Bordetella Pertussis Infection Research Articles

Bordetella pertussis Infection In Infants Hospitalized for Acute Bronchiolitis

Bordetella pertussis Infection In Infants Hospitalized for Acute Bronchiolitis

Epidemiological and Clinical Data of Bordetella pertussis Infection Among Children Younger Than One-Year-Old Treated in a University Hospital in Northern Mexico

Epidemiological and Clinical Data of Bordetella pertussis Infection Among Children Younger Than One-Year-Old Treated in a University Hospital in Northern Mexico

Immunological Signatures after Bordetella pertussis Infection Demonstrate Importance of Pulmonary Innate Immune Cells.

Effective immunity against Bordetella pertussis is currently under discussion following the stacking evidence of pertussis resurgence in the vaccinated population. Natural immunity is more effective than vaccine-induced immunity indicating that knowledge on infection-induced responses may contribute to improve vaccination strategies. We applied a systems biology approach comprising microarray, flow cytometry and multiplex immunoassays to unravel the molecular and cellular signatures in unprotected mice and protected mice with infection-induced immunity, around a B. pertussis challenge. Pre-existing systemic memory Th1/Th17 cells, memory B-cells, and mucosal IgA specific for Ptx, Vag8, Fim2/3 were detected in the protected mice 56 days after an experimental infection. In addition, pre-existing high activity and reactivation of pulmonary innate cells such as alveolar macrophages, M-cells and goblet cells was detected. The pro-inflammatory responses in the lungs and serum, and neutrophil recruitment in the spleen upon an infectious challenge of unprotected mice were absent in protected mice. Instead, fast pulmonary immune responses in protected mice led to efficient bacterial clearance and harbored potential new gene markers that contribute to immunity against B. pertussis. These responses comprised of innate makers, such as Clca3, Retlna, Glycam1, Gp2, and Umod, next to adaptive markers, such as CCR6+ B-cells, CCR6+ Th17 cells and CXCR6+ T-cells as demonstrated by transcriptome analysis. In conclusion, besides effective Th1/Th17 and mucosal IgA responses, the primary infection-induced immunity benefits from activation of pulmonary resident innate immune cells, achieved by local pathogen-recognition. These molecular signatures of primary infection-induced immunity provided potential markers to improve vaccine-induced immunity against B. pertussis.

Prior exposure to Bordetella species as an exclusion criterion in the baboon model of pertussis.

The baboon model of Bordetella pertussis infection is the newest and most clinically accurate model of the human disease to date. However, among the 15 experimentally infected baboons in this study, a subset of baboons did not exhibit the expected high bacterial colonization levels or increase in white blood cell count. Moreover, cultures of nasopharyngeal wash samples from several baboons suggested B. bronchiseptica coinfection. Analysis of serum antibodies recognizing filamentous hemagglutinin, pertussis toxin and B. pertussis lipo-oligosaccharide indicated that several baboons had likely been previously exposed to Bordetella species and that prior exposure correlated with partial protection from B. pertussis infection. Notably, all animals with a baseline Fha titer of 5 IU/ml or below exhibited symptoms typical of the model, suggesting this value can be used as inclusion criteria for animals prior to study enrollment. While B. pertussis infection is endemic to human populations and B. bronchiseptica is common in wild small mammals, this study illustrates that baboons can readily harbor both organisms. Awareness of Bordetella species that share antigens capable of generating protective immune responses and tracking of prior exposure to those species is required for successful use of the baboon model of pertussis.

Infantile thrombotic microangiopathy following Bordetella pertussis infection: Difficulty in differentiating aHUS from secondary TMA

Infantile thrombotic microangiopathy following Bordetella pertussis infection: Difficulty in differentiating aHUS from secondary TMA

Serological evaluation of Bordetella pertussis infection in adults with prolonged cough

