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Pertussis: An Old Disease That is Still With Us *

Heininger, Ulrich

Infectious Diseases in Clinical Practice: June-July 2002 - Volume 11 - Issue 5 - p 294-301
SPECIAL FEATURE
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Our knowledge of pathogenesis, clinical presentation and prevention of pertussis has improved substantially over recent years. We now better understand the function of long-known virulence factors for Bordetella pertussis, and genome sequencing has identified a multitude of new proteins; their functions are yet to be elucidated. Furthermore, improved diagnostic tools have revealed the broad spectrum of disease, and new insights into the host’s immune response have been gained. Finally, the development, evaluation, licensing and implementation of several new acellular pertussis vaccines with high acceptance have changed the epidemiology of pertussis in many countries (i.e. a shift towards an increasing burden of disease in adolescent persons and adults). These developments are likely to have great impact on the daily practice not only of paediatricians, but also of general practitioners, internists, gynaecologists and many other specialists in adolescent and adult medicine. The present review provides an update on recent progress.

University Children’s Hospital, Basel, Switzerland

*This article first appeared in Current Opinion in Infectious Diseases, 2001;14:329–335.

Correspondence to Ulrich Heininger MD, University Children’s Hospital (UKBB), PO Box, CH-4005 Basel, Switzerland

Tel: +41 61 685 6565; fax: +41 61 685 6012; e-mail: Ulrich.Heininger@unibas.ch

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Introduction

Abbreviations:ACT adenylate cyclase toxin, APV acellular pertussis vaccine, BvgBordetella virulence genes, BvgASBordetella virulence genes activator/sensor, FHA filamentous haemagglutinin, PCR polymerase chain reaction, PT pertussis toxin, WCPV whole-cell pertussis vaccine

Pertussis, or whooping cough, is an acute infection of the respiratory tract by Bordetella pertussis and, less frequently, by B. parapertussis [1]. The illness occurs worldwide, it affects all age groups, and is most serious in young, unprotected infants. Whooping cough caused by B. pertussis is preventable with vaccines.

Substantial progress has been made in the field of pertussis over the past few years. Basic laboratory research and use of gene-manipulated organisms in various animal models have improved our understanding of the pathogenesis of the disease [2•]. Polymerase chain reaction (PCR) has become widely available for early diagnosis of infection [3]. Improved diagnostic tools and increased research interest have uncovered the large clinical spectrum of pertussis in all age groups [4,5]. Acellular pertussis vaccines (APVs) were evaluated in large efficacy studies [6] and then introduced in many countries. Finally, the increasing acceptance of pertussis immunization in many countries, especially in Europe, has led to a change in the epidemiology of the disease [7,8], but also to concerns regarding antigenic shifts of the organism as a result of pressure from immunization [9]. In the present review the most recent major advances are summarized.

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Pathogenesis

Organisms of the genus Bordetella (bordetellae) are able to regulate gene expression in response to environmental changes by means of a two-component, signal transduction system termed Bordetella virulence genes (Bvg) activator/sensor (BvgAS) [10]. Various adhesins and toxins are expressed during the virulent Bvg+ phase. During the avirulent Bvg phase the genes that encode these proteins are downregulated, and various other proteins (the role of which are largely unknown) are activated [11]. Furthermore, an intermediate phase with reduced virulence and expression of specific proteins has recently been identified in bordetellae [12••].

Progress in sequencing the genome of B. pertussis has yielded a spectacular new field of research. By use of transcriptional transfusions, a multitude of new Bvg+ and Bvg phase genes were discovered, including those that encode adhesins, an operon that encodes a polysaccharide capsule, genes that encode autotransporters, and iron metabolism genes [13••,14]. Their roles in pathogenesis, however, remain to be elucidated.

Earlier reports that hypothesized that B. pertussis may survive within human neutrophils for a prolonged period were recently disproved [15•]. Although antibodies to filamentous haemagglutinin (FHA), which appear early during the course of disease, appear to antagonize phagocytosis [16], later the presence of neutralizing antibodies against adenylate cyclase toxin (ACT) allows effective phagocytosis [17•] and killing of the organism, which is highly susceptible to the acid milieu within phagocytes [18•]. Further evidence on the opposing roles of FHA and ACT was provided by experiments with epithelial cell lines [19]. Whereas FHA favours invasion of but not multiplication within these cells, ACT (and pertactin) strongly inhibit this process. The role of these in-vitro observations during natural infection is currently not known.

Although many virulence factors are shared between different Bordetella subspecies with different host ranges, lipopolysaccharide molecules of B. pertussis, B. parapertussis and B. bronchiseptica are distinct. It has been elegantly demonstrated [20•] that they may have evolved differently to serve specific needs during infection of the respiratory tract of their hosts.

