Immunogenicity of tetanus, diphtheria and acellular pertussis vaccination among pregnant women living with and without HIV.

OBJECTIVE: Vaccination during pregnancy with tetanus-diphtheria-acellular pertussis (Tdap) vaccine is recommended to protect the young infants against pertussis. There is a paucity of data on immune responses to Tdap in pregnant women with HIV (PWWH), and its impact on the protection of their infants has not been described. METHODS: In an open label phase IV clinical trial in South Africa, we evaluated the immunogenicity and safety of Tdap in PWWH compared with HIV-uninfected women. Antigen-specific immunoglobulin G (IgG) to pertussis toxoid, filamentous haemagglutinin, pertactin, fimbriae, diphtheria and tetanus were measured by electrochemiluminescence-based multiplex assay. RESULTS: Overall, 91 PWWH and 136 HIV-uninfected pregnant women were enrolled. All PWWH were on antiretroviral treatment and 94.5% had HIV viral loads <40 copies per millilitre. Antibody levels prevaccination were lower among PWWH compared with HIV-uninfected women for all antigens. At 1 month postvaccination PWWH compared with HIV-uninfected women had lower fold-increase and antibody concentrations for all epitopes. Also, a lower proportion of PWWH achieved ≥4-fold increase from pre to postvaccination for pertussis toxoid and pertactin, or diphtheria IgG levels ≥0.1 IU/ml and ≥1 IU/ml postvaccination. Adverse events postvaccination were similar in PWWH and HIV-uninfected. CONCLUSION: Tdap vaccination was safe and immunogenic. PWHW had, however, attenuated humoral immune responses, which could affect the effectiveness of protecting their infants against pertussis compared with those born to women without HIV.ClinicalTrials.gov identifier: NCT05264662.

Alterations of growth, biofilm-forming, and gene expression of Bordetella pertussis by antibiotics at sub-minimum inhibitory concentrations.

Bordetella pertussis is the primary agent of the acute respiratory disease pertussis. It has been reported that the disease has recently become more common, especially in adults and adolescents, and adaptation of the pathogen is thought to have an important influence on the recurrence of the disease. This study aims to determine the effect of erythromycin, azithromycin, and trimethoprim-sulfamethoxazole used in the treatment of pertussis on the virulence gene expressions (prn, ptxS1, fhaB), biofilm-forming and growth of B. pertussis. In this study, the minimum inhibitory concentration (MIC) values of azithromycin and erythromycin in B. pertussis local strain Saadet were determined to be 0.09 µg/mL and 0.3 µg/mL, respectively. However, the Tohama-I and Saadet strains were resistant to trimethoprim-sulfamethoxazole (MIC>32 µg/mL). The biofilm-forming of the Saadet strain decreased with the increase in antibiotic doses. It was observed that 1/32MIC erythromycin and 1/32MIC azithromycin upregulated the expression of fhaB in Tohama-I, whereas the expression of ptxS1 and prn significantly decreased in sub-MICs of erythromycin. In the Saadet strain, only ptxS1 was highly expressed at 1/16MIC azithromycin and erythromycin (p > 0.05). This is the first study to investigate the effect of sub-MIC antibiotics on the expression of virulence genes and biofilm-forming of B. pertussis.

The incidence, duration, risk factors, and age-based variation of missed opportunities to diagnose pertussis: A population-based cohort study.

OBJECTIVE: To estimate the incidence, duration and risk factors for diagnostic delays associated with pertussis. DESIGN: We used longitudinal retrospective insurance claims from the Marketscan Commercial Claims and Encounters, Medicare Supplemental (2001-2020), and Multi-State Medicaid (2014-2018) databases. SETTING: Inpatient, emergency department, and outpatient visits. PATIENTS: The study included patients diagnosed with pertussis (International Classification of Diseases [ICD] codes) and receipt of macrolide antibiotic treatment. METHODS: We estimated the number of visits with pertussis-related symptoms before diagnosis beyond that expected in the absence of diagnostic delays. Using a bootstrapping approach, we estimated the number of visits representing a delay, the number of missed diagnostic opportunities per patient, and the duration of delays. Results were stratified by age groups. We also used a logistic regression model to evaluate potential factors associated with delay. RESULTS: We identified 20,828 patients meeting inclusion criteria. On average, patients had almost 2 missed opportunities prior to diagnosis, and delay duration was 12 days. Across age groups, the percentage of patients experiencing a delay ranged from 29.7% to 37.6%. The duration of delays increased considerably with age from an average of 5.6 days for patients aged <2 years to 13.8 days for patients aged ≥18 years. Factors associated with increased risk of delays included emergency department visits, telehealth visits, and recent prescriptions for antibiotics not effective against pertussis. CONCLUSIONS: Diagnostic delays for pertussis are frequent. More work is needed to decrease diagnostic delays, especially among adults. Earlier case identification may play an important role in the response to outbreaks by facilitating treatment, isolation, and improved contact tracing.