Pertussis is a vaccine-preventable disease that is transmitted from infected to susceptible individuals by respiratory route. Bordetella pertussis infection may occur at any age as neither vaccine nor natural infection induced immunity lasts life-long. This study was planned to demonstrate the serological evidence of infection among adults, to raise awareness among clinicians and to provide data for the development of strategies to protect vulnerable infants. A total of 538 patients (345 female, 193 male) ages between 18-87 years who had a complain of prolonged cough for more than two weeks were included in the study. Anti-pertussis toxin (PT) IgG and anti-filamentous hemagglutinin (FH) IgG levels from single serum samples were measured by an in-house ELISA test which was standardized and shown to be efficient previously. Anti-PT IgG antibody levels of ≥ 100 EU/ml were considered as acute/recent infection with B.pertussis. In our study, 9.7% (52/538) of the patients had high levels of anti-PT IgG (≥ 100 EU/ml) and among those patients 43 (43/52; 82.7%) also had high (≥ 100 EU/ml) anti-FHA IgG levels. There were no statistically significant differences in terms of age, gender, education level, DPT (diphtheria-pertussis-tetanus) vaccination history, smoking history or average daily cigarette consumption (p> 0.05) between the cases with high antibody levels (n= 52). When the symptoms and the presence of cases with high antibody levels were evaluated, it was detected that no one parameter was significantly different from others, except that 24.1% of the cases with inspiratory whooping had high anti-PT levels. There was also no statistically significant difference between high anti-PT levels ≥ 100 EU/ml and the patients with risk factors [smoking (21/200; 10.5%), presence of disease that cause chronic cough and/or drug usage (19/171; %11.1), and whole factors which cause chronic cough (32/306; %10.5)] and without risk factors (p= 0.581; p= 0.357; p= 0.249, respectively). The distribution of anti-PT IgG geometric mean titer (GMT) according to the age groups, was as follows; 32.41 in 18-30 years; 36.28 in 31-50 years; 36.82 in 51-70 years and 31.15 in ≥ 71 years. Our results indicated that B.pertussis infections are also present among adult population with a frequency not to be underestimated (9.7%) and the results also emphasized that since typical whooping cough symptoms may not be seen in adults, pertussis infection should be considered as a differential diagnosis in adults with prolonged cough, even if there are some other underlying factors of cough. The data obtained from this study was also considered to be helpful in the development of adult vaccination policies for the protection of infants who have not completed the vaccination schedule yet.

Potential Role of Bordetella Pertussis in Celiac Disease

We discuss the correlation between the incidence of acute clinical Bordetella pertussis infection and celiac disease in children < 2 years of age during the Swedish celiac disease epidemic of the 1980s and 1990s.

Characterization of the immune response induced by pertussis OMVs-based vaccine

For the development of a third generation of pertussis vaccine that could improve the control of the disease, it was proposed that the immune responses induced by the classic whole cell vaccine (wP) or after infection should be used as a reference point. We have recently identified a vaccine candidate based on outer membrane vesicles (OMVs) derived from the disease etiologic agent that have been shown to be safe and protective in mice model of infection. Here we characterized OMVs-mediated immunity and the safety of our new candidate. We also deepen the knowledge of the induced humoral response contribution in pertussis protection. Regarding the safety of the OMVs based vaccine (TdapOMVsBp,) the in vitro whole blood human assay here performed, showed that the low toxicity of OMVs-based vaccine previously detected in mice could be extended to human samples.Stimulation of splenocytes from immunized mice evidenced the presence of IFN-γ and IL-17-producing cells, indicated that OMVs induces both Th1 and Th17 response. Interestingly TdapOMVsBp-raised antibodies such as those induced by wP and commercial acellular vaccines (aP) which contribute to induce protection against Bordetella pertussis infection. As occurs with wP-induced antibodies, the TdapOMVsBp-induced serum antibodies efficiently opsonized B. pertussis. All the data here obtained shows that OMVs based vaccine is able to induce Th1/Th17 and Th2 mixed profile with robust humoral response involved in protection, positioning this candidate among the different possibilities to constitute the third generation of anti-pertussis vaccines.

Plasmacytoid dendritic cell-derived IFNα modulates Th17 differentiation during early Bordetella pertussis infection in mice.

