Pertussis

Pertussis

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Kevin Forsyth

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Pertussis (also called “whooping cough”) is a highly contagious respiratory infection caused by Bordetella pertussis or parapertussis These organisms produce a potent toxin that causes disease Classically, pertussis manifests as a respiratory infection with a chronic cough that comes in paroxsyms, followed by post-tussive vomiting or an inspiratory “whoop” Young children can develop pneumonia, apnea and encephalopathy Pertussis affects 30–50 million humans each year, killing at least 200,000—mostly young children Diagnosis is usually based on a combination of clinical recognition, serology, PCR and culture Treatment does not usually affect the clinical course of pertussis, but treatment can interrupt transmission. Treatment usually involves macrolide antimicrobial such as erythromycin or a derivative A highly effective vaccine exists for all age groups and immunization is the primary mechanism of controlling pertussis Unfortunately, the World Health Organization (WHO) estimates that only 80% of children receive three doses of anti-pertussis vaccines, and very few adults in resourcelimited settings receive anti-pertussis vaccines

INTRODUCTION Pertussis is a debilitating respiratory disease that can affect humans throughout life, but pertussis has a particularly high mortality in infants less than 6 months of age. The mainstay of public health management is for widespread immunization approaches. This not only reduces individual cases of disease, but avoids epidemic disease. Pertussis, commonly referred to as “whooping cough”, is a highly contagious respiratory infection. It is caused by Bordetella pertussis or Bordetella parapertussis and is transmitted by respiratory droplets. It most commonly presents as a respiratory illness with rhinorrhea and fever, and can lead to pneumonia. A paroxysmal cough is common, often associated with an inspiratory “whoop”. In young children, the clinical picture can be complicated by apnea, seizures and encephalopathy. The cough can become chronic, especially in older children and adults. Control of pertussis rests largely upon immunization programs. Whole cell (wP) and acellular (aP)-based anti-pertussis vaccines exist

in the form of combination anti-diphtheria and anti-tetanus vaccines (DTwP, DTaP). All infants should receive three doses of such vaccines in infancy, a booster at around 18 months and a further booster at pre-school age. Older children and adults should receive regular 10 year boosters with Tdap (the size of the letters corresponds with the amount of antigen contained in the vaccine). The WHO estimates that global vaccine coverage of young children with DTP-3 (completion of three doses) approximates 80%, and global coverage of older children and adults with Tdap is significantly lower [1] (Fig. 40.1).

EPIDEMIOLOGY Pertussis is an important cause of vaccine-preventable deaths with approximately 200,000 deaths in children worldwide in 2008 [1]. Despite the fact that fewer than 150,000 cases are officially reported to the WHO each year, it is thought that globally, 30–50 million cases occur annually, 90% of which are in developing countries; many of the deaths occur during infancy. The very young, particularly those less than 6 months of age, are at particular risk from pertussis. Global reported pertussis disease incident rates (some based on clinical confirmation only in those countries with limited access to laboratory services) are provided from WHO data in Table 40-1. These data will significantly under-represent actual cases. In the USA, approximately 30,000 cases of pertussis are reported each year. Over the last 30 years, there has been an increase in reported cases of pertussis in the USA, especially among older children, teenagers and young adults, and also among children younger than 6 months of age [2]. Within Australia, a developed country of 20 million people with high vaccination rates, there is a national notifiable disease surveillance system that provides active surveillance data. During the period 1991– 1996 there were 19,815 notifications of pertussis, which yielded a pertussis rate of 22–57.6 notifiable cases per 100,000 Australian populations [3]. Given that this estimate is for notifiable cases only, the real figure could be considerably higher (it is thought that true versus notified cases is in the order of up to 300-fold higher). At a global level, there are, for example, a considerable number of cases identified in Afghanistan [4]. Pertussis is endemic in school age children in the UK where, in a prospective analysis of 172 children aged 5–16 years who presented at a general practitioner with a cough lasting 14 days or more, 37% had serologic evidence of a recent pertussis infection; of these, 86% had been fully immunized [5]. There are only occasional confirmed cases from China, although the true burden is not known [6]. In an analysis of immunization rates in the African region of the Expanded Immunization programme, DPT-3 coverage increased by 15% from 54% in 2000 to 69% in 2004, resulting in a decline in non-immunized children from 1.4 million in 2002 to 900,000 in 2004 [7] (Fig. 40.2). There is increasing evidence that pertussis remains an active problem in communities whose young children are well immunized with DTP-3. In 2004, the Centers of Disease Control and Prevention

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HUNTER’S TROPICAL MEDICINE AND EMERGING INFECTIOUS DISEASE 2,500,000

100

2,000,000

80 70

1,500,000

60 50

1,000,000

40

Number of cases Official coverage WHO/UNICEF estimates

30

500,000

Immunization coverage (%)

90

Number of cases

20 10

0

0 1980 1981 1982 1983 1984 1985 1986 1987 1988 1989 1990 1991 1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009

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FIGURE 40.1 Pertussis global annual reported cases and DTP3 coverage (1980–2009).