Understanding and preventing vaccination errors.

INTRODUCTION: Vaccine-related medication errors can occur at each step of the vaccination process: prescribing, dispensing, preparation, administration, monitoring, transport, and storage. We aimed to describe current knowledge of vaccination-related errors to identify areas for improvement. MATERIAL AND METHODS: We performed a literature review on PubMed, using MeSH terms, from 1998 to 2020 to identify articles that would illustrate vaccine-related medication errors. We developed a questionnaire for health professionals concerning prescribing, dispensing, or administering vaccines via Facebook, and then identified priority areas for information to reduce vaccine-related medication errors. RESULTS: A total of 227 answers were collected from midwives (N = 90), pharmacists or technicians (N = 75), and physicians or interns (N = 62). Practitioners gave wrong answers on live vaccines administered during pregnancy (>10 % of physicians), incorrect acronyms for the DTCaP (diphtheria, tetanus, pertussis, poliomyelitis) vaccine corresponding to branded products (72 % of midwives), lack of marketing authorization knowledge for the influenza vaccine (46 %), duration of vaccine conservation outside of the refrigerator (52 %), or intravenous administration of the rotavirus vaccine (23 %). Most health professionals mentioned the possibility of writing procedures for the various steps of the vaccine process, but only few of them have actually done it (15 % for dispensing/administration versus 61 % for storage). Ten key points for initial or ongoing training of health professionals have been summarized. CONCLUSION: There is partial mastery of vaccine knowledge among health professionals. Our final table presents the most important elements of these results for educating health professionals on potential vaccine-related medication errors.

Whole-Cell and Acellular Pertussis Vaccine: Reflections on Efficacy.

Pertussis is a common respiratory infection caused by the bacterium Bordetella pertussis. Although most cases occur in developing countries, it is considered endemic globally. The World Health Organization estimates there are 20-40 million cases of pertussis annually. Pertussis vaccines played a pivotal role in reducing the burden of pertussis disease as well as infant morbidity and mortality. Although the two forms of pertussis vaccine are effective, each has its advantages and drawbacks. This review aims to review the current knowledge on pertussis vaccines, emphasizing vaccine effectiveness in different populations within a community. Clinical trials have shown favorable vaccine efficacy with acellular pertussis (aP)vaccine. However, observational and population-level studies showed that introducing at least a single dose of whole-cell pertussis (wP) vaccine within the routine immunization schedule is associated with better disease protection and a longer duration of immunity. On the other hand, wP vaccine is more reactogenic and associated with higher adverse events. Therefore, the selection of vaccine should be weighed against the effectiveness, reactogenicity, and cost-effectiveness. Due to its safety profile, aP vaccine can be offered to wider population groups. Booster adolescent and pregnant immunization programs have been implemented globally to control outbreaks and protect vulnerable infants. Due to the variable effectiveness performance of both vaccines, different countries adopted distinctive immunization programs. Determining the right vaccination approach depends on financial consideration, immunization program infrastructure, adverse event monitoring, and pertussis surveillance in the community.

Tosferina en el adulto: el enemigo visible / Whooping Cough: The Visible Enemy

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[Translated article] Whooping Cough: The Visible Enemy / Tosferina en el adulto: el enemigo visible

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Novel Strategies to Inhibit Pertussis Toxin.