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Antigenic variation

Reports from The Netherlands on genetic polymorphisms of pertactin and pertussis toxin (PT) in isolates of B. pertussis obtained during an outbreak of pertussis among vaccinated persons [9] have caused serious concerns that vaccination with a specific type of B. pertussis strain may ultimately lead to antigenic shifts, followed by vaccine failure. However, momentary relief was yielded by further studies from Italy, Finland and the USA [21,22,23•]. In Italy (where pertussis vaccine uptake has been low, with presumably little evolutionary pressure) and in Finland (where pertussis vaccine coverage has been high, but no major outbreaks have occurred among vaccinated children), antigenic changes similar to those in The Netherlands were found in B. pertussis strains [21,22]. In an experimental approach, a genetically changed PT molecule was still neutralized by vaccine-induced antibodies as effectively as was the wild-type toxin [23•]. This indicates that significant genetic changes may occur in the PT molecule without adverse effect on antibody recognition. Finally, genetic changes in the pertactin molecule have also been observed in isolates of B. bronchiseptica in the absence of vaccination pressure [24]. Taken together, these data suggest that the observations from The Netherlands are a coincidence, rather than representing cause and effect.

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Cell-mediated immunity

Increasing knowledge has accumulated with respect to the role of cell-mediated immunity against pertussis. Studies in mice immunized with either APV or whole-cell pertussis vaccine (WCPV) [25•] have shown that protection against challenge with live bacteria is independent of circulating serum antibodies. In these mice immunization led to effective priming, as demonstrated by the presence of memory T and B lymphocytes. More importantly, sustained vaccine efficacy was documented in young children several years after immunization with three doses of APV, despite significant antibody decline [26]. Surprisingly, lymphoproliferative responses to PT, FHA and pertactin in these vaccinees were higher than in unvaccinated control children with a history of clinical pertussis [27•]. These results suggest that cellular immunity may be at least as important as humoral immunity in protection against B. pertussis infection.

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Disease

Typically, pertussis is a three-stage illness (catarrhal, paroxysmal and convalescent), with paroxysmal cough as the most typical feature [1]. B. parapertussis infection is similar, but less severe [28]. B. holmesii, which was originally isolated from the blood of severely immunocompromised patients [29], has recently also been found to cause whooping cough in humans [30•].

During the recent prospective pertussis vaccine trials [4], it was realized that mild illness is more common than was previously thought, especially in vaccinated individuals. In those parts of Germany where uptake of pertussis vaccine had been low until recently, circulation of B. pertussis still leads to large numbers of cases in young, nonimmunized children. In a report of 725 laboratory confirmed cases in persons aged 2 yeas [31•], only 4.5% were hospitalized, and 48% of these with some sort of complication. Prospective case findings might have led to early antibiotic treatment, thus preventing a higher rate of complications. Of the hospitalized cases, 27% were younger than 2 months of age. This is not surprising, because pertussis is most serious in neonates and young infants [32•,33•]. Extremely high leukocytosis is occasionally observed in this age group, and this is a predictor of poor outcome [34].

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Diagnosis

In typical cases, a diagnosis of whooping cough can be made on the basis of clinical presentation. However, it should be kept in mind that a variety of viral and bacterial pathogens other than B. pertussis can cause paroxysmal cough, and, to complicate matters further, mixed infections frequently occur [35•,36••]. Therefore, it is wise to use laboratory tests to confirm a diagnosis of Bordetella infection.

Demonstration of the organism in nasopharyngeal specimens is possible during the first few weeks of illness. Unfortunately, the sensitivity of culture is only approximately 20–40%, especially in vaccinated individuals or when antibiotic treatment has already been initiated. Thankfully, PCR procedures have been developed, evaluated and gradually made available for general use. They have sensitivity rates that are twofold to threefold higher than those of culture [37•]. A number of different primers are currently in clinical use, and it has to be kept in mind that the above-mentioned antigenic variation in the coding sequence of PT may theoretically interfere with recognition of the template in the specimen [38]. Another caveat with use of PCR is its susceptibility to contamination, and internal and external controls are needed for quality assurance. Consensus recommendations have been formulated [39], and a technique that fulfils all of these has been developed [40•].

Later during the course of disease isolation of the organism or amplification of genomic material becomes difficult, and the diagnosis should then be made by use of serology. Under study conditions, paired serum specimens can be obtained for demonstration of significant antibody titre changes against specific pertussis antigens by use of enzyme-linked immunosorbent assay technology. For daily routine practice, however, the diagnosis needs to be made based on single serum analysis. This requires careful analysis of the magnitude of background antibody values in healthy control individuals to define cutoff values with reasonable sensitivity and specificity [41•].

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Treatment

Although a great number of antibiotics has been investigated for activity against B. pertussis (and other bordetellae) [42], including novel quinolones [43], macrolides and erythromycin in particular remain the therapeutic ‘gold standard’. If erythromycin is used in young infants the association between erythromycin and hypertrophic pyloric stenosis should be kept in mind, and parents need to be educated about symptoms of this rare but significant risk [44•,45•].

