Neisseria meningitidis W-135 Carriage During the Hajj Season 2003

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1 Scand J Infect Dis 36: 264/268, 2004 Neisseria meningitidis W-135 Carriage During the Hajj Season 2003 HANAN H. BALKHY 1,2, ZIAD A. MEMISH 1,3, MAHA A. ALMUNEEF 1,2 and ABIMBOLA O. OSOBA 4 From the Departments of 1 Infection Prevention and Control, 2 Paediatrics, and 3 Internal Medicine, King Abdulaziz Medical City, King Fahad National Guard Hospital Riyadh, Saudi Arabia, and 4 Department of Pathology and Laboratory Medicine, King Khalid National Guard Hospital, Jeddah, Saudi Arabia During the 2003 Hajj pilgrimage to Mecca, 344 pilgrims of 29 different nationalities were screened by means of a throat swab to detect Neisseria meningitidis carriage. N. meningitidis was isolated from 11 subjects; 2 were serogroup W-135, 1 serogroup B, and 8 were non-groupable. The results indicate a very low colonization rate for N. meningitidis among the tested cohort, with a predominance of non-groupable strains. These results, combined with a review of the published data, warrant a re-evaluation of current recommendations by the Saudi Ministry of Health for the use of ciprofloxacin for Saudi pilgrims departing at the end of the Hajj season. However, vaccination with the meningococcal quadrivalent vaccine, for all pilgrims, should continue to be recommended. The possibility of new strains arising as a cause of future meningococcal outbreaks should be considered, and annual surveillance may give an early warning. Z. A. Memish, Department of Infection Prevention and Control, NGHA, King Abdulaziz Medical City, King Fahad National Guard Hospital, P.O. Box 22490, Riyadh 11426, Saudi Arabia (Tel. / , fax. / , . memish@ngha.med.sa) INTRODUCTION During the Hajj season, Saudi Arabia hosts over 2 million Muslim pilgrims in a small confined area, (i.e. the cities of Mecca and Madina) thereby creating a high risk of disease transmission (1, 2). In 1987, N. meningitidis serogroup A was implicated in Hajj related worldwide meningococcal outbreaks and, since then, the bivalent meningococcal (AC) vaccine became mandatory for all pilgrims entering Saudi Arabia (3). When the meningococcal W-135 strain became a major cause of morbidity and mortality following the Hajj pilgrimage of the y 2000 and 2001 (4, 5), the quadrivalent vaccine became the choice for those performing the Hajj in place of the bivalent vaccine (6). Taking no risks, the Saudi Ministry of Health recommended, for the eradication of W-135 from the nasopharynx, that local pilgrims from Saudi Arabia should receive a dose of ciprofloxacin on the last d of the religious ceremony, before returning to their families (7). The strict implementation of the quadrivalent vaccine to all local and international pilgrims has eliminated the outbreaks related to N. meningitidis W-135, and no outbreaks were identified following the pilgrimage of y 2002 and 2003 (7). In this study, selected multinational pilgrims were screened to identify the rate of N. meningitidis colonization and to detect the predominant serogroup. We then analysed the available data on N. meningitidis nasopharyngeal carriage among pilgrims and the possible effect of the recent change in vaccination strategy, i.e. switching from the bivalent to the quadrivalent vaccine. METHODS Site of the study During each Hajj pilgrimage season, the Saudi Arabian National Guard Health Affairs provides free medical care to all pilgrims at 3 main areas; Mina, Muzdalifa and Arafat. During the pilgrimage d, 9/15, of the Holy Month of Dul-Hijjah, an average of 10,000 patients present at our walk-in clinics, which are male and female general clinics and a dental clinic. Since the majority of the time is spent in Mina, most patients presented to Mina Hospital outpatient clinics; therefore this site was selected for the study. Patient selection Any pilgrim is allowed to attend our clinics for medical care. Those presenting between 10:00 am and 2:00 pm on d 10, 11, and 12 were selected, and gave their verbal consent for participation in the study. At the study site, separate male and female triage areas were available to assess the patients upon presentation. The patients were then directed to the appropriate clinic. Throat swabs were obtained by a male or female physician, by