Pertussis is an acute disease of the respiratory tract

Clinical Manifestations of Bordetella pertussis Infection in Immunized Children and Young Adults* Einat Yaari, MD; Yael Yafe-Zimerman, MD; Shepard B. Schwartz, MD; Paul E. Slater, MD, MPH; Pesach Shvartzman, MD; Nachum Andoren, PhD; David Branski, MD; and Eitan Kerem, MD Study objectives: The incidence and prevalence of pertussis in adults have increased in recent years. It has been shown that previously immunized adults and adolescents are the main sources of transmission of Bordetella pertussis. The aim of this study was to describe the clinical presentation and the clinical course of pertussis in children and young adults who were immunized previously against B pertussis. Design: Retrospective study. Subjects: Children and young adults who were reported by local physicians to the Department of Epidemiology in the Israeli Ministry of Health with serologically confirmed pertussis and who were immunized previously were included. Information sought included personal data, epidemiologic data, signs and symptoms, laboratory results, initial diagnosis, and treatment. Results: In the 95 previously immunized patients with serologically confirmed pertussis (mean age [ SD], 8.9 4.4 years old; range, 5 to 30 years old), the mean duration from onset of symptoms until the final diagnosis of pertussis was 23 15 days. The disease was usually atypical and generally mild. All the described patients had cough, usually prolonged, lasting 4 3.6 weeks. Only 6% had the classic whoop. The mean WBC count was 8.7 2.6 cells/mm 6, and the lymphocyte count was 40 12%. Two patients were admitted to the hospital for severe pneumonia. Among the reported cases, the proportion of patients between the ages of 10 and 45 years increased from 6.5% during the period from 1971 to 1980, to 26% during the period from 1980 to 1990, and to 38% during a 1989 outbreak. Conclusions: Pertussis in previously immunized individuals is usually characterized by an atypical and relatively mild clinical course. Patients suffer mainly from a prolonged and persistent cough. Early diagnosis may lead to prompt administration of therapy. Prophylaxis of exposed persons might be effective in decreasing both severity and transmission of the disease. (CHEST 1999; 115:1254 1258) Key words: pertussis, clinical course; pertussis, epidemiology; pertussis, immunization Pertussis is an acute disease of the respiratory tract caused by Bordetella pertussis and characterized by progressive, repetitive, and paroxysmal coughing. It is regarded as a vaccine-preventable childhood illness. Classic pertussis lasts for 6 to 8 weeks, and it *From the Department of Pediatrics (Drs. Yaari, Yafe-Zimerman, Schwartz, Branski, and Kerem) and Unit of Pediatric Respiratory Medicine (Dr. Kerem), Shaare Zedek Medical Center, Jerusalem, Israel; Department of Epidemiology (Dr. Slater), Israel Ministry of Health, Jerusalem, Israel; Department of Family Medicine (Dr. Shvartzman), Faculty of Health Sciences, Ben Gurion University of the Negev, Beer Sheva, Israel; and Government Central Laboratories (Dr. Andoren), Israel Ministry of Health, Jerusalem, Israel. Manuscript received May 12, 1998; revision accepted December 3, 1998. Correspondence to: Eitan Kerem, MD, Pediatric Respiratory Medicine, Shaare Zedek Medical Center, PO Box 3235, Jerusalem 91031, Israel; e-mail: ek@cc.huji.ac.il may be divided into three stages of clinical illness: catarrhal, paroxysmal, and convalescent. Whooping cough, cyanotic spells, and brief apnea episodes may also occur. Leukocytosis (20,000 to 100,000 cells/ L) with absolute lymphocytosis is characteristic. A chronic cough may persist for several months. 1 Since the introduction of routine childhood immunization, pertussis morbidity and mortality have declined markedly. 2 However, despite widespread vaccination, the disease was not eradicated, and an increased incidence rate has been reported in the last 2 decades. 3 Cases have been reported primarily in nonimmunized or underimmunized populations, 3,4 although outbreaks in well-immunized populations have also occurred. Several reports of pertussis outbreaks have been documented recently among older children and young adults who were previously 1254 Clinical Investigations