Whooping cough is a highly contagious respiratory disease caused by Bordetella pertussis (B. pertussis). T helper 17 (Th17) cells have a central role in the resolution of the infection. Emerging studies document that type I interferons (IFNs) suppress Th17 differentiation and interleukin (IL)-17 responses in models of infection and chronic inflammation. As plasmacytoid dendritic cells (pDCs) are a major source of type I IFNs, we hypothesize that during B. pertussis infection in mice, pDC-derived IFNα inhibits a rapid increase in Th17 cells. We found that IFNα-secreting pDCs appear in the lungs during the early stages of infection, while a robust rise of Th17 cells in the lungs is detected at 15 days post-infection or later. The presence of IFNα led to reduced Th17 differentiation and proliferation in vitro. Furthermore, in vivo blocking of IFNα produced by pDCs during infection with B. pertussis infection resulted in early increase of Th17 frequency, inflammation, and reduced bacterial loads in the airways of infected mice. Taken together, the experiments reported here describe an inhibitory role for pDCs and pDC-derived IFNα in modulating Th17 responses during the early stages of B. pertussis infection, which may explain the prolonged nature of whooping cough.

Clinicopathologic, Immunohistochemical, and Ultrastructural Findings of a Fatal Case of Middle East Respiratory Syndrome Coronavirus Infection in the United Arab Emirates, April 2014

Middle East respiratory syndrome coronavirus (MERS-CoV) infection causes an acute respiratory illness and is associated with a high case fatality rate; however, the pathogenesis of severe and fatal MERS-CoV infection is unknown. We describe the histopathologic, immunohistochemical, and ultrastructural findings from the first autopsy performed on a fatal case of MERS-CoV in the world, which was related to a hospital outbreak in the United Arab Emirates in April 2014. The main histopathologic finding in the lungs was diffuse alveolar damage. Evidence of chronic disease, including severe peripheral vascular disease, patchy cardiac fibrosis, and hepatic steatosis, was noted in the other organs. Double staining immunoassays that used anti–MERS-CoV antibodies paired with immunohistochemistry for cytokeratin and surfactant identified pneumocytes and epithelial syncytial cells as important targets of MERS-CoV antigen; double immunostaining with dipeptidyl peptidase 4 showed colocalization in scattered pneumocytes and syncytial cells. No evidence of extrapulmonary MERS-CoV antigens were detected, including the kidney. These results provide critical insights into the pathogenesis of MERS-CoV in humans.

Seroprevalence of Antibodies to Pertussis Toxin among Different Age Groups in Thailand after 37 Years of Universal Whole-Cell Pertussis Vaccination.

Despite the high coverage of prophylactic vaccine against Bordetella pertussis infection in many countries for more than three decades, pertussis remains a common vaccine-preventable disease. Infections have been detected more commonly in countries using acellular pertussis vaccine in their Expanded Program of Immunization. Thailand implemented a routine infant immunization program with whole-cell pertussis vaccine in 1977, and since 1992, the national vaccine policy has offered a five-dose whole-cell pertussis vaccine for children given at the ages of 2, 4, 6, 18, and 48 months. This study aimed to investigate the seroprevalence of antibodies to pertussis toxin among healthy people across all ages to determine the level of whole-cell vaccine-induced immunity in the population, and to identify which age group should be targeted for a booster dose. The lowest seronegative rate and highest geometric mean concentrations were found in the 0–10 years age group, corresponding to their recent pertussis vaccination. The proportion of people with undetectable IgG level was prominent, starting after 11 years of age onwards. Now that a reduced-dose pertussis vaccine with fewer adverse effects is available, a booster dose during adolescence should be considered in order to reduce the incidence of pertussis disease. Further studies exploring how long the reduced-dose pertussis vaccine can provide protective immunity against pertussis disease when administered to adults and adolescents should also be performed.

Structural Investigation into Calmodulin's Role in Activating Bordetella Pertussis Adenylyl Cyclase Toxin CyaA