Pertussis, also known as whooping cough, is a respiratory disease caused by infection with Bordetella pertussis, which releases several virulence factors, including the AB-type pertussis toxin (PT). The characteristic symptom is severe, long-lasting paroxysmal coughing. Especially in newborns and infants, pertussis symptoms, such as leukocytosis, can become life-threatening. Despite an available vaccination, increasing case numbers have been reported worldwide, including Western countries such as Germany and the USA. Antibiotic treatment is available and important to prevent further transmission. However, antibiotics only reduce symptoms if administered in early stages, which rarely occurs due to a late diagnosis. Thus, no causative treatments against symptoms of whooping cough are currently available. The AB-type protein toxin PT is a main virulence factor and consists of a binding subunit that facilitates transport of an enzyme subunit into the cytosol of target cells. There, the enzyme subunit ADP-ribosylates inhibitory α-subunits of G-protein coupled receptors resulting in disturbed cAMP signaling. As an important virulence factor associated with severe symptoms, such as leukocytosis, and poor outcomes, PT represents an attractive drug target to develop novel therapeutic strategies. In this review, chaperone inhibitors, human peptides, small molecule inhibitors, and humanized antibodies are discussed as novel strategies to inhibit PT.

Macrolide susceptibility and molecular characteristics of Bordetella pertussis.

OBJECTIVE: To analyse macrolide resistance and molecular characteristics of Bordetella pertussis clinical isolates from western China, and to explore the relationship between macrolide-resistance and genotypes. METHODS: Susceptibilities of B. pertussis clinical isolates to erythromycin, azithromycin and clarithromycin were determined by epsilometer test (E-test). Isolated strains were sequenced to ascertain the presence of the 23S rRNA gene A2047G mutation. Strains were typed using multilocus antigen sequence typing, multilocus variable-number tandem-repeat analysis (MLVA) and pulsed-field gel electrophoresis (PFGE). RESULTS: Of 58 B. pertussis strains isolated in this study, 46 were macrolide-resistant and 12 were macrolide sensitive. All macrolide-resistant strains carried the A2047G mutation and were the prn1/ptxP1/ptxA1/fim3-1/fim2-1 genotype; the MLVA types were MT195 (19/58), MT55 (13/58) and MT104 (14/58), and the PFGE profiles were classified into BpSR23 (17/58) and BpFINR9 (29/58) types. None of the macrolide-sensitive strains carried the A2047G mutation; genotypes were (prn9 or prn2)/ptxP3/ptxA1/fim3-1/fim2-1, and all were MT27. PFGE profiles differed from the macrolide-resistant strains. CONCLUSIONS: B. pertussis clinical isolates from western China were severely resistant to macrolides. Genotypes differed between macrolide-resistant and macrolide-sensitive strains, and there may be a correlation between acquisition of macrolide resistance and changes in specific molecular types.

Effects of Early Administration of Macrolides on Whooping Cough in Adolescents and Adults: A Single-center Retrospective Cohort Study.

Objective This study aimed to elucidate the effects of early macrolide administration on genetically confirmed pertussis-induced cough in adolescents and adults. Methods This single-center, retrospective cohort study examined the effects of the early administration of macrolides and antitussive agents on cough secondary to pertussis. We divided the patients into two groups based on the median duration from the beginning of the cough to the initiation of macrolide administration: early macrolide administration group (EMAG) and non-early macrolide administration group (NEMAG). The clinical improvement of cough was defined as maintaining a cough awareness score of ≤3 points for 3 consecutive days. Patients The medical records of 40 patients diagnosed with pertussis (≥12 years old) who were able to maintain a cough diary and received no other antibiotics aside from macrolides were included in the study. A diagnosis of pertussis was made using the loop-mediated isothermal amplification (LAMP) test. Results The EMAG (24 patients) showed a significantly shorter total cough period than the NEMAG [16 patients; 20.0 (95% confidence interval (CI), 16-28) vs. 30.5 (95% CI, 27-40) days; log-rank test, p=0.002]. There was no significant difference in the post-administration cough periods between the EMAG and NEMAG [11.0 (95% CI, 7-19) vs. 13.0 (95% CI, 5-23) days; log-rank test, p=0.232]. Antitussive agents did not affect the cough. Conclusion The early administration of macrolides, but not antitussive agents, is effective for treating pertussis. Therefore, macrolides should be administered as soon as possible for this disease.

Whooping cough complicating pulmonary hypertension in pregnancy.