immunized by vaccination. 5 10 Furthermore, the incidence and prevalence of pertussis in adults are far higher than previously reported. 11 15 Investigations of outbreaks have documented that adults develop infection with B pertussis and transmit the organism to susceptible children or other adults. Thus, previously immunized adults and adolescents are the main sources of transmission of B pertussis. 15,16 The period of immunity induced by the pertussis vaccine tends to wane within 5 to 10 years and is shorter than that induced by the disease itself. 17 Although the number of susceptible adults is increasing, it is difficult to determine the true incidence of pertussis in adults. Studies of adults with prolonged cough have found that 20 to 25% have serologic evidence of recent pertussis infection. 11 14,18 20 However, adults may have an atypical presentation of pertussis with a modified clinical course. 18 20 Because the signs and symptoms are usually nonspecific, pertussis is rarely considered in adults. This may lead to underdiagnosis and lack of, or a delay in, treatment. Furthermore, in vaccinated populations, adults maintain the ability to transmit B pertussis and are now the primary source of infection to susceptible children who may develop severe disease. Several studies on a small number of adult patients with pertussis reported the association between pertussis and chronic cough. However, to the best of our knowledge, the disease in previously immunized children and adults was documented in a limited number of patients. Therefore, the aim of this study was to investigate the clinical presentation and the course of the disease in previously immunized patients suffering from B pertussis infection. Materials and Methods Data regarding pertussis cases were obtained from the reports of local physicians of the Israel Ministry of Health. In Israel, physicians are required to report all cases of pertussis. Retrospectively, we analyzed all serologically confirmed cases between the years of 1986 and 1991 among individuals between the ages of 5 and 30 years old whose medical records were accessible. In all cases, the Pertussis Laboratory of the Ministry of Health Central Laboratories confirmed the diagnosis of pertussis. For the purpose of this study, serologic confirmation of pertussis required an agglutination titer 1:640, or a fourfold rise in agglutination titers obtained 2 to 3 weeks apart, or positive pertussis IgM levels determined by enzyme-linked immunosorbent assay method. 21 As cutoff, negative, and positive control, we used in-house standards calibrated by using a pertussis kit (Virotech GmbH; Russelsheim, Germany). Cultures were not taken. The reporting physicians were contacted and asked to complete a questionnaire based on the patient s medical records. Information sought included personal data, epidemiologic data, signs and symptoms, laboratory results, initial diagnosis, treatment, and complications. Results Since 1956, when pertussis immunization was first introduced in Israel, the number of yearly cases has declined from 10,000 in 1955 to 100 in 1996 (data reported by Israel Ministry of Health). Nonetheless, outbreaks of pertussis were reported between 1980 and 1990. 9 Of the 1,091 cases reported between the years 1971 and 1980, the percentage of cases in the group aged 10 to 45 years was 6.5%. This figure increased during the next decade to 26% of the 754 reported cases. In 1989, 38% of the 219 reported cases occurred among individuals between the ages of 10 and 45 years. Of the 552 cases of pertussis reported to the Ministry of Health from January 1986 to December 1991, 283 were children and young adults between the ages of 5 and 30 years (mean age, 10.4 4.3 years old; median, 10 years old). Only 180 patients completed pertussis vaccination during childhood (63%). Clinical information was available for 95 individuals (39% were male) aged 5 to 30 years (mean age, 8.9 4.4 years old; median, 9 years old). Seventy patients were 5 to 10 years old, 16 were 11 to 14 years old, and 9 were 15 to 30 years old. In 66% of these 95 patients, a history of contact with other individuals with pertussis was documented. The mean duration from onset of symptoms until the final diagnosis of pertussis was 23 15 days (range, 7 to 90 days; median, 14 days). In 46% of the cases, pertussis was the initial diagnosis; most of the patients who developed the disease were diagnosed in a small kibbutz community during a pertussis outbreak after the diagnosis of a first case. Various incorrect diagnoses were ascribed until the diagnosis of pertussis was established. Mycoplasma pneumoniae infection was the most common initial diagnosis (17%). Other initial diagnoses included sinusitis (7%), upper respiratory tract infection (4%), asthma (4%), laryngitis (3%), and suspected cystic fibrosis (1%). Table 1 shows the frequency of symptoms in the 95 vaccinated patients with serologically confirmed pertussis. The disease in these patients was atypical, because the clinical course was generally mild. All the described patients had cough, usually prolonged, lasting 4 3.6 weeks (range, 1 to 24 weeks; median 3 weeks). The cough was productive in 7% of the patients, whereas the rest had a dry cough; only 6% had the classic whoop. Of the patients, 13% had temperature 37.5 C. Five of the patients visited an emergency department due to severe cough and dyspnea. Two required hospitalization: a 5-year-old girl with hypoxemia and a 10-year-old boy who CHEST / 115 / 5/ MAY, 1999 1255