Whooping cough is a respiratory disease resulting from Bordetella pertussis infection that remains a globally significant cause of vaccine-preventable deaths. As a major virulence factor, the adenylyl cyclase toxin (ACT) of Bordetella pertussis (CyaA) has evolved a unique mode of activation by host cell calmodulin (CaM), thereby making it a potential target for the design of novel therapeutics. Currently, no high-resolution structure of intact CaM bound to CyaA exists, so the molecular pathways controlling enzymatic activation remain unclear. Previously, we have identified unique sites of intermolecular association between CyaA and CaM that directly impact CaM's structure, metal-binding properties, and conformational stability. In this study, we utilized site-directed mutagenesis, biophysical, and biochemical techniques to investigate the roles of metal-binding and CaM-dependent interactions in regulating CyaA structure and function. Site-specific mutations mapping to metal-binding site I or II of CaM reduced CyaA binding affinity and cAMP production without significantly altering CaM conformation. Moreover, inactivation of sites I or II in CaM modulated the global conformation of the CaM/CyaA complex in a metal-dependent manner. In the absence of CaM, CyaA exhibited multiple thermal transitions during unfolding experiments, but domain-specific interactions with wild-type or mutant CaM increased the thermal stability of the complex. Together, these data support that CaM-dependent CyaA activation occurs by novel structural mechanisms. This study sheds light on the molecular details of CaM-regulated ACTs, knowledge which may be exploited in the rationale design of inhibitory compounds.

Whooping Cough in Adults: A Series of Severe Cases.

Bordetella pertussis is a gram-negative aerobic coccobacillus causing contagious respiratory tract disease called whooping cough. The virulence factors consist of pertussis toxin, filamentous hemagglutinin, fimbriae, lipooligosaccharide, and adenylate cyclase toxin. The disease causes a worldwide threat to public health despite a high vaccination coverage. The course of whooping cough in adults is frequently atypical, causing difficulty in diagnosis. In this report we present five patients hospitalized with Bordetella pertussis infection manifesting atypical and severe symptoms. The diagnosis was based on serological tests: serum concentration of specific antibodies against pertussis toxin and sputum cultures. We observed a wide spectrum of symptoms, from benign (sinus pain - 80 %, headaches - 20 %), through moderate (hemoptysis - 40 %; chest pain 60 %) to severe symptoms (cardiac arrhythmia - 40 %; syncope - 60 %). Bordetella pertussis infection can cause life-threatening complications and exacerbation of concomitant chronic diseases. Most vaccination programs cover only the first few months of life. Booster doses should be considered in adults, especially those immunocompromised or with pulmonary complications, but also in healthcare workers who are exposed to the contagion and also may spread the infection.

Laboratory-based surveillance of pertussis using multitarget real-time PCR in Japan: evidence for Bordetella pertussis infection in preteens and teens

Between January 2013 and December 2014, we conducted laboratory-based surveillance of pertussis using multitarget real-time PCR, which discriminates among Bordetella pertussis, Bordetella parapertussis, Bordetella holmesii and Mycoplasma pneumoniae. Of 355 patients clinically diagnosed with pertussis in Japan, B. pertussis, B. parapertussis and M. pneumoniae were detected in 26% (n = 94), 1.1% (n = 4) and 0.6% (n = 2), respectively, whereas B. holmesii was not detected. It was confirmed that B. parapertussis and M. pneumoniae are also responsible for causing pertussis-like illness. The positive rates for B. pertussis ranged from 16% to 49%, depending on age. Infants aged ≤ 3 months had the highest rate (49%), and children aged 1 to 4 years had the lowest rate (16%, p < 0.01 vs. infants aged ≤ 3 months). Persons aged 10 to 14 and 15 to 19 years also showed high positive rates (29% each); the positive rates were not statistically significant compared with that of infants aged ≤ 3 months (p ≥ 0.06). Our observations indicate that similar to infants, preteens and teens are at high risk of B. pertussis infection.

Prevalence, diagnosis, and disease course of pertussis in adults with acute cough: a prospective, observational study in primary care.