swabbing both tonsils and the posterior pharynx using cotton tip swabs kept at room temperature. The samples were transported to King Khalid National Guard Hospital in Jeddah on a daily basis, within 12 h of collection, for immediate bacteriological processing. A questionnaire was completed by each pilgrim, including basic demographics such as age, gender, country of origin, smoking history, date of previous meningococcal vaccination and any history of recent antimicrobial use. The type of the meningococcal vaccination received, i.e. bivalent or quadrivalent, was recorded when available. The pilgrim was considered vaccinated if he/she received the vaccine no more than 4 y and no less than 10 d prior to this Hajj season. Microbiology All throat swabs were inoculated on sheep blood agar, chocolate agar and Thayer-Martin media (chocolate agar modified by the addition of vancomycin, colistin and nystatin). The plates were # 2004 Taylor & Francis. ISSN DOI: /

2 Scand J Infect Dis 36 Neisseria meningitidis carriage during the Hajj 265 incubated at 358C inco 2 for 24 h. If no growth was seen, the plates were further incubated for another 24 h. Colonies suspected to be Neisseria by characteristic morphology were tested by the oxidase test and Gram stain. Subcultures of oxidase-positive, Gram-negative diplococci were made on fresh blood agar plates and incubated for 18/24 h at 35 o C in an atmosphere of 5% CO 2. N. meningitidis was confirmed by the carbohydrate utilization test of glucose and maltose, but not sucrose, fructose and lactose (8, 9). Susceptibility tests were carried out using the Kirby-Bauer technique. Grouping of the strains was carried out by slide agglutination test using meningococcal typing serum (Wellcome Laboratories, UK). RESULTS A total of 5004 patients presented to the National Guard Hospital and outpatient clinics in Mina, with the majority presenting on d 10 and 11 of the pilgrimage. A total of 344 pilgrims were screened during the time period allocated for the study. Each pilgrim provided only 1 sample and a questionnaire was completed. Demographics Of the 344 pilgrims, 155 (45%) were males and 189 (55%) females. The majority of the patients were between 20 and 50 y of age (Table I), representing a total of 29 nationalities. The statistical difference among the culture positive and culture negative groups with regard to age, gender or smoking habit was non-significant. Microbiology results A total of 11 throat cultures were positive for N. meningitidis; 2 were serogroup W-135, 1 was serogroup B, and 8 were non-groupable. Seven of the isolates were from Saudi pilgrims and 1 isolate each from a Pakistani, Moroccan, Iranian, and Bahraini pilgrim. The antimicrobial susceptibilities of all isolated strains were determined for penicillin, ampicillin, ciprofloxacin, cefotaxime and ceftriaxone. All isolates were susceptible to all antimicrobials tested except for 1 isolate that was resistant only to cefotaxime. None of the isolates produced beta-lactamase. Symptom analysis and vaccination rate Among the culture positive patients, headache, runny nose, sneezing and coughing was common. The difference however, was not statistically significant when compared with the culture negative group (Table II). None of the patients were hospitalized for sepsis or meningitis, and there were no deaths. The total number of study pilgrims vaccinated within the past 4 y was 151 (44%); 139 (92%) received the quadrivalent vaccine and 12 (8%) received the bivalent vaccine; 27% were not sure of their vaccination status, and the remainder Table I. Demographic data of Hajj Surveillance 1423H (2004 G) Results of culture Characteristics Positive % Negative % Total Odds ratio (95%Cl) Gender Male (0.12/1.69) Female Age group (in y) a 0/ (0.12/7.13) 20/ (0.54/10.98) 40/ (0.06/1.97) Nationality b Saudi (0.13/2.20) Pakistani (0.14/7.66) Moroccan b (1.22/37.2) Irani b (2.24/46.0) Bahraini Others c Type of Meningitis vaccination d Quadrivalent (0.29/4.85) Bivalent (0.21/24.3) Unknown (0.12/4.11) Non-vaccinated Smokers Yes (0.09/5.20) No a Each age group compared to remaining groups. b Each nationality compared to remaining nationalities, Bahraini and others not done because include 0. c 24 other nationalities included. d Each vaccine group compared to non- vaccinated.

