacin in the African green monkey model of pneumonic plague. Clinical Infectious Diseases, 70(Suppl. 1), S60-S65. https://doi.org/10.1093/cid/ciz1234

10.1093/cid/ciz1234 ↗ (opens in a new tab)

Across all 533 US plague cases from 1942 to 2018, death was roughly five times more likely among patients who received only weaker antibiotics: 51 percent died, against 9 percent of those given one of the effective drug classes. The authors conclude that what matters most is recognising plague early and starting any effective antibiotic.

Among 533 total reported plague cases during 1942-2018, 426 (80%) received high-efficacy antimicrobial therapy. Mortality differed significantly among those receiving high-efficacy therapy (9%) and only limited-efficacy therapy (51%). [...] Early recognition and early treatment with any of these antimicrobial classes remain the most important steps to improving survival of plague. (Abstract)

Kugeler, K. J., Mead, P. S., Campbell, S. B., & Nelson, C. A. (2020). Antimicrobial treatment patterns and illness outcome among United States patients with plague, 1942-2018. Clinical Infectious Diseases, 70(Suppl. 1), S20-S26. https://doi.org/10.1093/cid/ciz1227

10.1093/cid/ciz1227 ↗ (opens in a new tab) Open licence, no PDF link verified

Pooling 2,631 treated plague cases from eighty years of literature, the pneumonic form had the highest fatality of the three clinical forms at 31 percent. Tetracyclines, chloramphenicol and aminoglycosides had the lowest death rates, while penicillin, which does not work against this organism, was associated with 75 percent fatality.

Among cases classified by primary clinical form of plague, 93.6% were bubonic, 5.9% pneumonic, and 0.5% septicemic with associated case fatality of 14.2%, 31.1%, and 20.0%, respectively. Case fatality rate among patients who received monotherapy with tetracyclines, chloramphenicol, aminoglycosides, or sulfonamides was 1.3%, 1.4%, 7.5%, and 20.2%, respectively. [...] Penicillin was associated with a case fatality rate of 75%. (Abstract, Results)

Godfred-Cato, S., Cooley, K. M., Fleck-Derderian, S., Becksted, H. A., Russell, Z., Meaney-Delman, D., Mead, P. S., & Nelson, C. A. (2020). Treatment of human plague: A systematic review of published aggregate data on antimicrobial efficacy, 1939-2019. Clinical Infectious Diseases, 70(Suppl. 1), S11-S19. https://doi.org/10.1093/cid/ciz1230

10.1093/cid/ciz1230 ↗ (opens in a new tab) Open licence, no PDF link verified

The only randomised controlled trial of plague treatment in people. Both gentamicin and doxycycline worked, with favourable response rates of 94 and 97 percent. The three deaths all occurred on the first or second day of treatment in patients who were already critically ill when therapy started.

Three patients, 2 of whom were treated with gentamicin and 1 of whom was treated with doxycycline, died on the first or second day of treatment, and these deaths were attributed to advanced disease and complications including pneumonia, septicemia, hemorrhage, and renal failure at the start of therapy. All other patients experienced cure or an improved condition after receiving therapy, resulting in favorable response rates of 94% for gentamicin (95% CI, 81.1%-99.0%) and 97% for doxycycline (95% CI, 83.4%-99.8%). (Abstract, Results)

Mwengee, W., Butler, T., Mgema, S., Mhina, G., Almasi, Y., Bradley, C., Formanik, J. B., & Rochester, C. G. (2006). Treatment of plague with gentamicin or doxycycline in a randomized clinical trial in Tanzania. Clinical Infectious Diseases, 42(5), 614-621. https://doi.org/10.1086/500137

10.1086/500137 ↗ (opens in a new tab)

Documented spread of a drug-resistant plague strain between people. A 2013 Madagascar outbreak of 22 cases was caused by a strain resistant to streptomycin, then the recommended first-line treatment there. Three untreated patients died and the other 19 recovered on a different antibiotic combination. The same resistance mutation has now arisen independently at least three times.