BackgroundMost cases of adult pertussis probably remain undiagnosed.AimTo explore the prevalence, diagnosis, and disease course of acute pertussis infection in adult patients presenting with acute cough.Design and settingProspective observational study between 2007 and 2010 in primary care in 12 European countries.MethodAdults presenting with acute cough (duration of ≤28 days) were included. Bordetella pertussis infection was determined by polymerase chain reaction (from nasopharyngeal flocked swabs and sputa) and by measurement of immunoglobulin G antibodies to pertussis toxin (PT) in venous blood at day 28. An antibody titre to PT of ≥125 IU/ml or PCR positive result in a respiratory sample defined recent infection. Patients completed a symptom diary for 28 days.ResultsSerum and/or respiratory samples were obtained in 3074 patients. Three per cent (93/3074) had recent B. pertussis infection. Prior cough duration >2 weeks discriminated to some extent between those with and without pertussis (adjusted odds ratio 1.89, 95% confidence interval = 1.17 to 3.07; P = 0.010). Median cough duration after presentation was 17 and 12 days in patients with and without pertussis, respectively (P = 0.008). Patients with pertussis had longer duration of phlegm production (P = 0.010), shortness of breath (P = 0.037), disturbed sleep (P = 0.013) and interference with normal activities or work (P = 0.033) after presentation.ConclusionPertussis infection plays a limited role among adults presenting with acute cough in primary care, but GPs should acknowledge the possibility of pertussis in uncomplicated lower respiratory tract infection. As in children, pertussis also causes prolonged symptoms in adults. However, pertussis is difficult to discern from other acute cough syndromes in adults at first presentation.

Clinical analysis of 247 children with whooping cough and the risk factors of severe cases

To summarize the clinical characteristics of whooping cough in children and analyze the risk factors for severe whooping cough. A retrospective analysis was made on the clinical data of 247 children with whooping cough in Children's Hospital of Chongqing Medical University between Jan 2013 and Dec 2014. Of these patients, 126 were male, 121 were female, the median age was 3.1 months (23 days-4 years and eight months old). The patients were divided into two groups, group 1 had infants less than 3 months of age (n=120) and group 2 had infants and young children older than 3 months (n=127) according to their age. On the other hand, the patients were also divided into two groups according to vaccination status: vaccinated group (received diphtheria toxoid, tetanus toxoid, and acellular pertussis, DTP) (n=31) and unvaccinated group (n=188). Pure Bordetella pertussis infection was seen in 106 cases, and 141 cases had mixed infection. Severe disease was seen in 13 cases, and the other 234 cases had the modest disease. Clinical data were retrospectively analyzed and compared. (1) Bordetella pertussis was identified in 57/680 cases (8.4%) in 2013, and 190/1 856 cases (10.2%) in 2014. The disease could be seen throughout the year, but 182 cases (73.7%) occurred in summer or autumn; 202 cases (81.8%) were less than 6 months. (2) Paroxysmal cough was seen in 238 cases (96.4%) , 61 cases (24.7%) had inspiratory whoop. Infants in group 1 often had episodes of cyanosis, apnea and suffocation (χ² = 19.999, 12.081, 6.508, P<0.05), persistent cough was often seen in group 2 (χ² = 9.885, P<0.05). Complications such as severe pneumonia, pulmonary consolidation and encephalopathy were more common in the group 1 than in group 2 (χ² = 17.340, 6.080, 11.030, 23.545, P<0.05). (3) The length of stay of group 1, and of unvaccinated group was significantly longer than that of group 2 and of vaccinated group (t=19.331, 26.741, P<0.05). (4) Leukocytosis was found in 224 cases (90.7%), 182 cases (73.7%) had predominant lymphocytosis. White blood cell in group 1, unvaccinated group and severe disease group was higher than the corresponding group (t=11.075,13.739,3.469, P<0.05). (5) Patients who had a history of exposure, fever, leukocytosis and pulmonary consolidation or atelectasis on chest imaging were prone to develop into severe pertussis (OR=4.521, 4.900, 1.085, 4.792, 50.400; P<0.05). A total of 244 cases (98.8%) recovered, 3 cases (1.2%) died, they were less than 3 months old and unvaccinated. The number of cases with whooping cough in Chongqing area tends to be rising. The disease occurred mostly in summer and fall. Infants less than 3 months old, unvaccinated with DTP had high susceptibility to pertussis, often had a severe clinical presentation and severe complications, had a high mortality rate.

T-cell immune responses to Bordetella pertussis infection and vaccination.

