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Background: Yersinia pestis is the etiological agent of plague, which can manifest as bubonic, septicemic, and/or pneumonic disease. Plague is a severe and rapidly progressing illness that can only be successfully treated with antibiotics initiated early after infection. There are no FDA-approved vaccines for plague, and some vaccine candidates may be less effective against pneumonic plague than bubonic plague. Y. pestis is not known to impact males and females differently in mechanisms of pathogenesis or severity of infection. However, one previous study reported sex-biased vaccine effectiveness after intranasal Y. pestis challenge. As part of developing a safe and effective vaccine, it is essential that potential sex differences are characterized. Methods: In this study we evaluated novel vaccines in male and female BALB/c mice using a heterologous prime-boost approach and monitored survival, bacterial load in organs, and immunological correlates. Our vaccine strategy consisted of two subcutaneous immunizations, followed by challenge with aerosolized virulent nonencapsulated Y. pestis. Mice were immunized with a combination of live Y. pestis pgm- pPst-Δcaf1, live Y. pestis pgm- pPst-Δcaf1/ΔyopD, or recombinant F1-V (rF1-V) combined with adjuvants. Results: The most effective vaccine regimen was initial priming with rF1-V, followed by boost with either of the live attenuated strains. However, this and other strategies were more protective in female mice. Males had higher bacterial burden and differing patterns of cytokine expression and serum antibody titers. Male mice did not demonstrate synergy between vaccination and antibiotic treatment as repeatedly observed in female mice. Conclusions: This study provides new knowledge about heterologous vaccine strategies, sex differences in plague-vaccine efficacy, and the immunological factors that differ between male and female mice. [ABSTRACT FROM AUTHOR]

BackgroundYersinia pestis is the etiological agent of plague, which can manifest as bubonic, septicemic, and/or pneumonic disease. Plague is a severe and rapidly progressing illness that can only be successfully treated with antibiotics initiated early after infection. There are no FDA-approved vaccines for plague, and some vaccine candidates may be less effective against pneumonic plague than bubonic plague. Y. pestis is not known to impact males and females differently in mechanisms of pathogenesis or severity of infection. However, one previous study reported sex-biased vaccine effectiveness after intranasal Y. pestis challenge. As part of developing a safe and effective vaccine, it is essential that potential sex differences are characterized. MethodsIn this study we evaluated novel vaccines in male and female BALB/c mice using a heterologous prime-boost approach and monitored survival, bacterial load in organs, and immunological correlates. Our vaccine strategy consisted of two subcutaneous immunizations, followed by challenge with aerosolized virulent nonencapsulated Y. pestis. Mice were immunized with a combination of live Y. pestis pgm- pPst-Δcaf1, live Y. pestis pgm- pPst-Δcaf1/ΔyopD, or recombinant F1-V (rF1-V) combined with adjuvants. ResultsThe most effective vaccine regimen was initial priming with rF1-V, followed by boost with either of the live attenuated strains. However, this and other strategies were more protective in female mice. Males had higher bacterial burden and differing patterns of cytokine expression and serum antibody titers. Male mice did not demonstrate synergy between vaccination and antibiotic treatment as repeatedly observed in female mice.ConclusionsThis study provides new knowledge about heterologous vaccine strategies, sex differences in plague-vaccine efficacy, and the immunological factors that differ between male and female mice.

The pneumonic influenza pandemic was, on a world scale, the deadliest of the entire 20th century. Between spring 1918 and April 1919, it raged in Portugal in three successive waves, with an irregular and unusual virulence, which were marked by an intense scientific debate. It happened at a time when the etiologic agent of influenza (the influenza virus) had not been identified and the antibiotics had not been discovered, launching numerous prophylactic and therapeutic challenges to national and international health authorities. In this article, some of these aspects are approached, based on medical literature of that period and the research developed later, trying to discuss some of the biological characteristics of the epidemic that may explain, in part, the seriousness of this epidemic phenomenon.

