Southeast Asian J Trop Med Public Health

DIPHTHERIA OUTBREAK IN , 2012; SEROPREVALENCE OF DIPHTHERIA ANTIBODIES AMONG THAI ADULTS AND ITS IMPLICATIONS FOR IMMUNIZATION PROGRAMS

Nasamon Wanlapakorn1, Pornsak Yoocharoen2, Piyanit Tharmaphornpilas2, Apiradee Theamboonlers1 and Yong Poovorawan1

1Center of Excellence in Clinical Virology, Department of Pediatrics, Faculty of Medicine, University, ; 2Bureau of General Communicable Disease, Department of Disease Control, Ministry of Public Health, , Thailand

Abstract. An age distribution shift in diphtheria cases during a 2012 outbreak in northeastern of Thailand suggests adults are increasingly at risk for infection in Thailand. Data regarding immunity against diphtheria among the adult Thai population is limited. We review a 2012 diphtheria outbreak in Thailand and conducted a nationwide seroepidemiological survey to determine the prevalence of diphtheria antibodies among Thai adults in order to inform immunization programs. A total of 41 confirmed cases, 6 probable cases and 101 carriers of diphtheria were reported from northeastern and upper . The diphtheria outbreak in northeastern Thailand occurred among adults aged ≥15 years; sporadic cases occurred among children from upper southern Thailand. We conducted a seroepidemiological survey of 890 Thai adults from 4 age groups (20-29, 30-39, 40-49 and 50-59 years) in 7 different geographical areas of Thailand (, Ratchaburi, Chon Buri, , , and ). Diptheria toxin antibody levels were measured with a com- mercially available ELISA test. The seroprotection rate ranged from 83% to 99%, with the highest in eastern Thailand (Chon Buri, 99%) and the lowest in (Chiang Mai, 83%). Diphtheria antibodies declined with increasing age. We recommend one dose of diphtheria-tetanus toxoid (dT) vaccine once after 20 years of age in order to boost the antibody and revaccinations every 10 years to prevent future outbreaks. Keywords: diphtheria, outbreak, seroprevalence, immunization, adult

Correspondence: Yong Poovorawan, Center of INTRODUCTION Excellence in Clinical Virology, Department of Pediatrics, Faculty of Medicine, Chulalong- Diphtheria is an infection character- korn University, Bangkok 10330, Thailand. ized by sore throat, low-grade fever and Tel: +66 (0) 2256 4909; Fax: +66 (0) 2256 4929 an adherent membrane on the tonsils, E-mail: [email protected] pharynx, and/or nasal cavity. Diphtheria

1132 Vol 45 No. 5 September 2014 Diphtheria in Thailand toxin produced by C. diphtheriae can cause in an outbreak in Saraburi Province (CDC, myocarditis and polyneuritis (Atkinson 1996). In 1996, a diphtheria outbreak was et al, 2012). Diphtheria is spread by direct reported in Buri Ram Province (Pantu- contact or by inhalation of aerosolized se- kosit et al, 2008) with a total number of cretions from infected individuals. Before 31 cases. The annual rate of diphtheria the wide-spread use of the diphtheria- infection in Thailand has gradually in- tetanus toxoid and whole cell pertussis creased, amounting to 77 cases per year (DTP) vaccines, the case-fatality rates in 2010 (Tonghong, 2010), the majority of from respiratory tract diphtheria ranged which (71 out of 77) were from southern from 2% to 20%, with an average of 10% Thailand. The ages of infected individu- for patients who received attentive medi- als ranged from 7 years to 50 years. The cal care (Brenzel et al, 2006). majority were children aged ≤15 years; While once common, diphtheria is however, 10% (8 of 77 cases) were among now rare because of the wide-spread use adults. This suggests some age groups are of the DTP vaccine. The percentage of in- more vulnerable to infection, most likely fants receiving 3 doses of the DTP vaccine due to lower vaccine coverage or waning increased from 20% in 1980 to 78% in 2005 antibody levels in adulthood. in developing contries, with substantial The duration of protective immunity variation by district and country (Scheif- after primary immunization has become ele and Ochnio, 2009). Thailand began a subject of interest. Diphtheria antibody a routine infant immunization program levels among adults aged ≥20 years show with 2 doses of the DTP vaccine for all a significant age-related decrease in anti- infants in 1977 (Tharmaphornplas et al, body levels with increasing age, reaching a 2001), and with 3 doses beginning in 1982. minimum in the 30-39 year old age group, After wide-spread use of the vaccine in with fewer than half of subjects having Thailand, rates of diphtheria among Thais protective antibody levels (Pachón et al, declined substantially from 1,600-2,400 2002; Kurugöl et al, 2011). The concept of cases per year during 1971-1977 to 19 cases herd immunity (National Network for Im- per year in 2002 (Tiparat and Kooharat, munization Information, 2014) states that 2002). By 2000, DTP vaccine coverage in outbreaks of diphtheria among adults are Thailand was estimated to be 97% among possible when less than 85% of the popu- infants below one year of age and since lation has protective antibody levels. In then has continually increased (WHO, Thailand, a seroepidemiological survey 2013). However, diphtheria remains a of diphtheria immunity was conducted problem in spite of efforts to achieve vac- among 364 people aged 2-86 years in Na- cination coverage, especially in southern khon Ratchasima Province (Chasangbong Thailand, where vaccination coverage et al, 2004). Although the antibody titers of estimates for infants aged ≤12 months all 364 people exceeded protective levels were lower compared to other regions (>0.1 IU/ml), the study found that im- (69% in Pattani Province, 74% in Yala munity to diphtheria declined with age. Province and 85% in Narathiwat Province) Another seroepidemiological survey of (Tonghong, 2010). Sporadic cases of diph- diphtheria immunity in Khon Kaen Prov- theria have also been reported in many ince, Thailand in 2011 found adults aged provinces in recent years. In 1994, a total 20-50 years were at the highest risk for of 18 cases of diphtheria were identified diphtheria infection (Bansiddhi et al, 2012).