The recent immunological investigations, stemming from the studies performed in the nineties within the clinical trials of the acellular pertussis vaccines, have highlighted the important role played by T-cell immunity to pertussis in humans. These studies largely confirmed earlier investigations in the murine respiratory infection models that humoral immunity alone is not sufficient to confer protection against Bordetella pertussis infection and that T-cell immunity is required. Over the last years, knowledge of T-cell immune response to B. pertussis has expanded broadly, taking advantage of the general progress in the understanding of anti-bacterial immunity and of refinements in methods to approach immunological investigations. In particular, experimental models of B. pertussis infection highlighted the cooperative role played by T-helper (Th)1 and Th17 cells for protection. Furthermore, the new baboon experimental model suggested a plausible explanation for the differences observed in the strength and persistence of protective immunity induced by the acellular or whole-cell pertussis vaccines and natural infection in humans, contributing to explain the upsurge of recent pertussis outbreaks. Despite the progress, open questions remain, the answer to them will possibly provide better tools to fight one of the hardest-to-control vaccine preventable disease.

Concurrent pertussis and influenza A (H1N1) infections in a 28 day-old infant

Pediatric patients suffering from independent or concomitant influenza A (H1N1) and Bordetella pertussis infections pose a diagnostic dilemma and may benefit from time-sensitive treatment. We report a case of influenza A (H1N1) and B. Pertussis co-infection in a previously healthy 28 day-old infant.

Genetic Variation of Bordetella pertussis in Austria.

In Austria, vaccination coverage against Bordetella pertussis infections during infancy is estimated at around 90%. Within the last years, however, the number of pertussis cases has increased steadily, not only in children but also in adolescents and adults, indicating both insufficient herd immunity and vaccine coverage. Waning immunity in the host and/or adaptation of the bacterium to the immunised hosts could contribute to the observed re-emergence of pertussis. In this study we therefore addressed the genetic variability in B. pertussis strains from several Austrian cities. Between the years 2002 and 2008, 110 samples were collected from Vienna (n = 32), Linz (n = 63) and Graz (n = 15) by nasopharyngeal swabs. DNA was extracted from the swabs, and bacterial sequence polymorphisms were examined by MLVA (multiple-locus variable number of tandem repeat analysis) (n = 77), by PCR amplification and conventional Sanger sequencing of the polymorphic regions of the prn (pertactin) gene (n = 110), and by amplification refractory mutation system quantitative PCR (ARMS-qPCR) (n = 110) to directly address polymorphisms in the genes encoding two pertussis toxin subunits (ptxA and ptxB), a fimbrial adhesin (fimD), tracheal colonisation factor (tcfA), and the virulence sensor protein (bvgS). Finally, the ptxP promoter region was screened by ARMS-qPCR for the presence of the ptxP3 allele, which has been associated with elevated production of pertussis toxin. The MLVA analysis revealed the highest level of polymorphisms with an absence of MLVA Type 29, which is found outside Austria. Only Prn subtypes Prn1/7, Prn2 and Prn3 were found with a predominance of the non-vaccine type Prn2. The analysis of the ptxA, ptxB, fimD, tcfA and bvgS polymorphisms showed a genotype mixed between the vaccine strain Tohama I and a clinical isolate from 2006 (L517). The major part of the samples (93%) displayed the ptxP3 allele. The consequences for the vaccination strategy are discussed.

The potential of adjuvants to improve immune responses against TdaP vaccines: A preclinical evaluation of MF59 and monophosphoryl lipid A

The successful approach of combining diphtheria, tetanus and pertussis antigens into a single vaccine has become a cornerstone of immunization programs. Yet, even if vaccination coverage is high, a resurgence of pertussis has been reported in many countries suggesting current vaccines may not provide adequate protection. To induce better tailored and more durable immune responses against pertussis vaccines different approaches have been proposed, including the use of novel adjuvants. Licensed aP vaccines contain aluminum salts, which mainly stimulate humoral immune responses and might not be ideal for protecting against Bordetella pertussis infection. Adjuvants inducing more balanced T-helper profiles or even Th1-prone responses might be more adequate. In this study, two adjuvants already approved for human use have been tested: MF59 emulsion and the combination of aluminum hydroxide with the Toll-Like Receptor 4 agonist MPLA. Adjuvanticity was evaluated in a mouse model using a TdaP vaccine containing three B. pertussis antigens: genetically detoxified pertussis toxin (PT-9K/129G), filamentous hemagglutinin (FHA) and pertactin (PRN)The physico-chemical compatibility of TdaP antigens with the proposed adjuvants, together with a quicker onset and changed quality of the antibody responses, fully supports the replacement of aluminum salts with a new adjuvant to enhance aP vaccines immunogenicity.