3 266 Z. A. Memish et al. Scand J Infect Dis 36 Table II. Common symptoms among culture-positive and culturenegative pilgrims Positive (11) Negative (333) Symptoms No. % No. % Fever Throat pain Cough Sputum Chest pain Headache Sneezing Runny nose Myalgia Arthralgia denied receiving a meningococcal vaccine in the past 3 /4 y (29%). Vaccination status among the pilgrims Of the 11 pilgrims who were culture positive, 7 were Saudi national. Among them, 4 were vaccinated (Table III). None of the 7 had received antimicrobials prior to the Hajj. The remaining culture positive pilgrims had been vaccinated. Interestingly, 10 Pakistani pilgrims were among non-vaccinees, and all were residents of either Mecca or Jeddah. Statistical analysis The data were analysed using the Epi Info statistics software, version 6.04 (CDC, Atlanta, GA). Univariate analysis was done using a statistical significance of a p-valueb/0.05 by a Fischer exact test or Student s t-test as appropriate. DISCUSSION In our study, only those who elected to attend our clinic in Mina seeking medical care could be targeted. The majority were seen with upper respiratory tract symptoms. Pilgrims screened were of different nationalities, so we are unable to conclude that the low carriage rate of N. meningitidis, or the most common serogroup, was related to a specific nationality. However, it could be concluded that the overall carriage rate was low. A possible explanation for this could be that the pilgrims are self-medicating with antibiotics during the pilgrimage period, as the fear and awareness of meningitis transmission during the Hajj is high. This would no doubt decrease the nasopharyngeal carriage rate. As we were unable to easily communicate with all the pilgrims because of a language barrier, the history of medication ingestion was inadequate. In general, many of the pilgrims were under the impression that a single dose of ciprofloxacin would prevent meningitis and requested the medication be given to them. When feasible, we explained the rationale behind giving ciprofloxacin, and gave the dose to those who attended the clinic on the last d of the pilgrimage. Receiving the meningococcal vaccination would be another possible explanation for the low rate of nasopharyngeal carriage of N. meningitidis. It was determined that the overall meningitis vaccination rate among the cohort was 44%, with the majority receiving the quadrivalent vaccine. Strict requirements for meningococcal vaccination are applied by the Saudi government. However, as some of the non-saudi pilgrims reside in Saudi Arabia, implementing this rule on such pilgrims becomes very difficult. An earlier study carried out on military recruits showed that the bivalent meningococcal polysaccharide vaccine decreased and inhibited colonization with meningococcal serogroups A and C. However, an increased prevalence of serogroup Y was noticed (10). Unfortunately, similar data on the role of the quadrivalent vaccine in reducing the carriage rate for serogroups W-135 and Y is lacking. It is logical to hypothesize that disease transmission from a vaccinated carrier to an unvaccinated contact could still take place. A few years ago, the Center for Disease Control (CDC) conducted a study on departing and returning pilgrims from JFK airport in New York City, USA. Overall, returning pilgrims were more likely to be positive for N. meningitidis than departing pilgrims. A total of 27 positive cultures were Table III. Vaccination status, types and antibiotic use among the study population Vaccination status Type of vaccine Antibiotic use Nationality Culture Yes No Total Quadrivalent Bivalent Unknown Yes No Total Saudi Positive Negative Pakistani Positive Negative Moroccan Positive Negative Irani Positive Negative Bahraini Positive Negative Others Positive Negative

4 Scand J Infect Dis 36 Neisseria meningitidis carriage during the Hajj 267 identified; 4 (0.9%) from the pre-hajj group and 23 (2.6%) from the post-hajj group. 