We report a case of a previously fit woman who presented at 26 weeks into her fourth pregnancy with a dry cough. Following a nasopharyngeal swab, she was diagnosed with a pertussis infection, and treated with antibiotics. A chest X-ray showed right atrial dilatation and an echocardiogram was scheduled outpatient. However, after re-presenting with worsening cough and dyspnoea, an inpatient echocardiogram was performed which suggested elevated pulmonary pressures with significant tricuspid regurgitation, as confirmed by subsequent cardiac catheterisation. She had an elective caesarean section at 34 weeks and underwent repeat right heart catheterisation which revealed persistent, and likely pre-existing, pulmonary arterial hypertension. This case highlights the importance of thorough assessment of non-obstetric symptoms in pregnancy in formulating alternative differentials, even after a diagnosis has been made, to prevent potentially life-threatening conditions from being missed. It also shows that although often associated, respiratory and cardiac causes may coexist separately.

Cytokine expression patterns in hospitalized children with Bordetella pertussis, Rhinovirus or co-infection.

Mechanisms of interaction between Bordetella pertussis and other viral agents are yet to be fully explored. We studied the inflammatory cytokine expression patterns among children with both viral-bacterial infections. Nasopharyngeal aspirate (NPA) samples were taken from children, aged < 1 year, positive for Rhinovirus, Bordetella pertussis and for Rhinovirus and Bordetella pertussis. Forty cytokines were evaluated in NPA by using human cytokine protein arrays and a quantitative analysis was performed on significantly altered cytokines. Forty cytokines were evaluated in NPA by using human cytokine protein arrays and a quantitative analysis was performed on significantly altered cytokines. Our results show that co-infections display a different inflammatory pattern compared to single infections, suggesting that a chronic inflammation caused by one of the two pathogens could be the trigger for exacerbation in co-infections.

Angioedema as a predominant symptom of Bordetella pertussis infection.

A 41-year-old woman was referred to our hospital with a 6-week history of severe angioedema, dyspnoea and coughing. Initial investigations focused on common causes of angioedema. Clinical presentation and resistance to treatment with antihistamines and steroids made histamine-mediated angioedema unlikely. Bradykinin-mediated angioedema, such as hereditary or drug-induced angioedema, was excluded by a thorough history investigation and laboratory testing for C1-esterase and C4.In rare cases, exogen pathogens cause angioedema. After profound testing for respiratory pathogens, Bordetella pertussis toxins IgA and IgG were found to be positive, indicating recent B. pertussis infection. Pertussis toxin may be responsible for increased vascular permeability causing angioedema. With adequate antibiotic treatment, the symptoms resolved quickly.This case is an example of an atypical presentation of B. pertussis infection in an unvaccinated adult. The recent resurgence of pertussis makes early diagnosis and disease prevention by vaccination crucial.

[Research advances in the treatment strategies for severe pertussis in children].

At present, effective antibiotics and comprehensive symptomatic/supportive treatment as early as possible are mainly used for the treatment of severe pertussis in clinical practice. However, some children with severe pertussis have unsatisfactory response to commonly used drugs and treatment measures in the intensive care unit and thus have a high risk of death. Studies have shown that certain treatment measures given in the early stage, such as exchange transfusion, may help reduce deaths, but there is still a lack of uniform implementation norms. How to determine the treatment regimen for severe pertussis and improve treatment ability remains a difficult issue in clinical practice. This article reviews the advances in the treatment of severe pertussis, in order to provide a reference for clinical treatment and research.

Clinical impact of respiratory syncytial virus infection on children hospitalized for pertussis.

BACKGROUND: Although Respiratory syncytial virus (RSV) is one of the common pathogens in children with pertussis and viral coinfection, the clinical impact of RSV infection on pertussis remains unclear. We compared clinical characteristics and sought differences between infants with single Bordetella pertussis (B. pertussis) infection and those with RSV coinfection. METHODS: We enrolled 80 patients with pertussis who were hospitalized in Shenzhen Children's Hospital from January 2017 to December 2019. Respiratory tract samples were tested for B. pertussis with real-time polymerase chain reaction and respiratory viruses with immunofluorescence assay. Clinical data were obtained from hospital records and collected using a structured questionnaire. RESULTS: Thirty-seven of 80 patients had B. pertussis infection alone (pertussis group) and 43 had RSV-pertussis coinfection (coinfection group). No significant differences were found with regard to sex, body weight, preterm birth history, pertussis vaccination, symptoms, presence of pneumonia, or lymphocyte count between the 2 groups. Univariate analysis showed patients with RSV coinfection were older (median, 4.57 months vs 4.03 months, p = 0.048); more commonly treated with ß-lactam antibiotics (21% vs 5%, p = 0.044); had higher rates of wheezes (40% vs 14%, p = 0.009) and rales (35% vs 14%, p = 0.028) on chest auscultation, a higher rate of readmission (40% vs 11%, p = 0.004), and a longer hospital stay (median, 10 days vs 7 days, p = 0.002). In the further binary logistic regression analysis, patients with RSV coinfection had higher rates of wheezes (OR = 3.802; 95% CI: 1.106 to 13.072; p = 0.034) and readmission (OR = 5.835; 95% CI: 1.280 to 26.610; p = 0.023). CONCLUSIONS: RSV coinfection increases readmission rate in children hospitalized for pertussis. RSV infection should be suspected when wheezes are present on auscultation of the chest in these patients. Early detection of RSV may avoid unnecessary antibiotic use.