Table 1 Rate of Symptoms of Pertussis Among Previously Immunized Patients (n 95) Symptoms developed secondary pneumonia with a small pleural effusion (pleurocentesis was not performed). CBC count was taken in 63 patients (66%). The mean WBC count was 8,700 2,600/mm 3 (range, 3,950 to 24,500/mm 3 ; median, 8,600/mm 3 ), and the lymphocyte count was 40 12% (range, 10 to 68%; median, 38%). A chest radiograph was performed on 41 patients (42%) and disclosed abnormalities in 8 (20%). Four radiographs showed enhanced interstitial markings, two revealed bilateral perihilar shadows, one showed a right lower lobe infiltrate with a small amount of pleural effusion that could not be tapped, and one showed a right middle lobe infiltrate. Sixty-eight patients (71%) received antibiotic therapy before the diagnosis of pertussis was made. The majority (78% of treated patients) received erythromycin, while others were treated with penicillin, amoxicillin, or doxycycline. In most patients there was no apparent clinical improvement with antibiotic therapy. Discussion % of Patients Cough 100 Dry cough 93 Paroxysmal nocturnal cough 21 Posttussive vomiting 13 Fever 13 Productive cough 7 Wheezing 7 Apnea 7 Whoop 6 Cyanosis 3 Hoarseness 2 In this study, the clinical presentation of pertussis in previously immunized children and young adults was found to be relatively mild yet protracted. The three typical stages of pertussis were absent. All patients had a prolonged cough that lasted for several weeks. The classic whooping cough was found in only a few patients, and lymphocytosis was generally absent. Thus, besides the long duration of cough, there may be no typical symptoms and signs that would alert the physician to consider the diagnosis of pertussis. Therefore, a heightened index of suspicion needs to be maintained. Considering the highly contagious potential of B pertussis, the history should be evaluated carefully to search for the presence of contacts suffering from similar symptoms. Many patients in our study were diagnosed in a small community during a pertussis outbreak after the diagnosis of the first case in an infant. Pertussis is rarely considered in adults until a child contact develops classic symptoms of the disease. 22 Long et al 23 underscored this fact in their study of the silent transmission of pertussis in families. Fifty percent of the contacts of pertussis had serologic evidence of a recent infection. Many had onset of illness before that of the index case. Most of the actual primary cases were 14 years old. Thus, adults are the most important source of pertussis infection in the community. Pertussis is much more common in adults than previously believed. In Israel, the proportion of adolescents and young adults among the reported pertussis cases increased dramatically from 6.5% from 1971 to 1980 to 26% from 1980 to 1990 and 38% during the 1989 outbreak. This trend is similar to that reported by the Centers for Disease Control and Prevention in the United States, 24 which found that the proportion of pertussis cases occurring in patients 10 years old increased from 15% from 1977 to 1978 to 28% during the time from 1992 to 1994. Before the vaccination era, the majority of pertussis cases occurred among infants. At that time, most of the population was exposed to pertussis and acquired natural immunity during the first years of life. Subsequent exposure to other infants and young children with pertussis served to boost immunity. However, the immunity induced by the whole-cell vaccination is shorter than the immunity induced by the disease itself, and tends to wane within 5 to 10 years. 17 Thus, several decades after the introduction of the pertussis vaccine, many adults became susceptible to pertussis. Although the vaccine has been very effective in controlling the disease, the transmission of B pertussis has not been eliminated by vaccination and still causes morbidity, even in the vaccinated population. 