The outbreak occurred in February 2013 in the Faratsiho district of Madagascar and involved 22 cases, including 3 untreated fatalities. The 19 other cases participated in funeral practices for the fatal cases and fully recovered after combination antimicrobial therapy: intramuscular streptomycin followed by oral co-trimoxazole. The Y. pestis strain that circulated during this outbreak is resistant to streptomycin resulting from a spontaneous point mutation in the 30S ribosomal protein S12 (rpsL) gene. (Abstract, Results)

Andrianaivoarimanana, V., Wagner, D. M., Birdsell, D. N., Nikolay, B., Rakotoarimanana, F., Randriantseheno, L. N., Vogler, A. J., Sahl, J. W., Hall, C. M., Somprasong, N., Cauchemez, S., Schweizer, H. P., Razafimandimby, H., Rogier, C., & Rajerison, M. (2022). Transmission of antimicrobial resistant Yersinia pestis during a pneumonic plague outbreak. Clinical Infectious Diseases, 74(4), 695-702. https://doi.org/10.1093/cid/ciab606

10.1093/cid/ciab606 ↗ (opens in a new tab) Open licence, no PDF link verified

Screening 536 Chinese plague strains found one, from a 1996 pneumonic outbreak in Tibet, with very high streptomycin resistance. The resistance came from a single mutation in the bacterium's own ribosome rather than from an imported plasmid, which means routine resistance monitoring has to look for chromosomal mutations too.

A clinical Y. pestis isolate (S19960127) exhibited high-level resistance to streptomycin (the MIC was 4,096 mg/L). The strain (biovar antiqua) was isolated from a pneumonic plague outbreak in 1996 in Tibet Autonomous Region, China [...] the genome sequencing and allelic replacement experiments demonstrated that an rpsL gene (ribosomal protein S12) mutation with substitution of amino-acid 43 (K43R) was responsible for the high-level resistance to streptomycin. (Abstract)

Dai, R., He, J., Zha, X., Wang, Y., Zhang, X., Gao, H., Yang, X., Li, J., Xin, Y., Wang, Y., Li, S., Jin, J., Zhang, Q., Bai, J., Peng, Y., Wu, H., Zhang, Q., Wei, B., Xu, J., & Li, W. (2021). A novel mechanism of streptomycin resistance in Yersinia pestis: Mutation in the rpsL gene. PLOS Neglected Tropical Diseases, 15(4), e0009324. https://doi.org/10.1371/journal.pntd.0009324

10.1371/journal.pntd.0009324 ↗ (opens in a new tab) Open-access PDF ↗ (opens in a new tab)

Shows the mechanism by which plague could pick up drug resistance in nature. Inside a flea's gut the plague bacterium mixes with ordinary gut bacteria, and an antibiotic resistance plasmid moved from E. coli into Y. pestis within three days. After four weeks, 95 percent of co-infected fleas carried resistant plague bacteria.

Transfer of an antibiotic resistance plasmid from an Escherichia coli donor to Y. pestis occurred in the flea midgut at a frequency of 10-3 after only 3 days of co-infection, and after 4 weeks 95% of co-infected fleas contained an average of 103 antibiotic-resistant Y. pestis transconjugants. [...] Horizontal gene transfer in the flea may be the source of antibiotic-resistant Y. pestis strains recently isolated from plague patients in Madagascar. (Abstract)

Hinnebusch, B. J., Rosso, M.-L., Schwan, T. G., & Carniel, E. (2002). High-frequency conjugative transfer of antibiotic resistance genes to Yersinia pestis in the flea midgut. Molecular Microbiology, 46(2), 349-354. https://doi.org/10.1046/j.1365-2958.2002.03159.x

10.1046/j.1365-2958.2002.03159.x ↗ (opens in a new tab)

The source of the numbers used in most pneumonic plague models. From past outbreaks the authors estimated an average latent period, the gap between infection and becoming infectious, of 4.3 days with a standard deviation of 1.8 days, and an infectious period averaging 2.5 days. Each case produced an average of 1.3 further cases before control measures began.

We provide a quantitative assessment of transmissibility based on past outbreaks that shows that the average number of secondary cases per primary case (R0) was 1.3 (variance = 3.1), assuming a geometric probability distribution, prior to outbreak control measures. We also show that the latent and infectious periods can be approximated by using lognormal distributions with means (SD) of 4.3 (1.8) and 2.5 (1.2) days. (Abstract)

Gani, R., & Leach, S. (2004). Epidemiologic determinants for modeling pneumonic plague outbreaks. Emerging Infectious Diseases, 10(4), 608-614. https://doi.org/10.3201/eid1004.030509

10.3201/eid1004.030509 ↗ (opens in a new tab) Open-access PDF ↗ (opens in a new tab)

The consensus statement that fixed the widely quoted incubation range. Symptoms appear 1 to 6 days after breathing in the bacterium, and the illness then deteriorates into septic shock over the following 2 to 4 days. The 1 to 6 day figure is why contacts are watched for about a week.

