Context: Pertussis is a highly communicable acute respiratory tract infection caused mainly by Bordetella pertussis. Since pertussis is life-threatening to young infants, it remains a growing public health concern in many countries in spite of vaccination coverage. Evidence Acquisition: We performed a selective literature search about the pertussis epidemiology in Asia over the past 15 years to provide a picture of the B. pertussis incidence rate in the area and help design an effective strategy for adolescent and adult vaccination. Results: The overall prevalence of B. pertussis seropositivity among the evaluated people (16,785) in Asia from 2000 to 2015 was 36%. The calculated prevalence rates were 38.4% for Iran, 29% for Japan, 29% for Turkey, 40% for Korea, 8% for China, 59% for Pakistan, 52.4% for Israel, 34% for Taiwan, and 97% for Singapore. The mean age of the total individuals was 27 ± 3 years. A high percentage of seropositivity was found in the warm months (between the early summer and early autumn). Conclusions: Results show that pertussis is endemic in Asia, particularly in adolescents and adults and in warm seasons. This study also shows the importance of laboratory diagnosis for pertussis, booster vaccinations for adolescents, development of a highly efficacious pertussis vaccine, and improving surveillance system. Keywords: Asia, Bordetella pertussis, ELISA, pertussis, seroepidemiology
Pertussis is a highly contagious and vaccine-preventable acute respiratory infection caused mainly by Bordetella pertussis. This organism is a Gram-negative, fastidious, pleomorphic bacillus, and the cause of a whooping cough which is one of the main ten causes of infant death in the world.[1],[2] Pertussis can occur at all ages, but the severity is higher among young infants who have not completed their immunization schedule.[3],[4] Although the disease has been decreased following the introduction of whole-cell pertussis vaccines in the 1950s, many studies have described the reemergence of pertussis during the past decade.[5],[6] Therefore, pertussis has not yet been eradicated. The causes of this problem are: (1) the difficulties related to case identification, (2) poor quality of vaccine, (3) the antigenic divergence in B. pertussis strains than one used in the vaccine, (4) waning of vaccine-acquired immunity, and (5) absence of a reliable diagnostic method and transmission from asymptomatic and undiagnosed cases.[7],[8],[9],[10] Pertussis is primarily a childhood infection, but in recent years high rates of pertussis have been observed among adolescents and adults in the frame of community outbreaks of pertussis, even in countries with high vaccination coverage.[11],[12],[13] Since pertussis often presents atypical manifestations in adolescents and adults such as asymptomatic infections and a chronic cough, rather than typical pertussis symptoms, it may be overlooked. Therefore, this population can be the potential source of infection, particularly to younger infants.[14],[15] Studies have shown that there are approximately 48.5 million annual cases of pertussis and 295,000 deaths worldwide.[16] This fact proves the necessity of national epidemiological searches.[17] Seroepidemiological surveys are widely used to study the incidence of bacterial infections. The determination of the seroepidemiology of pertussis helps the evaluation of pertussis infection and immunity patterns in a population, and the definition of the target population for pertussis booster vaccinations can help in the way of disease control.[18],[19] This review was performed to determine the epidemiology of pertussis in Asia. The results of this study can be helpful in getting a picture of the B. pertussis incidence rate in this area and also designing a strategy for vaccination in adolescents and adults.
In this study, data on notified pertussis cases were found using PubMed, MEDLINE, and Google Scholar. Searches were accomplished on articles published in Asia through 2000–2015 using the combination of these keywords: B. pertussis, seroepidemiology, epidemiology, pertussis, ELISA, seroprevalence, and Asia. All English language articles were read separately by two individuals. Nineteen papers on the vaccination serological surveys were excluded [Figure 1]. The collected information among individuals between the ages of 0–95 years old in the past 15 years was summarized in a table. We calculated the seropositivity rate in the countries separately and eventually obtained the overall seropositive rate in Asia. We also investigated laboratory diagnosis, seasonality, age distribution, and vaccination of pertussis in Asia in these years. Finally, the Excel 2007 software was used to compute the obtained data.