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Table 1 Diphtheria cases by age group and province during an outbreak in Thailand (June 2012 - January 2013).

Provinces Confirmed Probable Carriers Median age (range) cases cases (in years)

Northeastern region Loei 26 1 68 26 (2-72) 5 0 13 33 (20-37) Nong Bua Lam Phu 3 1 7 12.5 (9-48) 3 2 0 33.5 (33-43) 1 0 3 32 Maha Sarakham 0 1 2 9 Upper southern region 1 1 0 9 (8-10) Nakhon Si Thammarat 2 0 8 1.5 (1-2) Total 41 6 101 26 (2-72)

Declining seroprotection rate among cases were reviewed to determine disease adults suggests the potential for future patterns and determine the epidemiology. outbreaks of diphtheria. Several stud- The following case definitions were used ies recommend a booster dose of dT for by the Committee of the Department of adults to maintain diphtheria immunity Disease Control: a confirmed case was (Ilina, 2000; Kurugöl et al, 2011; Bansid- defined as a case presenting with fever, dhi et al, 2012). In Thailand, compliance throat exudate and throat swab culture with the recommendation to have a positive for Corynebacterium diphtheriae; a booster dose of dT among adults has been probable case was defined as a person pre- relatively low. Additional data regard- senting with clinical symptoms of diph- ing immunity against diphtheria among theria or a close contact of a confirmed Thais of various ages can help guide dT case; a carrier was defined as someone booster vaccine programs among adults. without clinical symptoms who had a We evaluate a 2012 diphtheria outbreak throat culture positive for Corynebacterium in Thailand and report a nationwide se- diphtheriae. roepidemiological study we conducted to The 2012 outbreak of diphtheria in Thai- determine the prevalence of diphtheria land susceptibility among Thai adults. A total of 38 confirmed cases, 5 prob- able cases and 93 carriers of diphtheria MATERIALS AND METHODS were reported from northeastern Thailand between June 2012 and January 2013. Data regarding diphtheria outbreaks There were also sporadic confirmed cases in Thailand were retrieved from the De- of diphtheria in the upper south of Thai- partment of Disease Control, Ministry of land during the same period of time as Public Health. The records of diphtheria shown in Table 1.

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from individuals aged 20-59 years from Khon Kaen Province, Thailand in June LAO PDR 2011. This second group consisted of in- Chiang Mai dividuals presenting for a routine health check-up and acutely ill patients seeking medical care at Chum Phae Hospital, Phitsanulok Khon Kaen Province, Thailand. These data were extracted from a previous seroepide- Khon Kaen MYANMAR miological survey of diphtheria immunity in Khon Kaen Province (Bansiddhi et al, 2012) using the same ELISA methods. The sample size was chosen based on Ratchaburi an assumption of a 90% prevalence of Chon Buri diphtheria antibodies and a significance

