Pneumonic Plague: Incidence, Transmissibility and Future Risks

Pneumonic plague outbreaks are relatively infrequent in modern times, but in the early part of the 20th century, they were commonplace including several well-documented epidemics responsible for the deaths of thousands. The transmissibility of this disease seems to be discontinuous since in some outbreaks few transmissions occur, while in others, the progression of the epidemic is explosive. Modern epidemiological studies explain that transmissibility within populations is heterogenous with relatively few subjects likely to be responsible for most transmissions and that ‘super spreading events’, particularly at the start of an outbreak, can lead to a rapid expansion of cases. These findings concur with outbreaks observed in real-world situations. It is often reported that pneumonic plague is rare and not easily transmitted but this view could lead to unnecessary complacency since future risks such as the spontaneous incidence of anti-microbial strains, climate change leading to a disruption of natural cycles within plague foci and use of plague as a bioweapon cannot be discounted. Carers and first responders are vulnerable, particularly in poorer countries where access to medicines and protection equipment may be limited, outbreaks occur in inaccessible areas or where there is a lack of surveillance due to a paucity of funds.

Pneumonic Plague: Incidence, Transmissibility and Future Risks

Pneumonic plague outbreaks are relatively infrequent in modern times but in the early part of the 20th century, they were commonplace including several well-documented epidemics responsible for the deaths of thousands. The transmissibility of this disease seems to be discontinuous since in some outbreaks few transmissions occur, while in others, the progression of the epidemic is explosive. Modern epidemiological studies explain that transmissibility within populations is heterogenous with relatively few subjects likely to be responsible for most transmissions and that ‘super spreading events’, particularly at the start of an outbreak, can lead to a rapid expansion of cases. These findings concur with outbreaks observed in real-world situations. It is often reported that pneumonic plague is rare and not easily transmitted but this view could lead to unnecessary complacency since future risks such as the spontaneous incidence of anti-microbial strains, climate change leading to a disruption of natural cycles within plague foci and use of plague as a bioweapon cannot be discounted. Carers and first responders are vulnerable, particularly in poorer countries where access to medicines may be limited, out-breaks occur in inaccessible areas or where there is a lack of surveillance due to a paucity of funds.

Combinatorial Viral Vector-Based and Live Attenuated Vaccines without an Adjuvant to Generate Broader Immune Responses to Effectively Combat Pneumonic Plague

Yersinia pestis , the causative agent of plague, is a Tier-1 select agent and a reemerging human pathogen. A 2017 outbreak in Madagascar with >75% of cases being pneumonic and 8.6% causalities emphasized the importance of the disease.

Pretreatment With Fluticasone Propionate Increases Antibiotic Efficacy During Treatment of Late-Stage Primary Pneumonic Plague

Severe and late-stage pneumonias are often difficult to treat with antibiotics alone due to overwhelming host inflammatory responses mounted to clear infection. These host responses contribute to pulmonary damage leading to acute lung injury, acute respiratory distress syndrome, and death. In order to effectively treat severe and late-stage pneumonias, use of adjunctive therapies must be considered to reduce pulmonary damage when antimicrobial agents can be administered. Pneumonic plague, a severe pneumonia caused by inhalation of Yersinia pestis , is a fatal disease that causes death within six days without antibiotic intervention. Late-stage pneumonic plague is difficult to treat, as antibiotics must be delivered within 24 hours after onset of symptoms to be effective. Here, we use a murine model of primary pneumonic plague to examine how host inflammatory responses impact antibiotic treatment of late-stage pneumonic plague. We developed a murine infection model demonstrating the poor outcomes associated with delayed delivery of antibiotics. We show that pretreatment of mice with intranasal fluticasone propionate increased efficacy of delayed antibiotic delivery and enhanced murine survival. Mice receiving fluticasone propionate also showed decreased bacterial burden and reduced inflammatory pathology in the lungs. Further, we show that treatment and survival correlated with decreased levels of IL-6 and reduced neutrophil infiltration to the lungs. This work demonstrates how host inflammatory responses complicate treatment of late-stage pneumonic plague, and suggests that targeting of host inflammatory responses may improve treatment of severe, late-stage pneumonia.

Novel RNA Extraction Method for Dual RNA-seq Analysis of Pathogen and Host in the Early Stages of Yersinia pestis Pulmonary Infection

Pneumonic plague, caused by Yersinia pestis, is a rapidly progressing lethal infection. The various phases of pneumonic plague are yet to be fully understood. A well-established way to address the pathology of infectious diseases in general, and pneumonic plague in particular, is to conduct concomitant transcriptomic analysis of the bacteria and the host. The analysis of dual RNA by RNA sequencing technology is challenging, due the difficulties of extracting bacterial RNA, which is overwhelmingly outnumbered by the host RNA, especially at the critical early time points post-infection (prior to 48 h). Here, we describe a novel technique that employed the infusion of an RNA preserving reagent (RNAlater) into the lungs of the animals, through the trachea, under deep anesthesia. This method enabled the isolation of stable dual mRNA from the lungs of mice infected with Y. pestis, as early as 24 h post-infection. The RNA was used for transcriptomic analysis, which provided a comprehensive gene expression profile of both the host and the pathogen.