Twenty-seven studies from 2000 to 2015 on seroprevalence of B. pertussis in different Asian countries were collected including 6 Iranian, 5 Japanese, 7 Turkish, 2 Korean, 2 Chinese, 2 Pakistani, 1 Israeli, 1 Taiwanese, and 1 Singaporean study [Table 1]. A total of 16,785 people with a mean age of 27 ± 3 years were evaluated during 15 years. The incidence rate of pertussis was high in the age group of 13–19 years. In general, the seropositivity rate of B. pertussis were 1261 (38.4%) for Iran, 831 (29%) for Japan, 1039 (29%) for Turkey, 546 (40%) for Korea, 190 (8%) for China, 258 (59%) for Pakistan, 1039 (52.4%) for Israel, 318 (34%) for Taiwan, and 261 (97%) for Singapore. In this way, the overall anti-pertussis seropositivity rate was 36% in Asia. The frequency of anti-pertussis seropositivity in various countries is demonstrated in [Figure 2]. Based on the results obtained in this study, culture and polymerase chain reaction (PCR) are suitable for identifying B. pertussis in children younger than 3 months, and serological methods such as ELISA to an assigned IgG anti-pertussis toxin (PT) are appropriate for participants older than 10 years old. The age distribution of the disease has been shown in specific ages including under the age of vaccination, school entry age, teens, and in old age. The highest prevalence of a whooping cough was found in the warm seasons (April–September). The study also showed a relative reduction in the incidence of the disease from 2000 to 2015 in Asia [Figure 3].
Seroepidemiology Pertussis is considered a vaccine-preventable childhood disease. After the beginning of general vaccinations, the disease prevalence declined significantly, but a shift in the age distribution of this infection has been reported in many countries even with high vaccination coverage.[6] Although infection is commonly milder in adolescents and adults than in children, high prevalence of the disease among people in this age group is alarming. This is due to the fact that infected adolescents and adults serve as a reservoir for disease transmission to young children and infants who are susceptible to severe pertussis and its life-threatening complications.[3],[12],[23] Therefore, it will be necessary to design a strategy that decreases natural pertussis infection in adolescents and adults and subsequently its transmission to children.[9],[18] For this purpose, the epidemiological and clinical features of pertussis should be monitored in the community. This article systematically studied the latest data on the epidemiology of pertussis in Asia. Nowadays, pertussis is endemic in Asia. As shown in [Table 1], the overall rate of seroepidemiology was 36%, with the explanation that it ranges from 8% to 97%. The lowest rate of seroepidemiology was reported from China (7.83%),[16] while the highest in Singapore (97%).[13] High seroprevalence rates can be due to the vaccination program during childhood without any booster dose in adulthood, given that acquired immunity from vaccination wanes over time. Certainly, the obtained high pertussis seroprevalence in this study is due to natural exposure. On the other hand, similarly to several studies, the prevalence rate has been shown to be higher in some age groups.[24],[25] Low seroprevalence rate may be because that only 40%–50% of pertussis cases had a classical clinical appearance of a paroxysmal cough. Hence, heterogeneity in disease expression with shorter duration and absence of spasmodic cough results in misdiagnosis as a general respiratory infection and a failure to investigate for pertussis. On the other hand, laboratory diagnosis of B. pertussis was not routinely performed in China, many of the asymptomatic pertussis cases among vaccinated children, adolescents, and adults were not recognized and were possibly considered as common respiratory infections. The studies performed over the past 15 years in Asian countries showed that the seropositivity rate decreased from 60.63% in 2002 to 19.1% in 2015 [Figure 3]. The reduction in the seropositivity rate may be contributed by multiple factors. First, in recent years, a booster dose of pertussis vaccine was introduced and used in some countries. Second, by knowing more about adult pertussis, many people may have modified their habits leading to decrease in the transmission rate. Third, case discovery rate increased and with timely treatment dropped the spread of disease. However, the number of studies was low during the 2000–2005 periods; therefore, no suggestion can be made concerning these results during this period. On the other hand, according to [Figure 2], from the observed peaks during certain years it can be concluded that pertussis is still present in the region with peaks that happen every few years. Laboratory detection of pertussis disease The laboratory diagnosis methods of pertussis are challenging. The sensitivity of culture and PCR has been described to be low in the identification of pertussis in some studies, particularly when the specimens were not obtained in optimal timing and with a correct sampling method. On the other hand, the culture results require a long incubation period of up to 10–14 days which caused a delay in critical treatment and subsequently expansion of infection to the other persons with contact.