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Epidemiology

In recent years it has been rediscovered that pertussis is not only an illness of children, but also occurs in adolescent persons and adults [46•,47••], and the latter frequently serve as the source from which infants and children acquire the disease [33•]. Frequent B. pertussis infections in older individuals with waning vaccine or natural immunity are also the most likely explanation for epidemics of pertussis that occur every 2–5 years, even in highly immunized populations [7], although recent epidemiological data from England and Wales [48•] provide evidence for an overall reduction in transmission as a result of immunization. However, undiagnosed pertussis among elderly people is still frequent [49]. Furthermore, vaccinated children can serve as potential ‘silent reservoirs’ for transmission of the organism in their communities, even it the absence of pertussis symptoms [50]. In this regard, new molecular diagnostic tools, primarily pulsed-field gel electrophoresis, have made tracing and monitoring sources of outbreaks possible [51•], and guidelines for the standardized use of this methodology have been created [52•].

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Prevention by Immunization

Over the past 15 years several APVs, containing various numbers and quantities of B. pertussis antigens, have been developed; evaluated for safety, immunogenicity and efficacy; licensed; and finally implemented in many countries [1]. In comparison with conventional whole-cell vaccines, the new APV products cause fewer adverse events. Despite higher costs when switching from WCPVs to APVs, the cost:benefit ratio is still favourable [53•]. Importantly, no clinically significant immunological interference occurs when APVs are used in combination with other vaccines [54••].

All APVs contain PT, most of them contain FHA, and a few also contain fimbrial antigens or pertactin. Although one should generally not switch from one product to another during primary immunization, if unavoidable this can be done without risking an impaired antibody response in the vaccinee [55•].

An as yet unanswered question relates to the optimal schedule and number of immunizations necessary to induce protection against B. pertussis infection. In the UK, three doses at 2, 3 and 4 months of age, but no further boosters, are currently recommended. However, a continuous rise in the number of notified pertussis cases in infants younger than 3 months of age since 1992 has raised doubts regarding whether this strategy is sufficiently protective for the community [56••]. In some countries, for example Sweden, three doses are recommended at 3, 5 and 12 months of age. In comparison with the US schedule (2, 4, 6 and 15 months), serum antibody values are higher after the third dose, but the lack of a fourth dose may be disadvantageous in the long run [57]. It is not easy to predict protection against disease by analysing antibody responses to pertussis immunization, although studies suggest that pertactin, fimbriae and PT are key antigens in APVs [58,59]. In one recent analysis [60], postimmunization mean antibody values against PT in children vaccinated with a monocomponent PT vaccine appeared to correlate with protection against pertussis. However, the ranges of individual values were largely overlapping, making it impossible to identify the protective cutoff levels.

Many countries currently recommend five doses of pertussis immunization in childhood, but experience with five consecutive doses of APV is still limited. Of initial concern is that rates of local reactions increase from dose to dose, and even entire limb swelling occurs occasionally [61,62•,63]. Fortunately, it transpired that this type of reaction is only temporary, and in general does not interfere with the child’s well-being and is without sequelae. Moreover, the overall rate of reported adverse events after APV is less than that of WCPV [64,65].

Pertussis can be an unpleasant or even serious illness in adolescent persons and adults [66••], and this is one reason why booster immunizations beyond childhood are currently being discussed [67•,68,69•,70•,71]. Several APVs, with and without combined other antigens such as diphtheria and tetanus toxoids and inactivated poliovirus, have recently been evaluated in adults [67•,68,69•,71] and adolescent persons [70•], and these studies supplement extensive similar experience obtained over the past 15 years (for review [72]). Taken together, these studies generally demonstrate excellent immunogenicity and tolerability of APVs when used in these older age groups. Some APVs have been designed to contain lower pertussis component contents as compared with childhood formulations, and still they induce antibody booster responses sufficiently [67•,68,70•,71]. Importantly, efficacy has been demonstrated for one APV in a large efficacy trail in adults, according to a preliminary report [73]. The point estimate of efficacy was 78%, and thus is in the same range as rates reported from the large childhood studies [6].

Although booster immunizations are already recommended on a routine basis for adolescent persons in France and Germany, no country has yet introduced boosters in adults. An open question in this regard is the appropriate interval. From a practical point of view, adding pertussis boosters to the existing recommendation of administration of tetanus and diphtheria toxoids every 10 years would be fairly easy to implement. In support of this empirical approach is the demonstration in one study [74•] that humoral and cellular-mediated immunity remained above baseline for at least 8 years after a single booster dose in adults.

Overall, APVs are a significant improvement over conventional WCPVs. However, several issues remain unresolved. What is the ideal composition of APV with respect to antigen contents? Is it possible to engineer mucosal vaccines to avoid injections that would induce protective local immunity? Do live recombinant vaccines, which could be produced at substantially lower costs and have demonstrated efficacy in a mouse model [75•], also have the potential to protect humans from pertussis? Research in these areas is ongoing [76,77•].

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Conclusion

Significant progress has recently been made in the field of pertussis. However, several objectives remain to be met. These include acquiring a better understanding of the pathogenesis of Bordetella infection; improving awareness among general practitioners about the role of pertussis in coughing adolescent persons and adults; further improvement and availability of laboratory methods for the diagnosis of pertussis; and optimizing existing immunization strategies; with special emphasis on high coverage in early childhood, but also considering booster immunizations in adolescent persons and possibly adults.