CAMBODIA level of p<0.05. These 890 samples were divided into four age groups (20-29, 30- 39, 40-49 and 50-59 years) residing in 7 different geographical areas of Thailand (Chiang Mai, Ratchaburi, Chon Buri, Nakhon Si Thammarat, Phitsanulok, Khon Kaen and Songkhla) (Fig 1). All the specimens in this study were kept at the Center of Excellence in Clinical Virology, Nakhon Si Thammarat Chulalongkorn University and Hospital. All personal identifiers, except age and Songkhla gender, were removed from the data set and specimens. The research protocol was approved by an institutional review board (IRB) at the Faculty of Medicine, Fig 1–Seroepidemiological survey areas con- Chulalongkorn University (IRB number ducted in February 2013 in six regions 042/56) and conducted in accordance and in June 2011 in Khon Kaen Province with the Helsinki Declaration II. The IRB Thailand (Bansiddhi et al, 2012). waived the need for consent because the samples were anonymous. Seroprevalence of antibody against diph- Laboratory methods theria toxin Diphtheria antibody levels were A cross sectional study was con- measured with a solid-phase IgG-specific ducted on 890 randomly selected Thai ELISA (IBL International, Hamburg, Ger- adults. These were divided into two many) according to a published protocol groups: the first group was comprised (Bansiddhi et al, 2012). The data were of healthy Thai blood donors aged 20-59 then classified according to the levels of years randomly chosen from provincial antitoxin: 0.01-0.099 IU/ml susceptible; blood blank centers in each region (299 0.1-0.99 IU/ml showed a satisfactory, pro- males and 300 females) in February 2013. tective level; 1-1.499 IU/ml showed a high The second group was comprised of 291 level of immunity; 1.5-2 IU/ml showed a

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level ≥ 0.1 IU/ml. The antibody levels and personal data were entered into SPSS ver- sion 15 (SPSS, IBM, Armonk, NY) by age group and gender.

RESULTS

The 2012 diphtheria outbreak in Thailand The 2012 diphtheria outbreak in Thai- land was first identified in Dan Sai District, Loei Province in June 2012. The first case was a 40-year-old immunocompromised alcoholic male, who subsequently died of acute myocarditis. The second case was a 25-year-old male from a nearby village; subsequent cases were reported in a vil- lage close to where the second case lived and then spread to neighboring provinces (Fig 2). In October, diphtheria cases were also reported in upper southern Thailand (Surat Thani and Nakhon Si Thammarat). A total of 6 fatalities from acute myocar- ditis were reported. The Ministry of Public Health (Rang- seewong and Siriarayaporn, 2013) stated that between June 2012 and January 2013, a total of 38 confirmed cases, 5 probable cases, and 93 carriers of diphtheria were reported from northeastern Thailand (Fig Fig 2–Areas where confirmed and probable 2). There were also sporadic confirmed diphtheria cases were reported during a cases reported from upper southern Thai- diphtheria outbreak during June 2012 - land. The majority of confirmed cases in January 2013, Thailand. the northeastern outbreak were reported among adults. However, in upper south- very high level of immunity and ≥ 2 IU/ml ern Thailand, all the cases occurred among showed long-lasting immune protection. children aged <15 years (Table 1). Statistical analysis Seroprevalence of antibodies against diph- Geometric mean titers (GMTs) were theria toxin calculated using the log transformation The highest GMT was found among of serological titers and from taking the subjects aged 50-59 years (GMT 0.49 IU/ antilog mean of the transformed values. ml). Followed by those aged 20-29 and Seroprotection rates (SPRs) for each age 40-49 years (0.43 IU/ml and 0.38 IU/ml, group were defined as the fraction of the respectively). The lowest GMT was found population with a diphtheria antibody among those aged 30-39 years (GMT 0.34

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a IU/ml). The overall GMT was 0.40 IU/ml. The overall seroprotection rate among )

n Thai adults was 90.9%; however, middle- - 91 (202) %, ( aged adults aged 30-39 years had the Average 92.2 (212) 87.7 (200) 92.9 (195) 90.9 (809) lowest seroprotection rate (87.7%) (Table 2). The seroprotection rates in different seroprotection rate seroprotection regions ranged from 83% to 99%, with the highest rate being in Chon Buri (99%)

- 230 228 222 210 890

Total Total and lowest in Chiang Mai (83%). The subjects group with the lowest seroprotection in 4 provinces was the 30-39 year age group )

n (76% in Phitsanulok, 88% in Nakhon Si

91 (74) 90 (70) 92 (66) 291 Thammarat, 76% in Songkhla, and 90% in %, ( 100 (60) 92.8 (270) et al Khon Kaen Khon Kaen (Bansiddhi , 2012). Serological profiles varied by geo- )

n graphical areas but some common themes 99 %, ( 87 (21) 88 (22) 96 (24) 87 (86) were noted. In Phitsanulok, Ratchaburi, 76 (19) Songkhla Chon Buri and Songkhla Provinces, the lowest GMT values were seen in the 30-39