Patients with chronic obstructive pulmonary disease (COPD) often suffer acute exacerbations (AECOPD) and community-acquired pneumonia (CAP), named nonpneumonic and pneumonic exacerbations of COPD, respectively. Abnormal host defense mechanisms may play a role in the specificity of the systemic inflammatory response. Given the association of this aspect to some biomarkers at admission (e.g., C-reactive protein), it can be used to help to discriminate AECOPD and CAP, especially in cases with doubtful infiltrates and advanced lung impairment. Fever, sputum purulence, chills, and pleuritic pain are typical clinical features of CAP in a patient with COPD, whereas isolated dyspnea at admission has been reported to predict AECOPD. Although CAP may have a worse outcome in terms of mortality (in hospital and short term), length of hospitalization, and early readmission rates, this has only been confirmed in a few prospective studies. There is a lack of methodologically sound research confirming the impact of severe AECOPD and COPD + CAP. Here, we review studies reporting head-to-head comparisons between AECOPD and CAP + COPD in hospitalized patients. We focus on the epidemiology, risk factors, systemic inflammatory response, clinical and microbiological characteristics, outcomes, and treatment approaches. Finally, we briefly discuss some proposals on how we should orient research in the future. [ABSTRACT FROM AUTHOR]

Francisella tularensis is a highly infectious Gram-negative bacterium that is the etiologic agent of tularemia in animals and humans. The incidence of tularemia is very low with a lack of comprehensive data that describe disease in humans due to difficulty in understanding time and routes of exposure. Under the title Operation Whitecoat, researchers at Ft. Detrick, MD conducted 40 clinical studies of tularemia from 1958 to 1968. In these studies, one of the objectives was to evaluate candidate countermeasures for treatment or prophylaxis of disease after exposure to Francisella tularensis strain Schu S4 by inhalation. These studies were reviewed retrospectively to delineate the early signs and symptoms or natural history of pneumonic tularemia and examine the efficacy of tetracycline in controlled human clinical studies. Using vital signs, onset of fever was objectively defined and calculated for each subject, while Adverse Events reported after exposure were also used to define the timing of disease onset and symptoms of early disease. There was a dose response relationship between time to fever onset and exposed dose at 200 cfu (172.8 h), 700 cfu (163.2 h), 2,500 cfu (105.3 h), and 25,000 cfu (75.5 h). Onset of fever was typically the earliest sign of disease at all doses but was often accompanied by symptoms such as headache, myalgia, chest pain, and nausea, irrespective of dose except at 200 cfu where only 50% of subjects exhibited fever onset or symptoms. Examining the efficacy of different treatment regimens of tetracycline, ineffective treatments were indicated by relapse of disease (fever and Adverse Events) after cessation of antibiotic treatment. Stratification of the data suggested that treatment for

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.

The death rate for persons with treated pneumonic plague is often reported as 50%, but firm evidence for this figure is minimal. We conducted a meta-analysis of articles reporting the death rate for persons treated for pneumonic plague. The rate was 17%, substantially lower than the frequently cited 50%. [ABSTRACT FROM AUTHOR]

In Malaysia, pneumonic pasteurellosis is one of the major problems in the small ruminant industry. Small ruminants especially goats are more susceptible to the disease that usually occurs due to stressful conditions. Cortisol plays an important role in the disease development of pneumonic pasteurellosis. The main objective of this study was to determine the correlation between cortisol concentration in vaccinated and non-vaccinated pneumonic goats. A total of 15 normal goats and 9 clinically infected pneumonic goats were selected from 2 vaccinated farms, whereas 15 normal goats and 31 clinically infected pneumonic goats from 2 non-vaccinated farms were selected for this study. Goats with clinical signs of nasal discharges, coughing with crackle lung sound were diagnosed as pneumonic goats. Blood samples were collected from the selected goats for cortisol evaluation. The study revealed that non-vaccinated clinically infected pneumonic goats exhibited a slightly higher (p>0.05) cortisol value compared to the other experimental goats. Therefore, it can be concluded that the use of plasma cortisol concentration as a measure of stress contributing towards pneumonic pasteurellosis in goats might not be the best way to confirm the influences of the disease. [ABSTRACT FROM AUTHOR]

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The analysis of clinical-epidemiological features of plague in Mongolia in 1986-2009 demonstrated the decrease of the number of primary pulmonary plague cases, prevalence of bubonic plague, increase of the morbidity in women and children in the last decade. Considering the high epidemiologic potential of foci of the marmot's type, where the marmots are captured illegally by poachers, considerable probability of the bubonic plague being complicated with pneumonia or sepsis, it is necessary to improve plague epidemiologic surveillance in Mongolia.