TABLE 40-1  World Health Organization Regional and Global Summaries of Pertussis Incidence, 1980, 1990 and 1996–2005 Year Location

1980

1990

1996

1997

1998

1999

2000

2001

2002

2003

2004

2005

Africa

367,961

89,515

35,682

12,101

38,961

11,066

52,008

50,386

19,452

16,418

26,335

22,139

Americas

123,763

38,009

17,901

16,496

28,375

22,089

18,144

12,811

15,162

12,756

26,194

8747

Eastern Mediterranean

171,631

27,437

2823

3210

4367

2840

2112

4257

2650

1161

81,987

5164

90,546

129,735

54,745

67,307

56,317

48,897

53,675

31,084

25,176

25,530

42,220

26,425

Southeast Asia

399,310

156,028

22,479

41,940

46,666

127,76

34,930

37,813

43,250

39,371

39,002

37,764

Western Pacific

829,173

35,653

8009

25,953

15,875

17947

25,282

32,182

30,682

11,348

21,106

21,560

1,982,384

476,377

141,339

167,007

185,561

115,615

186,151

168,533

13,6372

106,584

236,844

121,799

151

164

155

163

151

156

159

162

162

150

165

156

Europe

Global Noumber of countries

(CDC) noted a 19-fold increase in the number of cases reported in individuals aged 10–19 years and a 16-fold increase in persons over 20 years of age. Data such as these are what has prompted the recommendation that anti-pertussis immunization not stop in young childhood (which was the previous recommendation).

is the pertussis toxin. It is possible that the pertussis toxin acts within the central nervous system to exacerbate coughing fits. Hence, there are both central and local factors inducing cough.

NATURAL HISTORY, PATHOGENESIS AND PATHOLOGY

Pertussis is essentially a disease of the respiratory system. Initial symptoms consist of a runny nose and perhaps mild fever, but are quite nonspecific. This is considered the early phase of the disease, generally up to one week, followed by persistent coughing, which is the key feature of pertussis. The cough has a characteristic repetitive nature to it, with bursts of coughing triggered by a number of external factors, including cold air, exercise and inhaled irritants, or it can just occur spontaneously. One of the traps for the unwary clinician is that a parent can give a history typical of pertussis, describing particularly in a young infant a terrible repetitive cough. When examined by the doctor the child may appear to have no respiratory signs whatsoever and can be dismissed from the doctor’s room only to have a spasm of coughing on going outside after receiving a blast of cold air as an irritant. Hence, history is critical in this condition—a history characterized by repetitive spasmodic coughing.

Following a usual incubation period of 5–10 days, individuals with clinical pertussis may manifest with a prodromal period lasting a few days to one week with upper respiratory symptoms (rhinorrhea, fever), followed by a hacking, paroxysmal cough. The second phase— the characteristic phase of pertussis with its coughing paroxysms— lasts 2–6 weeks, while the third phase—convalescence —may last up to 4 months: this phase is characterized by gradual reduction in coughing. The organisms of pertussis, B. pertussis and B. parapertussis (and, less commonly, Bordetella bronchiseptica) infect respiratory mucosa, leading to mucus hypersecretion and cilial paresis. The organisms release a number of toxins, the most important of which

CLINICAL MANIFESTATIONS

Per tussis

FIGURE 40.2 Immunization coverage with DTP3 vaccines in infants (2009).