25 The 1993 pertussis outbreak in Cincinnati 6 occurred primarily among immunized children, demonstrating that the vaccine did not give full protection against the disease. It is now appreciated that adults are a major reservoir for the spread of the infection to infants. 15,16,20 Pertussis was also isolated from adults infected with HIV who complained of persistent cough. 26 Yet, many physicians are unaware that adults may themselves develop pertussis. 27 This, in addition to the nonspecific or relative lack of symptoms among adults with pertussis, has led to under-recognition of the disease in this age category. 18 The only typical finding of pertussis in our study was a prolonged and disturbing cough that lasted from several weeks to several months. Only 5% had whoop. Similarly, Wright et al 12 reported that cough 1256 Clinical Investigations

was found in 85% of the immunized adults with pertussis. Whoop and lymphocytosis were not observed. Prospective studies suggested that 20 to 25% of adults with persistent cough might have pertussis. 3,19 Therefore, epidemiologic studies are needed to determine the incidence of pertussis in adults with respiratory illness. In our study, the duration of time until the final diagnosis was 23 15 days. This delay in diagnosis may be critical, because initiation of therapy after 3 weeks will not shorten the course of the disease or prevent its spread. 28 Early diagnosis of pertussis relies on clinical suspicion, and the definitive diagnosis of pertussis relies on laboratory tests. Cultures are difficult to obtain and need to be taken early in the course of the disease. 29 The percentage of positive cultures changes precipitously from 67 to 81% shortly after exposure to 25%, 14%, and 0% during the 3rd, 4th, and 5th weeks, respectively. Compared with cultures, direct fluorescent antigen detection is not more sensitive, and it is much less specific. Determination of antibody titer IgA and IgG to lymphocytosis promoting factor, filamentous hemagglutinin, and agglutinogens (antibodies against various virulent factors of B pertussis) is currently the most sensitive diagnostic test. 29,30 Polymerase chain reaction, using a specific probe for B pertussis, may offer an early diagnosis of pertussis with high specificity and sensitivity. 31 33 Pertussis in immunized children and young adults may be associated with morbidity. Five percent of the patients in our study visited an emergency department, and 2% were hospitalized. In addition, many patients had unnecessary and costly diagnostic evaluations and may have suffered from anxiety because of the undiagnosed chronic and protracted cough. Patients may experience loss of time from work or school due to the persistent cough of pertussis. Although the clinical presentation in immunized children and young adults is atypical and the course is usually benign, as shown in our study, pertussis may still cause morbidity. In conclusion, pertussis should be considered in the differential diagnosis of persistent cough in previously immunized children and adults. Given the relative unavailability of accurate diagnostic tests and the usual absence of whoop or lymphocytosis, a recommendation for prompt administration of erythromycin in patients presenting with persistent cough and the prophylaxis of exposed persons before culture or serologic results are available should be considered. This would be effective in decreasing both disease severity and transmission of B pertussis. 34 Because pertussis is not a life-threatening illness in adults, pertussis vaccination is not currently recommended in persons 6 years of age. However, the availability of the less reactogenic acellular vaccine may allow booster immunization and should be thoughtfully considered. References 1 Beherman RE, Kliegman R, eds. Nelson s textbook of pediatrics. 15th ed. Philadelphia, PA: WB Saunders, 1996; 779 784 2 Cherry JD. The epidemiology of pertussis and pertussis immunization in the United Kingdom and the United States: a comparative study. Curr Probl Pediatr 1984; 14:1 78 3 Black S. Epidemiology of pertussis. Pediatr Infect Dis J 1997; 16(4 suppl):s85 S89 4 Isaacson J, Trollfors B, Taranger J, et al. How common is whooping cough in a nonvaccinating country? Pediatr Infect Dis J 1993; 12:284 288 5 Halperin SA, Bortolussi R, MacLean D, et al. Persistence of pertussis in an immunized population: results of the Nova Scotia Enhanced Surveillance Program. J Pediatr 1989; 115: 686 693 6 Christie CD, Marx ML, Marchant CD, et al. 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