26% were serogroup W-135, all from returning pilgrims, underlining the likelihood of acquiring this emerging pathogen during the Hajj pilgrimage (11). Over the past 3 y, there has been an increased interest in identifying the serogroups colonizing those attending the pilgrimage, as evidenced by some recent publications. Wilder-Smith et al. in 2001 identified a significant increase in the nasopharyngeal carriage of N. meningitidis in returning Singaporian pilgrims in general, and specifically W-135 serogroup, at a time when ciprofloxacin was not routinely given to pilgrims (12). We conducted a similar study during 2001 to identify the rate of colonization of N. meningitidis among the local inhabitants of the Jeddah/Mecca area attending the pilgrimage (13). The overall carriage rate of 7.4% was within the normal expected limits, but 50% of the strains were W-135. This suggests that serogroup W-135 is becoming a major colonizing strain. Theoretically, if this serogroup continues to spread among specific areas around the world, the risk of disease transmission will continue to be a problem, since the close interaction of about 2 million pilgrims, in a more or less confined space during the Hajj pilgrimage, will no doubt bring those who are colonized with this strain in close proximity to susceptible naïve populations (1). Local data over the past 3 y included several reports indicating the low carriage of N. meningitidis among the pilgrims, with a remarkable predominance of N. meningitidis W-135 (Table IV). Azeri et al. reported carriage rates of 8% and 10.4% among a cohort of pilgrims of different nationalities pre- and post-hajj, respectively (14). Of the pre-hajj isolates, 5.3% were W-135, while 44.2% of the post-hajj isolates were W-135. Among the different nationalities, the highest conversion rate was among the Malaysian pilgrims (/51.3%) followed by the Indonesians (/6.4%), with the carrier conversion rate among the Indian, Bangladeshi and Sudanese pilgrims being /16.8%, /13.8% and/8.4%, respectively (i.e. lower rate of colonization post-hajj). Among all nationalities the overall conversion rate was /2.4%. The Malaysian pilgrims also had the highest conversion rate for W-135, with no W-135 isolates in the pre-hajj samples, but 26 samples of serogroup W-135 were isolated in the post-hajj samples from 76 Malaysian pilgrims screened (14). These results concur with Wilder-Smith et al. in their data collected prior to the routine use of ciprofloxacin. It is worth investigating the housing accommodation and also the living habits of the Malaysian pilgrims for possible improvement. Two other local studies by Ashoor (15) and Kholiedi (16), both performed outside the pilgrimage season, showed the carriage rate among locals from Mecca to be higher than that in Medina, the second most holy city for Muslims, and also higher than local inhabitants from the city of Riyadh, where there is no contact with pilgrims, being 1.1%, 0.1% and 0% respectively (Table IV). Furthermore, among the 700 oropharyngeal swabs investigated by Ashoor and his group, 38 samples were positive for Neisseria species other than N. meningitidis. Wilder-Smith also showed a significant difference in the carriage rate among Malaysians returning from Mecca after the Umrah (lesser Hajj), when compared to the Hajj returnees of y 2001(12, 17). This could be explained by the fact that intense interaction among the pilgrims during the Hajj is far greater than during the Umrah, and also greater than in other cities in the Kingdom which pilgrims do not visit, such as the capital, Riyadh. Thus, in reviewing the literature on N. meningitidis W-135 carriage among pilgrims published since y 2000, it is clear that this strain has become the predominant serogroup, ranging from 18% to 100% of all isolated N. meningitidis strains (Table IV). In conclusion, from the low carriage rate reported from several studies, it seems that the quadrivalent vaccine might be playing a role in decreasing or eliminating the carriage of N. meningitidis strains in the nasopharynx. The data available to date are insufficient to comment on the role of the vaccine in promoting colonization with strains other than in the vaccine or non-groupable strains of this organism. Further studies, evaluating the colonization pattern of vaccinated persons at different time frames from receiving the vaccine, are needed. If the quadrivalent vaccine Table IV. Published reports on Neisseria meningitidis carriage rates since y 2000 Total isolates W-135 isolates a Year of study Author (reference) Site Pre-Hajj Post-Hajj Pre-Hajj Post-Hajj 2001 CDC 11 JFK New York airport 0.9% (4/451) 2.6% (23/869) 0% 26% (6/23) 2001 Azeri 14 Mecca 8% (57/715) 10.4% (77/743) 5.3% (3/57) 44.2% (34/77) 2001 Wilder-Smith 12 Singapore 0.5% (1/204) 17% (29/171) 0% 90% (26/29) 2001 Balkhy 13 Jeddah/Mecca 7.4%(14/190) 0.7% (1/137) 35.7% (5/14) 100% (1/1) 2002 Ashoor 15 Riyadh / 0% 0/700 a / / 2002 Kholeidi 16 Mecca / 1.1% (16/1395) / / 2002 Kholeidi 16 Medina / 0.1% (2/1402) / / 2003 Balkhy b Mecca / 3.4% (11/324) / 18% (2/11) a Denominator is meningococcal isolates. b Current study.