<50% (6 countries or 3%) 50–79% (30 countries or 16%) 80–89% (35 countries or 18%) >=90% (122 countries or 63%)

The cough will, at times, lead to vomiting in a younger child, typically at the end of a period of coughing. At the end of a coughing bout there may be a sharp inspiration of air with the characteristic “whoop” sound. Any history of prolonged paroxysmal coughing followed by vomiting or whooping is highly characteristic of pertussis disease. The pertussis cough is sometimes colloquially termed “the 100 day cough”. Interestingly, this cough may appear to disappear and then reoccur within six months or so of the primary infection when the patient is exposed to certain irritants or another unrelated respiratory infection. It is important to emphasize that pertussis disease is particularly problematic in infants. Mortality rates for infants are high; they can present with atypical forms of the disease, such as apnea, encephalopathy or even multisystem organ failure unrelated to respiratory disease. Hence, early immunization of infants is critical. It is con­ sidered that three doses of vaccine are required to provide significant immunity to younger children. Three doses are not normally achieved until 5 or 6 months of age. Hence, infants in their first six months of life have little protection. In addition, they have small airways and appear highly vulnerable to the effects of pertussis toxin. In addition to the clear respiratory manifestations of pertussis disease, there are also multiple side effects from this disease, for example subconjunctival hemorrhages caused by the force of the coughing, is characteristic of pertussis. There can also be pneumonia, encephalopathy and seizures.

PATIENT EVALUATION CLINICAL DIAGNOSIS There have been a number of different criteria used for the clinical definition of pertussis. The WHO definition of pertussis illness requires a paroxysmal cough lasting for at least 21 days and laboratory confirmation or contact with a culture-positive case. Unfortunately, this rather strict definition requires a fairly severe form of illness given the 21-day cough requirement and availability of laboratory diagnostics. Another definition that is in common use is of 14 days of cough, which can have a sensitivity of 84–92% and a specificity of 63–90% [8].

There may need to be different clinical criteria used for episodic cases in contrast to epidemic cases. Given the elasticity in clinical case definition, where there are available laboratory diagnostics, a more substantive approach to diagnosis can be made through appropriate use of laboratory investigations.

LABORATORY DIAGNOSIS The classical way to provide laboratory confirmation of B. pertussis is through the collection of a nasopharyngeal swab plated onto appropriate media. Although this approach gives high specificity, it has low sensitivity and is not practical for rapid diagnoses.

SEROLOGY Serological diagnosis of pertussis by ELISA (using specific B. pertussis proteins as antigens) using paired sera with demonstration of a rise in antibodies of fourfold from the first sample to the second sample is the classical way to confirm infection by serology. However, this requires two blood tests and a delay in time which is not helpful for the acute diagnosis of pertussis. Hence, there have recently been moves to look at single serology estimates for the diagnosis of pertussis. Although different laboratories achieve different results, in general a single measurement of IgG ≥27 IU/ml can be considered appropriate for laboratory confirmation of clinical pertussis in adults in the first three weeks of an outbreak [9]. A more recent study [10] comparing high-sensitivity real time PCR assays and single serum pertussis serology showed that single serology was the most efficient diagnostic test with relatively high sensitivity (greater than 64%) and high specificity (greater than 90%). Using PCR, it was found that this was the second most efficient tool. An advantage of PCR is utilizing nasopharyngeal aspirates compared with blood. The precision (sensitivity and specificity) in the diagnosis of pertussis is, however, laboratory dependent. It is recommended that practitioners become familiar with the laboratory diagnostic test offered by their local laboratory service. All of these tests are ancillary and helpful in the diagnosis but need to be interpreted with some degree of caution. Clinicians need to be respectful of the overall clinical and laboratory

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setting in which the patient presents and the stability of the source material as it is transferred to the laboratory.

TREATMENT Bordetella pertussis and B. parapertussis are susceptible to a range of antibiotics in vitro. Antibiotics to which these organisms are sensitive include the penicillins, the macrolides, tetracyclines, chloramphenicol and trimethoprim-sulfamethoxazole. Unfortunately, the antibiotics make no difference to the course or outcomes of pertussis disease. What they are effective at is eliminating the organism from the nasopharynx. This is an important consideration. Efforts to reduce transmission to other people, particularly infants, require prioritization. Hence, if a case is confirmed, it is advised that elimination of the organism may reduce spread of this disease. The most commonly recommended antimicrobial to use is erythromycin estolate because of its higher levels of active antibiotic in the secretions of the respiratory tract. However, other forms of erythromycin are also considered to be acceptable. Short-term antibiotics (azithromycin for 3 to 5e days, or clarithromycin or erythromycin for 7 days) are as effective as long-term (erythromycin for 10 to 14 days) in eradicating B. pertussis from the nasopharynx but has fewer side effects. Trimethoprim/sulfamethoxazole for seven days is also effective. Contact prophylaxis of contacts older than 6 months of age with antibiotics does not significantly improve clinical symptoms or the number of cases developing culture-positive B. pertussis [11]. If there is an outbreak of pertussis, then immunization is the first step in management. Close contacts of an infected case can be treated with erythromycin or azithromycin, as recommended. However, most countries only recommend the use of antimicrobial prophylaxis for those at greatest risk from pertussis disease, i.e. young infants. Erythromycin treatment is not recommended for infants younger than 2 weeks of age.