An aerosolized plague weapon could cause fever, cough, chest pain, and hemoptysis with signs consistent with severe pneumonia 1 to 6 days after exposure. Rapid evolution of disease would occur in the 2 to 4 days after symptom onset and would lead to septic shock with high mortality without early treatment. (Abstract, Conclusions)

Inglesby, T. V., Dennis, D. T., Henderson, D. A., Bartlett, J. G., Ascher, M. S., Eitzen, E., Fine, A. D., Friedlander, A. M., Hauer, J., Koerner, J. F., Layton, M., McDade, J., Osterholm, M. T., O'Toole, T., Parker, G., Perl, T. M., Russell, P. K., Schoch-Spana, M., Tonat, K., & Working Group on Civilian Biodefense. (2000). Plague as a biological weapon: Medical and public health management. JAMA, 283(17), 2281-2290. https://doi.org/10.1001/jama.283.17.2281

10.1001/jama.283.17.2281 ↗ (opens in a new tab)

The current US authority source on what to give patients and what to give their contacts, replacing the 2000 consensus statement. It covers treatment, pre-exposure prophylaxis and post-exposure prophylaxis, and is the document that sets how long exposed people are given preventive antibiotics and watched.

Guidelines for treatment and postexposure prophylaxis of plague were published in 2000 by a nongovernmental work group; since then, new human clinical data, animal study data, and U.S. Food and Drug Administration approvals of additional countermeasures have become available. [...] these guidelines [...] provide recommended best practices for treatment and prophylaxis of human plague for both naturally occurring disease and following a bioterrorism attack. (Abstract)

Nelson, C. A., Meaney-Delman, D., Fleck-Derderian, S., Cooley, K. M., Yu, P. A., & Mead, P. S. (2021). Antimicrobial treatment and prophylaxis of plague: Recommendations for naturally acquired infections and bioterrorism response. MMWR Recommendations and Reports, 70(3), 1-27. https://doi.org/10.15585/mmwr.rr7003a1

10.15585/mmwr.rr7003a1 ↗ (opens in a new tab) Open licence, no PDF link verified

The definitive account of the 2017 Madagascar epidemic, the largest modern pneumonic plague event. Of 2,414 clinically suspected cases, 1,878 were reported as pneumonic, but only 418 of those were laboratory confirmed or probable: 32 confirmed and 386 probable. Fatality was much higher among confirmed cases than suspected ones, which is exactly what you would expect if many suspected cases were not plague at all.

2414 clinically suspected plague cases were reported, including 1878 (78%) pneumonic plague cases, 395 (16%) bubonic plague cases, one (<1%) septicaemic case, and 140 (6%) cases with unspecified clinical form. 386 (21%) of 1878 notified pneumonic plague cases were probable and 32 (2%) were confirmed. [...] The case fatality ratio was higher among confirmed cases (eight [25%] of 32 cases) than probable (27 [8%] of 360 cases) or suspected pneumonic plague cases (74 [5%] of 1358 cases). (Abstract, Findings)

Randremanana, R., Andrianaivoarimanana, V., Nikolay, B., Ramasindrazana, B., Paireau, J., ten Bosch, Q. A., Rakotondramanga, J. M., Rahajandraibe, S., Rahelinirina, S., Rakotomanana, F., Rakotoarimanana, F. M., Randriamampionona, L. B., Razafimbia, V., De Dieu Randria, M. J., Raberahona, M., Mikaty, G., Le Guern, A.-S., Rakotonjanabelo, L. A., Ndiaye, C. F., … Rajerison, M. (2019). Epidemiological characteristics of an urban plague epidemic in Madagascar, August-November, 2017: An outbreak report. The Lancet Infectious Diseases, 19(5), 537-545. https://doi.org/10.1016/S1473-3099(18)30730-8

10.1016/S1473-3099(18)30730-8 ↗ (opens in a new tab) Open licence, no PDF link verified

Over 2004 to 2014 the Democratic Republic of the Congo reported 54 percent of the world's plague cases, 4,630 suspected cases and 349 deaths, all from a single province. Pneumonic cases were 8.8 percent of the total and clustered in two large outbreaks in forest mining camps.

During 2004-2014, the Democratic Republic of the Congo (DRC) declared 54% of plague cases worldwide. [...] All 4,630 suspected human plague cases and 349 deaths recorded in DRC came from Orientale Province. Pneumonic plague cases (8.8% of total) occurred during 2 major outbreaks in mining camps in the equatorial forest, and some limited outbreaks were recorded in the Ituri highlands. (Abstract)

Abedi, A. A., Shako, J.-C., Gaudart, J., Sudre, B., Ilunga, B. K., Shamamba, S. K. B., Diatta, G., Davoust, B., Tamfum, J.-J. M., Piarroux, R., & Piarroux, M. (2018). Ecologic features of plague outbreak areas, Democratic Republic of the Congo, 2004-2014. Emerging Infectious Diseases, 24(2), 210-220. https://doi.org/10.3201/eid2402.160122

10.3201/eid2402.160122 ↗ (opens in a new tab) Open-access PDF ↗ (opens in a new tab)

Global totals for 2000 to 2009: 21,725 people affected and 1,612 deaths, a fatality rate of 7.4 percent, with 57 US cases and 7 deaths. The same review notes that both US deaths from occupational exposure in that decade involved scientists, one performing a mountain lion necropsy and one handling a strain believed to be harmless.