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References and recommended reading

Papers of particular interest, published within the annual period of review, have been highlighted as:

• of special interest

•• of outstanding interest

1. Cherry JD, Heininger U. Pertussis. In: Textbook of pediatric infectious diseases, 4th ed. Feigin RD, Cherry JD (editors). Philadelphia: WB Saunders; 1998. pp. 1423–1440.
2.• Kerr JR, Matthews RC. Bordetella pertussis infection: pathogenesis, diagnosis, management, and the role of protective immunity. Eur J Clin Microbiol Infect Dis 2000; 19:77–88. This is a useful review that summarizes the basic knowledge is some areas of current pertussis research.
3. Müller FM, Hoppe JE, Wirsing von König CH. Laboratory diagnosis of pertussis: state of the art in 1997. J Clin Microbiol 1997; 35:2435–2443.
4. Heininger U, Klich K, Stehr K, Cherry JD. Clinical findings in Bordetella pertussis infections: results of a prospective multicenter surveillance study. Pediatrics 1997; 100:e10.
5. Cherry JD. Epidemiological, clinical, and laboratory aspects of pertussis in adults. Clin Infect Dis 1999; 28(suppl 2):S112–S117.
6. Cherry JD. Comparative efficacy of acellular pertussis vaccines: an analysis of recent trials. Pediatr Infect Dis J 1997; 16(suppl 4):S90–S96.
7. Garcia-Corbeira P, Dal-Ré R, Aguilar L, Garcia-de-Lomas J. Seroepidemiology of Bordetella pertussis infections in the Spanish population: a cross-sectional study. Vaccine 2000; 18:2173–2176.
8. He Q, Viljanen MK, Nikkari S, et al. Outcomes of Bordetella pertussis infection in different age groups of an immunized population. J Infect Dis 1994; 70:873–877.
9. Mooi FR, van Orischot H, Heuvelman K, et al. Polymorphism in the Bordetella pertussis virulence factors P.69/pertactin and pertussis toxin in the Netherlands: temporal trends and evidence for vaccine-driven evolution. Infect Immun 1998; 66:670–675.
10. Weiss AA, Falkow S. Genetic analysis of phase change in Bordetella pertussis. Infect Immun 1984; 43:263–269.
11. Uhl MA, Miller JF. Integration of multiple domains in a two-component sensor protein: the Bordetella pertussis BvgAS phosphorelay. EMBO J 1996; 15:1028–1036.
12.•• Stockbauer KE, Fuchslocher B, Miller JF, Cotter PA. Identification and characterization of BipA, a Bordetella Bvg-intermediate phase protein. Mol Microbiol 2001; 39:65–78. This paper describes a first Bordetella protein that is expressed in an intermediate phase of the organism, thus revolutionizing our traditional view of two distinct phenotypic phases [Bvg+ (virulent) and Bvg (avirulent)]. Although still speculative, the intermediate phase may well have some function in transmission of the organism. Therefore, this and other yet to be identified factors may be of interest for future Bordetella vaccines.
13.•• Antoine R, Alonso S, Raze D, et al. New virulence-activated and virulence repressed genes identified by systematic gene inactivation and generation of transcriptional fusions in Bordetella pertussis. J Bacteriol 2000; 182:5902–5905. The detection of several new Bvg-regulated genes of B. pertussis by scanning large parts of its genome sequence is described. A new integrational vector was used to construct transcriptional fusions with a reporter gene. This enabled the authors to investigate the regulation of the new genes in vitro. This work is possibly the beginning of a new era of studies that could eventually widen our horizon and increase our knowledge on the pathogenicity of bordetellae and other bacteria.
14. Pradel E, Guiso N, Menozzi FD, Locht C. Bordetella pertussis TonB, a Bvg-independent virulence determinant. Infect Immun 2000; 68:1919–1927.
15.• Lenz DH, Weingart CL, Weiss AA. Phagocytosed Bordetella pertussis fails to survive in human neutrophils. Infect Immun 2000; 68:956–959. This study is important because it puts earlier reports that suggested that B. pertussis can survive intracellularly back into perspective. Bacteria were visualized by their expression of green fluorescent protein, and their localization (intracellular versus extracellular) could also be determined. Only approximately 1% of phagocytosed bacteria were able to survive.
16. Weingart CL, Weiss AA. Bordetella pertussis virulence factors affect phagocytosis by human neutrophils. Infect Immun 2000; 68:1735–1739.
17.• Weingart CL, Mobberley-Schuman PS, Hewlett EL, et al. Neutralizing antibodies by adenylate cyclase toxin promote phagocytosis of Bordetella pertussis by human neutrophils. Infect Immun 2000; 68:7152–7155. It has long been known that ACT can inhibit phagocytosis of B. pertussis. This study sheds further light on the mechanism of this effect and its blocking by specific antibodies. When bacteria are opsonized by neutralizing antibodies to ACT, Fc receptors signal the neutrophils to internalize the bacteria, followed by phagocytosis.
18.• Schneider B, Gross R, Haas A. Phagosome acidificationhas opposite effects on intracellular survival of Bordetella pertussis and B. bronchiseptica. Infect Immun 2000; 68:7039–7048. Why does B. pertussis not survive in phagocytes, whereas the closely related B. bronchiseptica does? This comparative investigation shows that the milieu within the phagosomes (i.e. pH of 4.5–5.0) is deleterious to B. pertussis. In contrast, B. bronchiseptica is acid tolerant, and leads to chronic infections in many mammals other than humans. The mechanism of survival remains to be elucidated.