) year old age group (0.24 IU/ml, 0.28 IU/ml, n 0.37 IU/ml and 0.21 IU/ml, respectively). 88 (22) 88 (22) 94 (94) %, ( 100 (25) 100 (25) In Nakhon Si Thammarat the lowest GMT Nakhon Si Thammarat was found in the 20-29 year old age group Table 2 Table

) (0.56 IU/ml); in Khon Kaen, the lowest n GMT was found in the 40-49 year old age %, ( 88 (22) 96 (24) 88 (22) 93 (93)

100 (25) group (0.36 IU/ml) and in Chiang Mai Ratchaburi the lowest GMT was found in the 50-59 year old age group (0.19 IU/ml) (Fig 3). Seroprotection rates against diphtheria by age group Seroprotection ) n

The majority of the studied subjects (632 100 96 (24) 99 (99)

%, ( out of 890, 71%) had diphtheria immunity 100 (25) 100 (25) 100 (25)

Chon Buri levels of 0.1-0.99 IU/ml; only 6.6% (59 out of 890) had a long-lasting immunity level

) (> 2 IU/ml). n

100 %, ( 96 (24) 76 (19) 84 (21) 80 (20) 84 (84) DISCUSSION Phitsanulok Percentage population susceptible to diphtheria by age group and province. province. and group age by diphtheria to susceptible population Percentage We examined a 2012 diphtheria out- )

n break and the prevalence of diphtheria

100 immunity in a Thai population. During %, ( 96 (24) 80 (20) 76 (19) 83 (83) 80 (20) the 2012 outbreak of diphtheria in the Chiang Mai northeast of Thailand, most of the af- fected individuals were between 15-44 years. This was most likely due to waning vaccine-induced immunity and decreased Age group subjects (years) Total 20-29 30-39 40-49 50-59 Overall Seroprotection rate was defined as the fraction of population with a diphtheria antibody level ≥ 0.1 IU/ml. Seroprotection

a opportunity to acquire natural immunity.

Vol 45 No. 5 September 2014 1137 Southeast Asian J Trop Med Public Health IU/m l IU/ml n =100 Central n =880 Ratchaburi Thailand (total) IU/ml IU/ml n =291 n =99 Northest Songkhla Khon Khan , 2012). et al South IU/ml IU/ml Thammarat n =100 n =100 Phitsanulok Nakhon Si North IU/ml IU/ml n =100 East n =100 Chiang Ma i Chonburi and in June 2011 in Khon Kaen Province, Thailand (Bansiddhi in Khon Kaen Province, and in June 2011 Fig 3–Percentages of seropositivity and diphtheria antitoxin levels by age group for various provinces during February 2013 in six regions regions six in 2013 during February provinces various for by age group diphtheria antitoxin levels and seropositivity of Fig 3–Percentages

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The sporadic diphtheria cases in southern (Klouche et al, 1995), a study from Turkey Thailand were mostly among those aged in 2003 found 30.6% of subjects aged 40- ≤15 years. Tonghong (2010) found vac- 49 years had protective antibody levels cination rates among children aged <12 (Alp Cavus et al, 2007). No diphtheria months in southern Thailand were lower outbreaks have been reported in Germany than other areas of Thailand. This find- or Turkey as opposed to Thailand; this ing underscores the need for continued may be because Thailand’s neighboring vaccination efforts, especially among countries such as Lao PDR, Cambodia and economically disadvantaged populations, Myanmar, have a higher incidence of C. such as tribal children and children from diphtheria, which can spread cross border families living in distant rural areas in to Thailand (WHO, 2014). southern Thailand. Several studies have found protective Since diphtheria among humans is antibody levels decrease with increasing caused by a toxin, carriers may transmit age (Souliou et al, 1997; Di Giovine et al, the pathogen to those not yet immunized. 2013), except for some elderly populations Maintaining herd immunity to prevent over 60 years old, where seroprotection outbreaks requires complete childhood rates for diphtheria were higher than in vaccination and booster dT vaccination in younger age groups. In our study, the adults (Scheifele and Ochnio, 2009). percentages of individuals with protective In the second part of this study we immunity varied by geographical area. conducted a nationwide seroepidemio- Based on herd immunity (Fine, 1993) logical survey of immunity to diphtheria (1-1/Ro) with a basic reproductive number among Thai adults. Among the studied (Ro) for diphtheria of 7, diphtheria im- population, 90.9% had protective immu- munity in at least 85% of the population nity to diphtheria; however, the results of is required to prevent a diphtheria out- our serological study suggested a higher break. The seroprotection rates in some percentage of diphtheria susceptibil- age groups in our study were lower than ity among adults aged 30-39 years. The this threshold, especially among those lower percentage of those seroprotected aged 30-59 years. Antibodies levels were in this age group was probably due to: 1) lower suggesting risk of future outbreaks. suboptimal seroconversion among those The 2012 diphtheria outbreak in Thai- who received two doses of DTP in infancy land raises questions about vaccination during 1977-1982, 2) lack of booster doses policy, including the timing a number during adulthood, and 3) reduction in of booster dT doses required to protect exposure to circulating C. diphtheriae. The adults. Since 2008, the national vaccine second lowest seroprotection rate was policy for Thailand recommends a DTP- found among adults aged 40-49 years HB (Diphtheria-Tetanus Toxoids–whole (91%). This group did not receive the DTP cell Pertussis and Hepatitis B) vaccine for vaccine during infancy. infants aged 2, 4 and 6 months, a DTP for The seroprotection rates in the Thai children aged 18 months and 4 years, and population was in our study are higher a booster dT vaccine at the age of 12 years than in studies from some other countries: before leaving primary school. This ex- a study from Germany in 1993 found 76% plains the high GMT values found among of people had protective antibody levels those aged 20-29 years. However, the