[9],[24] Other diagnosis methods were employed in the detection of pertussis such as bacterial agglutination tests but seem to lack specificity for an accurate diagnosis. This test can be impressed by various factors such as the condition of culture, bacteria obtained, the cross-reaction of serum antibodies. and nonspecific reactions.[10],[21] In a study from Japan, the measurement of fractional exhaled nitric oxide (FeNO) was suggested for identification of patients with a chronic cough. This trial was performed routinely since 2007. The sensitivity and specificity of this test were 72% and 70%, respectively. The measurement of FeNO concentrations can be helpful for diagnosis of pertussis from asthma patients, with the explanation that the mean FeNO value for the pertussis patients was meaningfully lower than that in asthma patients while not significantly different from that in a healthy population. However, they recommended improving the diagnostic accuracy, the combination of symptoms (chronic cough, postcough vomiting and/or gagging), and laboratory findings may be more helpful.[14] In pertussis, severe hyperleukocytosis with a predominance lymphocytes can also be seen, but since this mode is nonspecific and may be caused by other infections such as viral infections, it cannot be used for the confirmation of the disease alone. Nowadays, serological tests are commonly used in both investigational and clinical settings. This testing helps the diagnosis of pertussis in asymptomatic patients, especially if the clinical samples are collected at a later time than onset of the disease.[9] The measurement of pertussis-specific antibodies by ELISA depends on the PT, filamentous hemagglutinin (FHA), and other antigens. PT is the most specific antigen for B. pertussis so anti-PT antibody is the primary serodiagnostic of choice for pertussis cases and the false negative rate has been shown to be lower than 10%.[21] Based on the results shown in Asia [Table 1], studies also focus on the PT for ELISA. Unlike PT antibodies, FHA antibodies are not only produce after exposure to B. pertussis but could be induced after contact with other bacteria such as Bordetella species, Haemophilus influenza, Mycoplasma pneumonia and Chlamydia pneumonia.[18],[22] Since the clinical symptoms of pertussis can be almost identical to the manifestations of respiratory tract infection by mentioned bacteria, respiratory viruses and sometimes asthma, using the ELISA method by FHA antibodies because of cross-reaction can be misleading in the diagnosis. On the other hand, previous studies have focused, especially on anti-B. Pertussis IgG antibodies, because the role of IgA antibodies was uncertain in the vaccinated population.[6],[28] In recent years, to determine anti-PT IgG depending on the vaccination design and epidemiology of pertussis, various cutoff values have been proposed by various countries.[1],[5],[6],[10],[16],[19],[22] However, to achieve comparable results, a universal cutoff point should be assigned for the identification of the seropositivity rate in the world.[1] Eventually, studies showed that culture and PCR are profitable for young infants aged 0–3 months old and a serological method such as ELISA for the determination of IgG anti-PT is suggested for more than 10 years. The evaluation of antibodies by ELISA in the patients younger than 1 year, because of the presence of vaccine-acquired immunity is meaningless. Another flaw is that the ELISA test cannot discriminate the concentrations of anti-PT antibodies induced by vaccination and infection.[16],[29] With this description, we think that there is still a pressing need for more rapid, sensitive and specific tests that are not affected by the time of sample collection and other factors in the diagnosis of pertussis. Age distribution In general, pertussis occurred in young infants under 6 months of age who did not complete the primary program of diphtheria, tetanus and the whole-cell pertussis (DTwP) vaccination. Infants acquire protecting antibodies from mothers through a transplacental passage which decreases after some time. Therefore, infants under 2 months of age are highly prone to whooping cough and its complications.