19. Bassinet L, Gueirard P, Maitre B, et al. Role of adhesins and toxins in invasion of human tracheal epithelial cells by Bordetella pertussis. Infect Immun 2000; 68:1934–1941.
20.• Harvill ET, Preston A, Cotter PA, et al. Multiple roles for Bordetella lipopolysaccharide molecules during respiratory tract infection. Infect Immun 2000; 68:6720–6728. So far, the role of lipopolysaccharide structures in the pathogenesis of Bordetella infection has received little attention. This interesting collaborative study demonstrates the importance of a complete lipopolysaccharide molecule for virulence in mice. Interestingly, B. pertussis required a complete lipopolysaccharide to effectively colonize not only immunocompetent, but also immunodeficient mice.
21. Mooi FR, He Q, van Oirschot H, Mertsola J. Variation in the Bordetella pertussis virulence factors pertussis toxin and pertactin in vaccine strains and clinical isolates in Finland. Infect Immun 1999; 67:3133–3134.
22. Mastrantonio P, Spigaglia P, van Oirschot H, et al. Antigenic variants in Bordetella pertussis strains isolated from vaccinated and unvaccinated children. Microbiology 1999; 45:2069–2075.
23.• Hausman SZ, Burns D. Use of pertussis toxin encoded by ptx genes from Bordetella bronchiseptica to model the effects of antigenic drift of pertussis toxin on antibody neutralization. Infect Immun 2000; 68:3763–3767. PT encoded by B. bronchiseptica, which is distinctively different from PT encoded by B. pertussis, was cloned into B. pertussis and found to be biologically as active as wild-type PT. Importantly, despite several amino-acid changes, antibodies directed against wild-type PT were equally active against variant PT. This suggests that vaccine-induced antibodies should be robust, and should not easily lose their activity in case of antigenic drift.
24. Boursaux-Eude C, Guiso N. Polymorphism of repeated regions of pertactin in Bordetella pertussis, Bordetella parapertussis, and Bordetella bronchiseptica. Infect Immun 2000; 68:4815–4817.
25.• Mahon BP, Brady MT, Mills KH. Protection against Bordetella pertussis in mice in the absence of detectable circulating antibody: implications for long-term immunity in children. J Infect Dis 2000; 181:2087–2091. This elegant study demonstrated that immune effector cells protect mice from bacterial challenge, even in the absence of circulating antibodies at the time of inoculation. After a delay, a pronounced antibody memory response follows.
26. Salmaso S, Mastrantonio P, Wassilak SGF, et al. Persistence of protection through 33 months of age provided by immunization in infancy with two three-component acellular pertussis vaccines. Vaccine 1998; 13:1270–1275.
27.• Ausiello CM, Lande R, Urbani F, et al. Cell-mediated immunity and antibody responses to Bordetella pertussis antigens in children with a history of pertussis infection and in recipients of an acellular pertussis vaccine. J Infect Dis 2000; 181:1989–1995. This is an interesting, yet confusing and provocative paper. Several years after primary immunization, children still demonstrated cellular immunity against pertussis antigens, but serum antibodies had decreased substantially. In comparison, the pattern was reversed in unvaccinated children with a history of wild-type infection. The reason for this disparity is unclear.
28. Heininger U, Stehr K, Schmitt-Grohé S, et al. Clinical characteristics of illness caused by Bordetella parapertussis compared with illness caused by Bordetella pertussis. Pediatr Infect Dis J 1994; 13:306–309.
29. Weyant RS, Hollis DG, Weaver RE, et al. Bordetella holmesii sp. nov., a new gram-negative species associated with septicemia. J Clin Microbiol 1995; 33:1–7.
30.• Mazengia E, Silva EA, Peppe JA, et al. Recovery of Bordetella holmesii from patients with pertussis-like symptoms: use of pulsed-field gel electrophoresis to characterize circulating strains. J Clin Microbiol 2000; 38:2330–2333. Most laboratories add cephalexin to media for culture of bordetellae in order to suppress growth of normal nasopharyngeal flora. Although this antibiotic obviously is not active against B. pertussis and B. parapertussis, it is inhibitory to B. holmesii. This may be a reason why B. holmesii has not yet been isolated more frequently from patients with symptoms of pertussis.
31.• Stojanov S, Liese J, Belohradsky BH. Hospitalization andcomplications in children under 2 years of age with Bordetella pertussis infection. Infection 2000; 28:106–110. This paper is a useful addition to an earlier report from Germany [4] on the spectrum of pertussis in a highly industrialized country with suboptimal vaccine coverage.
32.• Hoppe JE. Neonatal pertussis. Pediatr Infect Dis J 2000; 19:244–247. This is a comprehensive overview on epidemiology, symptoms, treatment and prevention of pertussis in neonates.