Vol 45 No. 5 September 2014 1139 Southeast Asian J Trop Med Public Health immunity declines over time. The World University; the Integrated Innovation Aca- Health Organization (WHO) recom- demic Center (IIAC), Chulalongkorn Uni- mends people living in low endemic and versity; the Centenary Academic Develop- non-endemic areas need a booster every ment Project (CU56-HR01); the Ratchada- 10 years to maintain life-long protection pheisek Somphot Endowment Fund of (Scheifele and Ochnio, 2009). A study from Chulalongkon University (RES560530093), the Russian Federation (Brennan et al, King Chulalongkorn Memorial Hospital; 2000) reported adults with an unknown the National Blood Center, the Thai Red vaccination history or who are likely to Cross. We would like to thank the staff at be immunologically naive to toxigenic Chum Phae Hospital, Khon Kaen for pro- strains of diphtheria should receive at viding us the blood samples. We also thank least 3 doses of dT for protection. In Thai- Mr Brian Muchmore, Ms Petra Hirsch and land, the current guidelines recommend Dr Sompong Vongpunsawad for reviewing a booster dose of dT for those who have the manuscript. Finally, we would like to been vaccinated during childhood once thank MK Restaurant Company Limited, at age 20 years and then every 10 years. The Siam Cement Pcl and the Masu com- This study further provides evidence for pany for their support. the importance of adhering to the current recommendations. REFERENCES Inadequate immunity to diphtheria is likely in the near future due to waning Alp Cavus S, Avkan Oguz V, Yuce A. The se- immunity among adults. Adults should roprevalence of diphtheria among adults in Izmir-Turkey. Vaccine 2007; 25: 3851-4. receive dT booster vaccine to maintain adequate seroprotection levels following Atkinson W, Hamborsky J, Wolfe S. Diphthe- recommendations. For adults with an ria. In: Atkinson W, Hamborsky J, Wolfe S, eds. Epidemiology and prevention of unknown history of vaccination, 3 doses vaccine-preventable diseases. 12th ed. of dT vaccine are recommended. The dT Washington, DC: Public Health Founda- vaccine may be given during clinic visits tion; 2012: 75-86. for other reasons, such as for injuries or Bansiddhi H, Vuthitanachot V, Vuthitanachot during antenatal care in order to prevent C, Prachayangprecha S, Theamboonlers A, future outbreaks of diphtheria in Thailand. Poovorawan Y. Seroprevalence of antibody against diphtheria among the population ACKNOWLEDGEMENTS in Khon Kaen Province, Thailand. Asia Pac J Public Health 2012 Jun 28. [Epuls ahead This work was supported by The Bu- of print]. reau of General Communicable Diseases, Brennan M, Vitek C, Strebel P, et al. How many Department of Disease Control (DDC), doses of diphtheria toxoid are required Ministry of Public Health; the Higher Edu- for protection in adults? Results of a case- cation Research Promotion and National control study among 40- to 49-year-old Research University Project of Thailand, adults in the Russian Federation. J Infect Office of the Higher Education Com- Dis 2000; 181: S193-6. mission (HR 1155A-55, WCU-001-HR57, Brenzel L, Wolfson LJ, Rushby JF, Miller M, WCU-007-HR57); the Thailand Research Halsey NA. Vaccine-preventable diseases Fund (DPG5480002); the Center of Excel- In: Jamison DT, Breman JG, Measham lence in Clinical Virology, Chulalongkorn AR, et al, eds. Disease control priorities in

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