[9],[15] In many countries, the vaccination program starts 2 months after birth and continues up to 4, 6 and 18 months with a booster at 4–6 years old. Thus, detected antibodies in children over 2 months old could be due to previous vaccinations.[2],[17] On the other hand, this increase reflects the accession of natural immunity following the beginning of elementary school. However, more crowding students in this new community with a high probability of communicable disease and high rate of person to person transmission could be the other reason for enhancement in incidence rate in this age group. In recent years, a resurgence of pertussis has been reported in developed and developing countries even with high vaccination coverage. There has been a shift in the incidence rate toward adolescents and adults with an obvious peak in adolescents.[7],[16],[18],[27] According to two studies from Turkey, the incidence rate of pertussis was high in the age group of 13–19 years.[17],[19] This result is consistent with other studies from Israel and Japan.[6],[22] Therefore, adolescents and young adults with the lower protective antibody level against PT may be re-infected with B. pertussis. Several reasons can be considered for the resurgence of pertussis in the vaccinated population such as inadequate vaccination schedules, changes in vaccine quality, type of vaccine, waning immunity after primary vaccination, demographic changes, adaptation of the bacteria to vaccine-induced immunity, misdiagnosis and underreporting due to the absence of specific symptoms of pertussis, and subsequently transmission to vulnerable people. In spite of milder disease in older children and adults than in children, some researchers believe that pertussis can be complicated for adolescents and adults.[4],[7],[17],[18],[29] Some studies showed other peaks of incidence in the age category older than 60 years.[18],[26] This might indicate that infection rate increases if one is repeatedly exposed to the infection and Tdap booster vaccine (tetanus, diphtheria, a cellular pertussis vaccine) given at age 11–12 is not effective or not effective enough. Hence, the age-specific incidence patterns of pertussis certainly return to the dynamics of immunity and transmission in the society. Seasonality The increased prevalence in some seasons is a common phenomenon in infectious diseases, but its creator mechanisms are not fully understood. For respiratory pathogens, the survival of the pathogen outside the host is impacted by seasonal changes. In some seasons, due to favorable weather conditions, personal habits, social behaviors, crowding, host immunity, and other factors such as factors related to any microorganism, a higher frequency of disease can be observed. Based on studies in recent years, it has been proven that pertussis has seasonality, with a peak of activity in warm seasons.[14] Kwon et al. in a study indicated the highest prevalence rate in April, June, and September in infants younger than 6 months of age.[9] Similar studies from other countries have also shown the incidence peak in April [20] and August.[10] Miyashita et al. in a study focusing on a time frame of 7 years showed an obvious seasonal pattern in the incidence of disease between May and August each year.[14] Increased prevalence rate in these months in Japan and Korea could be due to the reopening of schools and universities as many outbreaks are reported at this point in time and place. On the other hand, in a study conducted in Iran, 41.7% and 33.3% of the 48 patients had symptoms in winter and autumn, respectively.[5] According to the study of Sedighi et al. from Iran, the high prevalence of infection was in October, explaining that autumn coincides with the beginning of the academic year in Iran.[1] Thus, the starting of schools and universities may play a role in seasonal increases in the prevalence of disease in countries. Studies in some European countries showed that pertussis seasonality pattern is similar to findings in Asia, as Gonfiantini et al. in a study in Italy showed that the pertussis prevalence peaks between March and August.