33.• Smith C, Vyas H. Early infantile pertussis; increasingly prevalent and potentially fatal. Eur J Pediatr 2000; 159:898–900. This series of nine cases of complicated pertussis (six fatal outcomes!) in infants aged under 7 weeks reminds us about the seriousness of the illness, especially in young infants.
34. Pierce C, Klein N, Peters M. Is leukocytosis a predictor of mortality in severe pertussis infection? Intensive Care Med 2000; 26:1512–1514.
35.• Vincent JM, Cherry JD, Nauschuetz WF, et al. Prolonged afebrile nonproductive cough illnesses in American soldiers in Korea: a serological search for causation. Clin Infect Dis 2000; 30:534–539. This interesting study demonstrates a close association of Mycoplasma pneumoniae, Chlamydia pneumoniae and B. pertussis infections by serological analyses in US soldiers with prolonged cough illnesses. The association is either sequential infections, mixed infections or cross-reacting antibodies. This has practical consequences for interpretation of antibody results.
36.•• Jackson LA, Cherry JD, Wang SP, Grayston JT. Frequency of serological evidence of Bordetella infections and mixed infections with other respiratory pathogens in university students with cough illnesses. Clin Infect Dis 2000; 31:3–6. Of university students with cough illnesses, 9% had evidence of B. pertussis infection. In one-third of them, coinfections with other respiratory pathogens were found. There were no major differences in clinical findings by aetiological agent. This study demonstrates the complexity of serological diagnosis of pertussis, and at the same time underlines the prominent role of B. pertussis in cough illnesses in adults.
37.• Heininger U, Schmidt-Schläpfer G, Cherry JD, Stehr K. Clinical validation of a polymerase chain reaction assay for the diagnosis of pertussis by comparison with serology, culture, and symptoms during a large pertussis vaccine efficacy trial. Pediatrics 2000; 105:e31. This is one of the few studies in which PCR, culture and serology were used in parallel to identify cases of B. pertussis infection. PCR is more sensitive than culture. However, most cases are proven by paired-serum specimens.
38. Nygren M, Reizenstein E, Ronaghi M, Lundeberg J. Polymorphism in the pertussis toxin promoter region affecting the DNA-based diagnosis of Bordetella infection. J Clin Microbiol 2000; 38:55–60.
39. Meade BD, Bollen A. Recommendations for use of the polymerase chain reaction in the diagnosis of Bordetella pertussis infections. J Med Microbiol 1994; 41:51–55.
40.• Farrell DJ, McKeon M, Daggard G, et al. Rapid-cycle PCR method to detect Bordetella pertussis that fulfills all consensus recommendations for use of PCR in diagnosis of pertussis. J Clin Microbiol 2000; 38:4499–4502. The authors describe a new PCR method that targets the outer membrane porin gene of Bordetella. Its sensitivity and specificity are evaluated by comparison with a nested-primer PCR.
41.• Melker HE, Versteegh FGA, Conyn-van Spaendonck MAE, et al. Specificity and sensitivity of high levels of immunoglobulin G antibodies against pertussis toxin in a single serum sample for diagnosis of infection with Bordetella pertussis. J Clin Microbiol 2000; 38:800–806. In this paper further evidence is given for the usefulness of a single serum to diagnose B. pertussis infection reliably in patients with prolonged cough illnesses.
42. Hoppe JE. State of art in antibacterial susceptibility of Bordetella pertussis and antibiotic treatment of pertussis. Infection 1998; 26:242–246.
43. Mortensen JE, Rodgers GL. In vitro activity of gemifloxacin and other antimicrobial agents against isolates of Bordetella pertussis and Bordetella parapertussis. J Antimicrob Chemother 2000; 45(suppl 1):S47–S49.
44.• Centers for Disease Control. Hypertrophic pyloric stenosis in infants following pertussis prophylaxis with erythromycin-Knoxville, Tennessee, 1999. MMWR Morb Morbid Wkly Rep 1999; 48:1117–1120. This is a technical report of an important clinical observation, supplemented by a thoughtful editorial note.
45.• Honein MA, Paulozzi LJ, Himelright IM, et al. Infantile hypertrophic pyloric stenosis after pertussis prophylaxis with erythromycin: a case review and cohort study. Lancet 1999; 354:2101–2105. This is basically the same report as [44•], converted into a scientific paper. A cluster of cases of hypertrophic pyloric stenosis was studied in neonates after use of erythromycin to control a pertussis outbreak in a hospital. The risk rates established are useful information for physicians who prescribe erythromycin to young infants.
46.• Güris D, Strebel PM, Bardenheier B, et al. Changing epidemiology of pertussis in the United States: Increasing reported incidence among adolescents and adults, 1990–1996. Clin Infect Dis 1999; 28:1230–1237. This is a nice summary of the current epidemiology of pertussis in the USA, based on reported cases.
47.•• Hodder SL, Cherry JD, Mortimer Jr EA, et al. Antibody responses to Bordetella pertussis antigens and clinical correlations in elderly community residents. Clin Infect Dis 2000; 31:7–14. This serological study in senior citizens demonstrates high rates of B. pertussis infections in this age group. Interestingly, 50% of infections occurred without compatible clinical symptoms. The paper contains an excellent discussion on potential problems with serological diagnosis of B. pertussis infections.