[Malignant pertussis in a three-week-old girl].

Whooping cough is an infectious disease caused by Bordetella pertussis. Particularly children under the age of six months can be severely affected by the infection. Severe leukocytosis may lead to thrombosis and pulmonary hypertension and eventually circulatory failure and death. This a case report of a three-week-old girl with malignant pertussis, who due to respiratory insufficiency was mechanically ventilated, and her severe leucocytosis was treated with exchange blood transfusion. Whooping cough may partially be prevented with efficient vaccination programmes.

Effectiveness of rapid multiplex polymerase chain reaction for early diagnosis and treatment of pertussis.

BACKGROUND: Pertussis, is an infectious respiratory disease caused by Bordetella pertussis. The incidence of pertussis has been increasing in South Korea to due to waning vaccine-induced immunity. Culture has a low sensitivity and a long turnaround time (TAT). Recently, a rapid multi-polymerase chain reaction (mPCR) test with a TAT of about 1 h was developed for the detection of respiratory pathogens (17 viruses and three bacteria), including B. pertussis. This study aimed to investigate the effectiveness of mPCR for early diagnosis and treatment of pertussis. METHODS: We performed a retrospective study of patients with pertussis diagnosed from May 2017 to June 2019 at a university hospital in South Korea. Nasopharyngeal swab specimens were tested using mPCR. Data were extracted from medical records. RESULTS: A total of 27 patients with a median age of 48.9 years (range: 3.3-82.2 years) were diagnosed with pertussis, of whom 9 (33.3%) were male. Eleven (40.7%) had fever, 12 (44.4%) had dyspnea, three (11.1%) had paroxysmal cough, and nine (33.3%) had inspiratory whooping. The median interval from symptom onset to diagnosis was 9.0 days (range: 1-31 days). Twenty-four patients (81.5%) were diagnosed within 2 weeks from symptom onset. All but one patient was prescribed macrolide antibiotics. Twenty-two patients (81.5%) required hospitalization, including three (11.1%) who required intensive care unit care for ventilation. CONCLUSION: Testing patients with respiratory symptoms using mPCR can improve early diagnosis of pertussis, ensure proper treatment, and may help with outbreak control.

Pharmacotherapy for Bordetella pertussis infection. I. A synthesis of laboratory sciences.

There is considerable history and practice experience both with laboratory susceptibility testing for Bordetella pertussis and clinical treatment. This two-part narrative review provides a synthesis of the laboratory and clinical sciences as they apply to this bacterium and the clinical consequences of treating infection. It is generally held that antibiotic susceptibility testing for B. pertussis is not sufficiently standardised, but there has not been an urgent need to consolidate the same given the lack global experience with major resistance profiles. Experience in China, however, has provided concern for high-level macrolide resistance. The nature of and frequency of such resistance has raised the bar for reconsideration of susceptibility testing given that first-line treatment may be regionally compromised. Disk diffusion and Etest susceptibility testing can be recommended for screening resistance among individual isolates of B. pertussis and on an ad hoc manner. Disk diffusion, Etest and/or critical agar dilution testing can be recommended for large-scale studies. Standards for inoculum, growth atmosphere, timing of interpretation, preferred testing media and controls can be extrapolated from the publications to date. Such methods should be able to detect high-level resistance to several antibiotics, but especially macrolides. Concern for intermediate-susceptible categories requires consideration as well as the correlation with bacteriological and clinical outcomes. Provisional standards can be applied at this time, and modification or fine-tuning of any such standards are open to future investigation.