5 268 Z. A. Memish et al. Scand J Infect Dis 36 significantly reduces the carriage rate for N. meningitidis, the Saudi Ministry of Health s recommendation for use of ciprofloxacin by local pilgrims at the end of the Hajj may be unnecessary, and may promote increased resistance among the organism. Finally, continued vaccination with the quadrivalent vaccine, for the time being, is to be recommended. REFERENCES 1. Memish ZA, Ahmed Q. Mecca Bound: the challenges ahead. J Trav Med 2002; 9: 202/ Memish ZA, Venkatesh S, Ahmed QA. Travel epidemiology: the Saudi perspective. Int J Antimicrob Agents 2003; 21: 96/ Novelli VM, Lewis RG, Dawood ST. Epidemic group A meningococcal disease in Hajj pilgrims. Lancet 1987; 2: From the Centers for Disease Control and Prevention. Serogroup W-135 meningococcal disease among travellers returning from Saudi Arabia to the United States, JAMA 2000; 283: Serogroup W-135 meningococcal disease among travellers returning from Saudi Arabia to the United States, MMWR Morb Mortal Wkly Rep 2000; 49: 345/6. 6. Memish ZA. Meningococcal disease and travel. Clin Infect Dis 2002; 34: 84/ Memish ZA, Alrajhi AA. Meningococcal disease. Saudi Med J 2002; 23: 259/ Finegold SM, Martin WJ. Diagnostic Microbiology. Vol St. Louis, MO: Mosby, Moore PS, Reeves MW, Schwartz B, Gellin BG, Broome CV. Intercontinental spread of an epidemic group A Neisseria meningitidis strain. Lancet 1989; 2: 260/ Stroffolini T, Angelini L, Galanti I, Occhionero M, Congiu ME, Mastrantonio P. The effect of meningococcal group A and C polysaccharide vaccine on nasopharyngeal carrier state. Microbiologica 1990; 13: 225/ Update: assessment of risk for meningococcal disease associated with the Hajj MMWR Morb Mortal Wkly Rep 2001; 50: 221/ Wilder-Smith A, Barkham TM, Earnest A, Paton NI. Acquisition of W-135 meningococcal carriage in Hajj pilgrims and transmission to household contacts: prospective study. Br Med J 2002; 325: 365/ Balkhy HH, Memish ZA, Osoba AO. Meningococcal carriage among local inhabitants during the pilgrimage 2000/2001. Int J Antimicrob Agents 2003; 21: 107/ Al-Azeri A, Ashoor B, Altuhami H, Al-Rabeah A, Alhamdan N, AlJefri M, Mohammad A, et al. Meningococcal carriage among Hajjis in Makkah, 1421H. Saudi Epidemiology Bulletin 2002; 9: 3 / Ashoor B, Turkistani A. Carriage of meningococcal meningitis among Riyadh population, Saudi Epidemiology Bulletin 2002; 9: Kholeidi A, Turkistani A, Nooh R, Bajeri K. Neisseria meningitidis colonization among residents of Makkah and Medinah before Hajj season, 1422H(2002). Saudi Epidemiology Bulletin 2002; 9: 17/ Wilder-Smith A, Paton NI, Barkham TM, Earnest A. Meningococcal carriage in Umra pilgrims returning from Saudi Arabia. J Travel Med 2003; 10: 147/9. Submitted November 27, 2003; accepted February 23, 2004