48.• Rohani P, Earn DJD, Grenfell BT. Impact of immunisation on pertussis transmission in England and Wales [letter]. Lancet 2000; 355:285–286. This research letter provides epidemiological data that indicate reduced transmission of B. pertussis after widespread use of childhood immunization; the interepidemic interval in large cities of England and Wales increased from approximately 2.5 to 4 years.
49. Gay NJ, Miller E. Pertussis transmission in England and Wales [letter]. Lancet 2000; 355:1553–1554.
50. Srugo I, Benilevi D, Madeb R, et al. Pertussis infection in fully vaccinated children in day-care centers, Israel. Emerg Infect Dis 2000; 6:526–529.
51.• Brennan M, Strebel P, George H, et al. Evidence for transmission of pertussis in schools, Massachusetts, 1996: Epidemiologic data supported by pulsed-field gel electrophoresis studies. J Infect Dis 2000; 181:210–215. This is an elegant work-up of pertussis outbreaks in schools in Massachusetts with at least 2 lessons: despite pertussis immunization in childhood, adolescents are susceptible to symptomatic B. pertussis infections; and different outbreaks of pertussis within a community are caused by different strains, again indicating waning immunity as the more likely cause than hypothetical ‘supervirulent’ strains.
52.• Mooi FR, Hallander H, Wirsing von König CH, et al. Epidemiological typing of Bordetella pertussis isolates: recommendations for a standard methodology. Eur J Clin Microbiol Infect Dis 2000; 19:174–181. The outcome of a consensus meeting is presented; it is a concise (but not complete) overview on current typing technologies for B. pertussis, with special emphasis on pulsed-field gel electrophoresis. The appendix contains standard protocols that are very helpful for those working with the organism.
53.• Ekwueme DU, Strebel PM, Hadler SC, et al. Economic evaluation of use of diphtheria, tetanus, and acellular pertussis vaccine or diphtheria, tetanus, and whole-cell pertussis vaccine in the United States, 1997. Arch Pediatr Adolesc Med 2000; 154:797–803. The authors performed a careful cost-benefit analysis based on the health care system of the USA. For each dollar spent for APVs, US$27 and US$9 are saved from the societal and health care system perspectives, respectively. Immunizing against pertussis pays!
54.•• Eskola J, Ward J, Dagan R, et al. Combined vaccination of Haemophilus influenzae type b conjugate and diphtheria-tetanus-pertussis containing acellular pertussis. Lancet 1999; 354:2063–2068. When Haemophilus influenzae type b vaccines are administered with acellular pertussis component vaccines in a single injection, a negative influence on the magnitude of anti-PRP (Haemophilus influenze type b) antibodies has been observed. This review summarizes the reassuring evidence that this observation is of no important clinical significance; function of antibodies and induction of immune memory are not impaired.
55.• Wirsing von König CH, Herden P, Palitzsch D, et al. Immunogenicity of acellular pertussis vaccines using two vaccines for primary immunization. Pediatr Infect Dis J 2000; 19:757–759. The most interesting finding of this study is the following; a vaccine, allegedly containing PT and FHA as the only pertussis components, did induce a significant antibody response to pertactin (an antigen not believed to be included in the vaccine) during the primary immunization series. If anything, this is advantageous for the vaccinee.
56.•• Beard SM, Finn A. Do we need to boost pertussis immunization within the existing UK vaccination schedule? J Public Health Med 2000; 22:349–356. A thoughtful review on the current evidence for and against the introduction of pertussis booster immunization in the UK is provided. The arguments are presented clearly and objectively, and have general implications beyond the situation in the UK.
57. Taranger J, Trollfors B, Knutsson N, et al. Vaccination of infants with a four-dose and a three-dose vaccination schedule. Vaccine 2000; 18:884–891.
58. Cherry JD, Gornbein J, Heininger U, Stehr K. A search for serologic correlates of immunity to Bordetella pertussis cough illnesses. Vaccine 1998; 16:1901–1906.
59. Storsaeter J, Hallander HO, Gustafsson L, Olin P. Levels of anti-pertussis antibodies related to protection after household exposure to Bordetella pertussis. Vaccine 1998; 16:1907–1916.
60. Taranger J, Trollfors B, Lagergard T, et al. Correlation between pertussis toxin IgG antibodies in postvaccination sera and subsequent protection against pertussis. J Infect Dis 2000; 181:1010–1013.
61. Centers for Disease Control and Prevention. Use of diphtheria toxoid-tetanus toxoid-acellular pertussis vaccine as a five-dose series. MMWR Morb Mortal Wkly Rep 2000; 49: RR13. pp. 1–8.
62.• Pichichero ME, Edwards KM, Anderson EL, et al. Safety and immunogenicity of six acellular pertussis vaccines and one whole-cell pertussis vaccine given as a fifth dose in four- to six-year-old children. Pediatrics 2000; 105:e11. This is a comprehensive follow-up report on a large pertussis vaccine trial, investigating different vaccines for side reactions and antibody responses. The overall safety profile of five doses of APV is very favourable and reassuring.