[30] Nevertheless, because of the low number of patients and similar clinical demonstrations with other respiratory infections, such as Mycoplasma pneumonia and adenovirus which may often associate with misdiagnosis of pertussis, one cannot rely on these results alone for the recognition of seasonality of pertussis. Hence, it seems that a functionally active surveillance system should be introduced and whooping cough should be monitored carefully in all seasons and at all ages to obtain an accurate pattern of seasonality of pertussis in different age groups. Pertussis vaccination Passive immunity can be transferred from maternal blood into the fetus through the placenta. This immunity could protect newborns for a short period after birth but after this time due to a decrease in the level of antibodies, they become susceptible to pertussis infection. In this period, asymptomatic healthy carriers such as parents, older siblings, medical staff or teachers, and all adolescents and adult population who communicate with children can be a source of transmission for them.[7],[9],[11],[16],[21] Pertussis vaccination was introduced into the national childhood vaccination program in many countries since the 1950s by triple DTwP vaccine. The vaccine is administered in a four-dose schedule at the 2nd, 4th, and 6th months of life with booster doses at 18 months and between 4 and 6 years of age.[18],[27],[31] According to studies, the vaccine-induced antibodies began to wane in children 3 and 5 years after the last dose of vaccination, and immunity to pertussis vaccine diminished to 0%–20% over the next 7–12 years.[3],[7],[11],[16],[20] In this way, primary vaccination failure and maintenance of pertussis immunity at appropriate and protective levels requires an additional booster dose during adolescents and adulthood. However, vaccination with a booster dose not only protects the vaccinated people of pertussis and its complications but may also decrease the risk of transmission to infants.[9],[18],[27] Recently, several countries, in accordance with Global Pertussis Initiative, suggested that adolescents should receive a single dose of Tdap vaccine instead of Td boosting at ages 11–12 years. Unfortunately, there is no schedule for adolescent and adult immunization against pertussis in many Asian countries such as Turkey, Iran, and Japan.[7],[25],[20] Therefore, probable whooping cough might spread in older children and adults and subsequently in younger children in the world. However, further studies are required to assess the produced immunity after the pertussis vaccination in adults, the duration of protection after each dose of the vaccine, the amount of created reactogenicity with repeated pertussis vaccination in adults and the best interval for doses of vaccine in adults. To determine the run-time booster dose in a country, the age-specific seroepidemiology of the disease should be well known. In recent years, another strategy suggested preventing infants’ mortality through pertussis immunization before birth.[3],[23],[29],[31] In terms of the transition of maternal antibodies through the placenta, some studies have advised the immunization of pregnant women. In the first trimester, a very small amount of IgG antibodies is transported to the fetus; transplacental transport starts at almost 17 weeks of gestation and increases gradually. Notwithstanding, the amount of transferred IgG is minimal until nearly 34 weeks of gestation. In this way, under the age of 32 weeks of gestation, the maternal antibody would not be effective on its own, while in turn the infant’s amount of antibody was higher and effective. Nevertheless, enough information is not available presently to confirm the safety and efficacy of pregnancy vaccination.[20],[29]
Pertussis continues as a challenge for the medical community and public health specialists. Therefore, the pertussis incidence rate and risks still need to be monitored. Moreover, age-cohort effects, vaccine effectiveness, seasonality and changes in testing patterns should be considered. This review and similar studies show that pertussis can be controlled by understanding the complete epidemiology of the disease among the community, reforming national vaccination policy, education, and design of effective methods in each country. Acknowledgments This project was financially supported by the Lung and Tuberculosis Diseases Research Center, Tabriz University of Medical Sciences. Financial support and sponsorship This project was financially supported by the Tuberculosis and Lung Diseases Research Center, Tabriz University of Medical Sciences. Conflicts of interest There are no conflicts of interest.
Source of Support: None, Conflict of Interest: None
[Figure 1], [Figure 2], [Figure 3]
[Table 1] |
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