IMMUNIZATION STRATEGIES Given that antimicrobial treatment can eliminate the organism and, hence, transmission to others, but has no impact on the course of disease in an individual patient, primary prevention through the use of immunization becomes paramount. The mainstay of immunization for pertussis over the years has been the whole cell pertussis vaccine. Three immunizations with the vaccine afford approximately 90% protective efficacy that lasts throughout infancy, but whole cell vaccines are associated with common moderate and severe local reactions and fever. “Acellular” vaccines contain subsets of immunogenic antigens from Bordetella and are much better tolerated, although they are more expensive. In resource-limited settings, childen often receive DTwP. In resource-rich settings, children usually receive DTaP. For children, as part of the Expanded Program in Immunization, most countries use a 2, 3, 4-, or 2, 4, 6-month immunization regimen of DTwP or DTaP. Historically, adults and older children did not receive booster immunizations. This was owing, in part, to the assumption that adults

were unlikely to get pertussis and the high adverse event profile of the whole-cell pertussis-based vaccines in older children and adults. As mentioned above, however, cases of pertussis among older children and adults has been increasing. This fact, and the development of safe, effective and well-tolerated acellular pertussis vaccine products has subsequently led to the endorsement of broader pertussis immunization programs for older children and adults with Tdap. Unfortunately, most older children and adults in resource-limited settings do not have access to, or the ability to receive, such vaccines. As a starting point, the Global Pertussis Initiative has recommended that a number of strategies that may be adopted at a country level in resource-limited settings to supplement the Expanded Program in Immunization program. In addition to adherence to standard immunization schedules, the Global Pertussis Initiative recommends that there be universal adolescent immunization of an anti-pertussis vaccine, that there be selective immunization of new mothers, family and close contacts of newborns (the cocoon strategy), that a preschool booster at 4 years of age be administered, that there be selective immunization of healthcare workers and childcare workers, and, possibly, a move towards a universal adult immunization strategy [12]. For public health benefits against pertussis to be realized, there needs to be a clear public health strategy at a country level. Such a public health strategy should include an effective vaccine delivery mechanism. This may be through regional child health clinics, family medicine clinics and local hospitals. Utility can only be measured through adequate surveillance processes.

REFERENCES 1. World Health Organisation. World Health Report 2011. Available at: http:// www.who.int/immunization_monitoring/diseases/pertussis/en/index.html (accessed March 3, 2012). 2. Centres for Disease Control and Prevention. Pertussis—United States. 2011. Available at: http://www.cdc.gov/pertussis/about/index.html (accessed March 3, 2012). 3. NNDSS Reports. Annual Reports. CDI 1999;23:11. 4. Kakar RM, Mojadidi MK, Mofleh J. Pertussis in Afghanistan 2007–2008. Emerg Infect Dis 2009;15:501. 5. Harnden A, Grant C, Harrison T, et al. Whooping cough in school age children with persistent cough: prospective cohort study in primary care. BMJ 2006; 333:174–7. 6. Wang J, Yang Y, Li J, et al. Infantile pertussis re-discovered in China. Emerg Infect Dis 2002;8:859–61. 7. Arevshatian L, Clements CJ, Lwanga SK, et al. An evaluation of infant immunization in Africa: is a transformation in progress? Bull WHO 2007;85: 449–57. 8. Patriarca P, Biellik R, Sanden G, et al. Sensitivity and specificity of clinical case definitions of pertussis. Am J Public Health 1998;78:833–6. 9. Mertens P, Stals F, Steyerbeg E, Richardus J. Sensitivity and specificity of single IGA and IGG antibody concentrations for early diagnosis of pertussis in adults: an evaluation for outbreak management in public health practice. DMC Infect Dis 2007;7:53. 10. Andre P, Caro V, Njamkepo E, et al. Comparison of serological and real-time PCR assays to diagnose Bordetella pertussis infection in 2007. J Clin Micro 2008;45:1672–7. 11. Altunaiji S, Kukuruzovic R, Curtis N, Massie J. Antibiotics for whooping cough (pertussis). Cochrane Database Syst Rev. 2007 Jul 18;(3):CD004404. 12. Forsyth K, Tan T, Wirsing Von Konig C-H, et al. Potential strategies to reduce the burden of pertussis paediatric. Infect Dis J 2005;24:S69–S74.