63. Rennels MB, Deloria MA, Pichichero ME, et al. Extensive swelling after booster doses of acellular pertussis-tetanus-diphtheria vaccines. Pediatrics 2000; 105:e12.
64. Braun MM, Mootrey GT, Salive ME, et al. Infant immunization with acellular pertussis vaccines in the United States: assessment of the first two years’ data from the Vaccine Adverse Event Reporting System (VAERS). Pediatrics 2000; 106:e51.
65. DuVernoy TS, Braun MM, VAERS Working Group. Hypotonic-hyporesponsive episodes reported to the Vaccine Adverse Event Reporting System (VAERS), 1996–1998. Pediatrics 2000; 106:e52.
66.•• De Serres G, Shadmani R, Duval B, et al. Morbidity of pertussis in adolescents and adults. J Infect Dis 2000; 182:174–179. In this report the clinical presentation of pertussis, including the spectrum of complications, in reported index cases and in actively identified secondary cases in persons aged 12 years or older is described. As expected, illness was less severe in actively identified secondary cases than in the primary cases (reporting bias). Teachers and health care workers were found to be at higher risk (twofold to fourfold) for pertussis than the general population, and could be the first target groups for an adult immunization programme.
67.• Halperin SA, Smith B, Russell M, et al. An adult formulation of a five-component acellular pertussis vaccine combined with diphtheria and tetanus toxoids is safe and immunogenic in adolescents and adults. Vaccine 2000; 18:1312–1319. A combined tetanus-diphtheria-acellular pertussis vaccine (TdaP) was studied in comparison to Td or aP alone, with favourable results. Adverse events were similar in all three vaccine groups, and slight differences in antibody responses to pertussis antigens are unlikely to be of clinical relevance.
68. Halperin SA, Smith B, Russell M, et al. Adult formulation of a five component acellular pertussis vaccine combined with diphtheria and tetanus toxoids and inactivated poliovirus vaccine is safe and immunogenic in adolescents and adults. Pediatr Infect Dis J 2000; 19:276–283.
69.• Schmitt HJ, Mohnike K, Kepp F, et al. Immunogenicity and reactigenicity of the Biken acellular pertussis vaccine in young adults. Vaccine 2001; 19:403–408. This study provides further confirmation of earlier reports that show that some childhood formulated APVs (i.e. full antigen amounts) can be given safely to adults in a single dose, irrespective of their previous pertussis immunization history.
70.• Tran Minh NN, He Q, Ramalho A, et al. Acellular vaccines containing reduced quantities of pertussis antigens as a booster in adolescents. Pediatrics 1999; 104:e70. Here the authors compared an APV with reduced antigen content with and without additional Td toxoids to Td only. Adding pertussis antigens did not increase side effects and provided marked humoral and cellular immuune responses to pertussis.
71. Van der Wielen M, Van Damme P, Joossens E, et al. A randomised controlled trial with a diphtheria-tetanus-acellular pertussis (dTpa) vaccine in adults. Vaccine 2000; 18:2075–2082.
72. Heininger U. Recent progress in clinical and basic pertussis research. Eur J Pediatr 2001; 160:203–213.
73. Ward J. Acellular pertussis vaccine efficacy and epidemiology of pertussis in adolescents and adults: NIH multicenter adult pertussis trial (Apert) [abstract]. Acellular Pertussis Vaccine Conference; November 12–14 2000; Bethesda, Maryland.
74.• Tran Minh NN, He Q, Edelman K, et al. Immune responses to pertussis antigens eight years after booster immunization with acellular vaccines in adults. Vaccine 2000; 18:1971–1974. This short report demonstrates the long-lasting effect of a single dose of APV given to adults, and has major implications for estimating the appropriate dosing intervals should adult pertussis immunization programmes become a reality.
75.• Nascimento IP, Dias WO, Mazzantini RP, et al. Recombinant Mycobacterium bovis BCG expressing pertussis toxin subunit S1 induces protection against an intracerebral challenge with a live Bordetella pertussis in mice. Infect Immun 2000; 68:4877–4883. This study is promising. A recombinant bacille Calmette-Guérin vaccine, expressing a PI subunit, protects mice form B. pertussis infection. Any other pertussis antigen could probably be introduced into this model. Unfortunately, bacille Calmette-Guérin may not be the ideal vector for such a vaccine.
76. Berstad AKH, Oftung F, Korsvold GE, et al. Induction of antigen-specific T cell responses in human volunteers after intranasal immunization with a whole-cell pertussis vaccine. Vaccine 2000; 18:2323–2330.
77.• Berstad AKH, Holst J, Frøholm LO, et al. A nasal wholecell pertussis vaccine induces specific sytemic and cross-reactive mucosal antibody responses in human volunteers. J Med Microbiol 2000; 49:157–163. Although very preliminary, this small study of intransally administered WCPV demonstrated induction of nasal fluid immunoglobulin A antibodies not only against pertussis antigens, but also against meningococcal outer membrane proteins in human volunteers. Sometimes, one gets more than expected.
© 2002 Lippincott Williams & Wilkins, Inc.