Impact of Toll-Like Receptor-Specific Agonists on the Host Immune Response to the Yersinia pestis Plague rF1V Vaccine

Relatively recent advances in plague vaccinology have produced the recombinant fusion protein F1-V plague vaccine. This vaccine has been shown to readily protect mice from both bubonic and pneumonic plague. The protection afforded by this vaccine is solely based upon the immune response elicited by the F1 or V epitopes expressed on the F1-V fusion protein. Accordingly, questions remain surrounding its efficacy against infection with non-encapsulated (F1-negative) strains. In an attempt to further optimize the F1-V elicited immune response and address efficacy concerns, we examined the inclusion of multiple toll-like receptor agonists into vaccine regimens. We examined the resulting immune responses and also any protection afforded to mice that were exposed to aerosolized Yersinia pestis. Our data demonstrate that it is possible to further augment the F1-V vaccine strategy in order to optimize and augment vaccine efficacy.

Clinical picture of pulmonary plague observed in the paediatric wards of antananarivo

Introduction: In Madagascar, plague is a highly contagious acute endemic infectious disease. The diagnosis of the most severe form of pneumonic plague remains difficult in children, hence the objectives of the present study; which is to identify the clinical signs of this clinical form in children and to describe its epidemiological and evolutionary profile. Methods: A retrospective case-control study was conducted in four pediatric wards in Antananarivo during the urban pneumonic plague outbreak from September 2017 to January 2018. Those cases were defined as children aged 0-15 years old suspected of having plague with positive RDT and PCR, and they were defined as children aged 0-15 years old with negative RDT and PCR. Results: Fifty-two cases of pneumonic plague were identified, half of which (50%) were under 24 months of age. A male predominance was noted with a sex ratio of 1.23 and 86.54% of the patients were from urban areas. Several clinical signs were found but none was specific for pneumonic plague: cough (59.62% p: 0.5), dyspnea (3.85% p: 0.16), chest pain (3.85% p: 0.26%), hemoptysis (7.69% p: 0.17), vomiting (9.62% p: 0.14), diarrhea (11.54% p: 0.45), altered general condition (38.46% p: 0.24%). Two deaths were noted (3.8%). Conclusion: No specific clinical warning signs have been identified in childhood pneumonic plague. In the event of an epidemic of urban pneumonic plague, any bacterial pneumonia should at least initially include active treatment against Yersinia pestis.

The Manchurian Plague and COVID-19: China, the United States, and the “Sick Man,” Then and Now

In this article, I explore the historical resonances between China’s 1911 pneumonic plague and our current situation with COVID-19. At the turn of the 20th century, China was labeled “the Sick Man of the Far East”: a once-powerful country that had become burdened by opium addiction, infectious disease, and an ineffective government. In 1911, this weakened China faced an outbreak of pneumonic plague in Manchuria that killed more than 60 000 people. After the 1911 plague, a revolutionized China radically restructured its approach to public health to eliminate the stigma of being “the Sick Man.” Ironically, given the US mishandling of the COVID pandemic, observers in today’s China are now calling the United States “the Sick Man of the West”: a country burdened by opioid addiction, infectious disease, and an ineffective government. The historical significance of the phrase “Sick Man”—and its potential to now be associated with the United States—highlights the continued links between epidemic control and international status in a changing world. This historical comparison also reveals that plagues bring not only tragedy but also the opportunity for change.

Protection Elicited by Attenuated Live Yersinia pestis Vaccine Strains against Lethal Infection with Virulent Y. pestis

The etiologic agent of plague, Yersinia pestis, is a globally distributed pathogen which poses both a natural and adversarial threat. Due largely to the rapid course and high mortality of pneumonic plague, vaccines are greatly needed. Two-component protein vaccines have been unreliable and potentially vulnerable to vaccine resistance. We evaluated the safety and efficacy of eight live Y. pestis strains derived from virulent strains CO92 or KIM6+ and mutated in one or more virulence-associated gene(s) or cured of plasmid pPst. Stringent, single-dose vaccination allowed down-selection of the two safest and most protective vaccine candidates, CO92 mutants pgm- pPst- and ΔyscN. Both completely protected BALB/c mice against subcutaneous and aerosol challenge with Y. pestis. Strain CD-1 outbred mice were more resistant to bubonic (but not pneumonic) plague than BALB/c mice, but the vaccines elicited partial protection of CD-1 mice against aerosol challenge, while providing full protection against subcutaneous challenge. A ΔyscN mutant of the nonencapsulated C12 strain was expected to display antigens previously concealed by the capsule. C12 ΔyscN elicited negligible titers to F1 but comparable antibody levels to whole killed bacteria, as did CO92 ΔyscN. Although one dose of C12 ΔyscN was not protective, vaccination with two doses of either CO92 ΔyscN, or a combination of the ΔyscN mutants of C12 and CO92, protected optimally against lethal bubonic or pneumonic plague. Protection against encapsulated Y. pestis required inclusion of F1 in the vaccine and was associated with high anti-F1 titers.