In the United States, 57 persons were reported to have the disease, of which seven died. Worldwide, 21,725 persons were affected with 1,612 deaths, for a case-fatality rate of 7.4%. [...] Two United States scientists suffered fatal accidental exposures: a wildlife biologist, who carried out an autopsy on a mountain lion in Arizona in 2007, and a geneticist with subclinical hemochromatosis in Chicago, who was handling an avirulent strain of Y. pestis in 2009. (Abstract)

Butler, T. (2013). Plague gives surprises in the first decade of the 21st century in the United States and worldwide. The American Journal of Tropical Medicine and Hygiene, 89(4), 788-793. https://doi.org/10.4269/ajtmh.13-0191

10.4269/ajtmh.13-0191 ↗ (opens in a new tab)

The reference case for laboratory-acquired plague. A university researcher died of septic shock after an unrecognised exposure to a strain of Y. pestis that had been deliberately weakened and was exempt from US select agent controls. An undiagnosed iron-overload condition, hereditary hemochromatosis, is thought to have supplied the iron the weakened strain could not otherwise obtain, restoring its ability to kill. The investigation concluded that biosafety practice should apply to attenuated strains too.

The patient, a researcher in a university laboratory, had been working along with other members of the laboratory group with a pigmentation-negative (pgm-) attenuated Y. pestis strain (KIM D27). The strain had not been known to have caused laboratory-acquired infections or human fatalities. [...] Researchers should adhere to recommended biosafety practices when handling any live bacterial cultures, even attenuated strains, and institutional biosafety committees should implement and maintain effective surveillance systems to detect and monitor unexpected acute illness in laboratory workers. (Abstract)

Fatal laboratory-acquired infection with an attenuated Yersinia pestis strain: Chicago, Illinois, 2009. (2011). JAMA, 305(14), 1403. https://doi.org/10.1001/jama.305.14.1403

10.1001/jama.305.14.1403 ↗ (opens in a new tab)

The experimental follow-up that tested the explanation for the 2009 laboratory death. In mice engineered to have iron-overload disease, strains of plague that are harmless to normal mice became lethal. The practical conclusion is that people with hereditary hemochromatosis should not be exposed to live attenuated plague strains.

Recently, a Y. pestis pgm strain was isolated from a researcher with hereditary hemochromatosis who died from laboratory-acquired plague. We used hemojuvelin-knockout (Hjv(-/-)) mice to examine whether iron-storage disease restores the virulence defects of nonpigmented Y. pestis. Unlike wild-type mice, Hjv(-/-) mice developed lethal plague when challenged with Y. pestis pgm strains. [...] individuals with hereditary hemochromatosis may be protected with subunit vaccines but should not be exposed to live-attenuated plague vaccines. (Abstract)

Quenee, L. E., Hermanas, T. M., Ciletti, N., Louvel, H., Miller, N. C., Elli, D., Blaylock, B., Mitchell, A., Schroeder, J., Krausz, T., Kanabrocki, J., & Schneewind, O. (2012). Hereditary hemochromatosis restores the virulence of plague vaccine strains. The Journal of Infectious Diseases, 206(7), 1050-1058. https://doi.org/10.1093/infdis/jis433

10.1093/infdis/jis433 ↗ (opens in a new tab)

An occupational exposure during a post-mortem examination. A wildlife biologist performed a necropsy on an infected mountain lion in his garage without protective equipment, developed fever and coughing of blood three days later, and died about six days after exposure. Genetic fingerprinting matched his bacteria to the animal's. None of the 49 contacts given preventive antibiotics fell ill.