Zabidi A Zabidi-Hussin Department of Paediatrics, School of Medical Sciences, Universiti Sains Malaysia, Kelantan, Malaysia Abstract: Having an organized, structured thinking process is critical in medicine. It is through this thinking process that enables one to go through the method of history-taking, which will eventually lead to making a definitive diagnosis and all other processes that follow. The use of mnemonic has been found to be useful for this purpose. The mnemonic VITAMINSABCDEK, is a convenient and practical way to assist in expanding the differential diagnoses and covers all possible causes of an illness. It is also easy to remember, as the vitamins whose letters are represented in this mnemonic cover the entire range of vitamins known. Keywords: mnemonic, differential diagnosis

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. [ABSTRACT FROM AUTHOR]

Plague is an acute infectious disease caused by the gram-negative cocco-bacillus Yersinia pestis . It has been responsible for 200 million deaths throughout history with three major pandemics. There are three forms: bubonic, septicaemic and pneumonic, each carrying a significant mortality rate. The usual transmission is from fleas carried by rodents. Recently, it has been listed as one of the reemerging infectious diseases globally, with a potential use in bioterrorism. At autopsy there may be lymphadenopathy, fulminant pneumonia or diffuse interstitial pneumonitis. However any organ may be affected with myocarditis, meningitis, pharyngitis and hepatic and splenic necrosis. The lethality of plague with the resurgence in numbers of cases, development of antibiotic resistance, recent occurrence in urban areas and the lack of a vaccine make it a disease not to be missed in the mortuary.

Francisella tularensis is a highly infectious Gram-negative bacterium that is the etiologic agent of tularemia in animals and humans. The incidence of tularemia is very low with a lack of comprehensive data that describe disease in humans due to difficulty in understanding time and routes of exposure. Under the title Operation Whitecoat, researchers at Ft. Detrick, MD conducted 40 clinical studies of tularemia from 1958 to 1968. In these studies, one of the objectives was to evaluate candidate countermeasures for treatment or prophylaxis of disease after exposure to Francisella tularensis strain Schu S4 by inhalation. These studies were reviewed retrospectively to delineate the early signs and symptoms or natural history of pneumonic tularemia and examine the efficacy of tetracycline in controlled human clinical studies. Using vital signs, onset of fever was objectively defined and calculated for each subject, while Adverse Events reported after exposure were also used to define the timing of disease onset and symptoms of early disease. There was a dose response relationship between time to fever onset and exposed dose at 200 cfu (172.8 h), 700 cfu (163.2 h), 2,500 cfu (105.3 h), and 25,000 cfu (75.5 h). Onset of fever was typically the earliest sign of disease at all doses but was often accompanied by symptoms such as headache, myalgia, chest pain, and nausea, irrespective of dose except at 200 cfu where only 50% of subjects exhibited fever onset or symptoms. Examining the efficacy of different treatment regimens of tetracycline, ineffective treatments were indicated by relapse of disease (fever and Adverse Events) after cessation of antibiotic treatment. Stratification of the data suggested that treatment for <14 days or doses <2g/day was associated with increased percentage of subjects with relapse of disease symptoms. Although these types of human challenge studies would not be ethically possible now, the climate post-World War II supported human testing under rigorous conditions with informed consent. Thus, going back and analyzing these unique clinical human challenge studies has helped describe the course of infection and disease induced by a biothreat pathogen and possible countermeasures for treatment under controlled conditions., (Copyright © 2019 Williams, Baker, Guina, Hewitt, Lanning, Hill, May, Fogtman and Pittman.)

Madagascar has just emerged from the grip of an acute urban pneumonic plague outbreak, which began in August 2017, before the usual plague season of October-April and outside the traditional plague foci in the northern and central highlands. The World Health Organization reported a total of 2417 confirmed, probable and suspected cases, including 209 deaths between 1 August and 26 November 2017. The severity and scope of this outbreak, which has affected those in higher socioeconomic groups as well as those living in poverty, along with factors including the potential for use of multi-drug-resistant strains of plague in bioterrorism, highlights the ongoing threat posed by this ancient disease. Factors likely to have contributed to transmission include human behaviour, including burial practices and movement of people, poor urban planning leading to overcrowding and ready transmission by airborne droplets, climatic factors and genomic subtypes. The outbreak demonstrates the importance of identifying targeted pneumonic plague therapies and of developing vaccines that can be administered in planned programmes in developing countries such as Madagascar where plague is endemic. The dominance of pneumonic plague in this outbreak suggests that we need to focus more urgently on the danger of person-to-person transmission, as well as the problem of transmission of plague from zoonotic sources.