The biologist conducted the necropsy in his garage without the use of personal protective equipment. Three days later, he developed fever and hemoptysis and died approximately 6 days after exposure. [...] Tissues from the mountain lion tested positive for Y. pestis, and isolates from the biologist and mountain lion were indistinguishable by pulsed-field gel electrophoresis. Among 49 contacts who received chemoprophylaxis, none developed symptoms consistent with plague. (Abstract, Results)

Wong, D., Wild, M. A., Walburger, M. A., Higgins, C. L., Callahan, M., Czarnecki, L. A., Lawaczeck, E. W., Levy, C. E., Patterson, J. G., Sunenshine, R., Adem, P., Paddock, C. D., Zaki, S. R., Petersen, J. M., Schriefer, M. E., Eisen, R. J., Gage, K. L., Griffith, K. S., Weber, I. B., Spraker, T. R., & Mead, P. S. (2009). Primary pneumonic plague contracted from a mountain lion carcass. Clinical Infectious Diseases, 49(3), e33-e38. https://doi.org/10.1086/600818

10.1086/600818 ↗ (opens in a new tab)

The systematic review of the rapid plague test used in the field. Against bacterial culture, the test almost never missed a true case, but its specificity in sputum was only about 71 percent, meaning roughly three in ten positive results in people without plague were false. A positive rapid test therefore has to be confirmed by culture or PCR, and only culture reveals which antibiotics will work.

Performed in sputum, F1RDT-IPM pooled sensitivity against culture was 100% (95% CI 0 to 100; 2 studies, 56 participants; very low-certainty evidence) and pooled specificity was 71% (95% CI 59 to 80; 2 studies, 297 participants; very low-certainty evidence). [...] False positive results mean culture or PCR confirmation may be needed. F1RDT does not replace culture, which provides additional information on resistance to antibiotics and bacterial strains. (Abstract)

Jullien, S., Dissanayake, H. A., & Chaplin, M. (2020). Rapid diagnostic tests for plague. Cochrane Database of Systematic Reviews, 2020(6), CD013459. https://doi.org/10.1002/14651858.CD013459.pub2

10.1002/14651858.CD013459.pub2 ↗ (opens in a new tab)

The most important paper for anyone counting plague cases. Reanalysing 2,136 samples from the 2017 Madagascar epidemic, the authors estimate that only 7 to 15 percent of notified cases were genuinely infected. Over-reporting was worst at the peak of the outbreak, and the rapid test performed considerably better in a calmer outbreak the following year, suggesting the chaos of a large response degrades the test itself.

Using latent class methods, we estimate that 7% to 15% of notified cases were Yersinia pestis-infected. Overreporting was highest during the peak of the outbreak and lowest in the rural settings endemic to Y. pestis. Molecular biology methods offered the best compromise between sensitivity and specificity. The specificity of the rapid diagnostic test was relatively low (PP: 82%, BP: 85%), particularly for use in contexts with large quantities of misclassified cases. (Abstract)

ten Bosch, Q., Andrianaivoarimanana, V., Ramasindrazana, B., Mikaty, G., Rakotonanahary, R. J. L., Nikolay, B., Rahajandraibe, S., Feher, M., Grassin, Q., Paireau, J., Rahelinirina, S., Randremanana, R., Rakotoarimanana, F., Melocco, M., Rasolofo, V., Pizarro-Cerdá, J., Le Guern, A.-S., Bertherat, E., Ratsitorahina, M., … Cauchemez, S. (2022). Analytical framework to evaluate and optimize the use of imperfect diagnostics to inform outbreak response: Application to the 2017 plague epidemic in Madagascar. PLOS Biology, 20(8), e3001736. https://doi.org/10.1371/journal.pbio.3001736

10.1371/journal.pbio.3001736 ↗ (opens in a new tab) Open-access PDF ↗ (opens in a new tab)

A 1,110-test laboratory evaluation of the field screening strip used on suspicious powders and air samples, which performed at 97.65 percent sensitivity and 96.57 percent specificity. The authors are explicit that any positive is only presumptive and must go to a reference laboratory for confirmation, which is the formal reason a case is not called confirmed on a field test alone.

A total of 1,110 LFA test results were obtained, and their analysis indicates that this LFA had a sensitivity of 97.65% and specificity of 96.57%. [...] Any positive specimen in this assay is considered presumptive positive and should be referred to the Centers for Disease Control and Prevention Laboratory Response Network for additional testing, confirmation, and characterization for an appropriate public health response. (Abstract)

Prentice, K. W., DePalma, L., Ramage, J. G., Sarwar, J., Parameswaran, N., Petersen, J., Yockey, B., Young, J., Joshi, M., Thirunavvukarasu, N., Singh, A., Chapman, C., Avila, J. R., Pillai, C. A., Manickam, G., Sharma, S. K., Morse, S. A., Venkateswaran, K. V., Anderson, K., Hodge, D. R., & Pillai, S. P. (2019). Comprehensive laboratory evaluation of a lateral flow assay for the detection of Yersinia pestis. Health Security, 17(6), 439-453. https://doi.org/10.1089/hs.2019.0094

10.1089/hs.2019.0094 ↗ (opens in a new tab) Open licence, no PDF link verified