Influenza a Common Viral Infection among Hajj Pilgrims: Time for Routine Surveillance and Vaccination

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1 Influenza a Common Viral Infection among Hajj Pilgrims: Time for Routine Surveillance and Vaccination Hanan H. Balkhy, Ziad A. Memish, Saleh Bafaqeer, and Maha A.Almuneef Background: The annual Hajj pilgrimage to Mecca, Saudi Arabia brings over two million people to a small confined area. Respiratory tract infection is the most common disease transmitted during this period. For most of the etiologic agents of upper respiratory tract infections, no vaccine or prophylaxis is available, except for influenza. Yearly influenza vaccination of high-risk groups is recommended, but no special recommendations are available for those performing the Hajj or other similar large congregational activities. Viral surveillance studies are being carried out through more than 100 centers around the world to identify newly emerging viruses. Saudi Arabia is not one of those centers and no routine surveillance takes place. Methods: Five hundred Hajj pilgrims presenting with upper respiratory tract symptoms from different parts of the world were screened by way of a throat swab for viral culture, including influenza A and B, parainfluenza, respiratory syncytial virus (RSV), adenovirus, herpes simplex virus (HSV), and enteroviruses. Information was collected on age, sex, nationality, smoking habits and upper respiratory tract symptoms. Vaccination status for influenza and meningococcus was obtained by self-declaration, since most pilgrims did not have their vaccination cards with them. Only those with symptoms including at least fever, reported by the patient to be 38.3 C, and/or sore throat were included. Pilgrims with any other symptoms, especially myalgia and fatigue alone, were excluded, since many of the physical chores during the pilgrimage may contribute to such symptoms. Results: Fifty-four patients (10.8%) had positive viral throat cultures. Of these, 27 (50%) were influenza B, 13 (24.1%) were HSV, 7 (12.9%) were RSV, 4 (7.4%) were parainfluenza, and 3 (5.6%) were influenza A. No enteroviruses or adenoviruses were detected, and no multiple infections were detected. Only 22 (4.7%) pilgrims received the influenza vaccine. When the results are applied to the total number of pilgrims in 2003, an estimate of 24,000 cases of influenza is obtained. Conclusion: The findings from this study suggest a high incidence of influenza as a cause of upper respiratory tract infection among pilgrims, estimated to be 24,000 cases per Hajj season, excluding those becoming ill from contact with Hajj pilgrims returning home. They also indicate a very low vaccination rate for the influenza vaccine; as well as poor knowledge of its existence. Continued surveillance during the Hajj pilgrimage is necessary. The influenza vaccine should be a priority for those attending the Hajj pilgrimage, and should also be considered for antiviral prophylaxis. Hanan H. Balkhy, MD, and Maha A. Almuneef, MD: Department of Infection Prevention & Control, and Department of Pediatrics, King Abdulaziz Medical City-King Fahad National Guard Hospital, Riyadh; Ziad A. Memish, MD: Department of Infection Prevention & Control, and Department of Internal Medicine, King Abdulaziz Medical City-King Fahad National Guard Hospital, Riyadh; Saleh Bafaqeer, MD: Department of Pediatrics, King Khalid National Guard Hospital, Jeddah, Saudi Arabia. This study was supported by GlaxoSmithkline and Roche. Apart from this, the authors had no financial or other conflicts of interest to disclose. Reprint requests: Ziad A. Memish, MD, CIC, FACP, FRCPC, FIDSA, Chief of Division, Adult Infectious Diseases, Dept. of Medicine, and Executive Director, Infection Prevention and Control, National Guard Health Affairs, King Abdulaziz Medical City-King Fahad National Guard Hospital, PO Box 22490, Riyadh 11426, Saudi Arabia. J Travel Med 2004; 11: Introduction Each year, over two million pilgrims from all over the world gather in Mecca to perform the Hajj pilgrimage. 1 Such congregation is certainly expected to facilitate the transmission of pathogenic organisms, especially viruses that lead to respiratory tract infections. 2 The common cold is one of the most common infections contracted during the Hajj. Other viral infections, such as influenza, may lead to severe disease among pilgrims, since significant numbers are children and old people. 3 The Centers for Disease Control (CDC) recommends yearly vaccination for influenza for high-risk groups, and more than 100 countries function as National Influenza Centers (NICs), where continuous surveillance activity takes place; Saudi Arabia is not one of them. 4 Unfortunately, no local efforts are made to monitor influenza activity among pilgrims,mainly due to the high cost of establishing a viral 82

2 Balkhy et al., Influenza a Common Viral Infection among Hajj Pilgrims 83 facility and recruiting trained personnel. In this study, we screened patients presenting to the National Guard hospital clinic in Mina with upper respiratory tract infection symptoms. They were tested for the most common respiratory viruses, so as to better understand the pattern of viruses circulating among pilgrims. Methods Table 1 Demographic Data on Hajj Pilgrims, 2003 Sex Age group (years) Nationality Smokers a p-value.01. Result of Culture Total Number of Characteristics Positive % Negative % Pilgrims Cultured % Male Female Saudi Sudanees Egyptian a Pakistani Syrian Bangladeshi Others Yes No Medical Services Provided by the National Guard Health Affairs During each Hajj pilgrimage season, the National Guard Health Affairs provides free medical care to all pilgrims at three main sites: Mina, Muzdalifa, and Arafat. During Hajj 2003, the year of our study, an average of 10,000 patients presented to our clinics as walk-in patients between days 9 and 15 of the holy month of Dul-Hijjah. Since pilgrims spend most of their time in Mina, more than 90% of the pilgrims present to our outpatient clinics and hospital in Mina and less than 10% present to our clinics in Muzdalifa and Arafat. The peak time for Hajj pilgrims to present to the clinics was day 11 to day 15. Patient Selection Any pilgrim or worker is allowed to present to our clinics for medical care.separate male and female triage areas were available to assess the patients upon presentation. They were then directed to the appropriate clinic.all physicians were instructed to direct patients with upper respiratory tract infection (URTI) to two physicians carrying out the study. This was to ensure that adequate sampling would take place. Upper respiratory tract symptoms included: sore throat, fever, cough, headache, runny nose, sneezing,and myalgia.all patients included in the study had a history of fever 38.3 C orally or a sore throat. A questionnaire was filled out by the physicians, including basic demographics (Table 1). A throat swab was collected using a wooden cotton-tip applicator by swabbing both tonsils, avoiding the tongue. Specimens were placed in viral transport media and kept at 4 C until they were transported to the laboratory. Samples were transported to the virology laboratory at King Abdulaziz University Hospital (KAUH) in Jeddah within 12 h of collection and stored at 83 C until they were tested. Viral Studies All samples were processed within 1 month of collection. Five hundred nonrepeat samples from 500 patients were included in the study. Samples were inoculated onto MDCK, A549 and LL19Ks cell lines using conventional methodology. 5 They were observed for 10 days for cytopathic effects. Cells showing cytopathic effects were screened by immunofluorescence for influenza A, influenza B, parainfluenza 1, 2 and 3, RSV, HSV, enteroviruses, and adenoviruses.

3 84 Journal of Travel Medicine, Volume 11, Number 2 Figure Number of cases distributed by result of viral culture. Results In total,5,004 patients presented to the National Guard Mina hospital outpatient clinic, on days 10 and 11 of the pilgrimage. Of these, 2,032 patients were triaged as having URTI symptoms during all 5 days. Patients presenting with URTI symptoms on days 10, 11 and 12 of the Hajj pilgrimage were referred to be swabbed. Owing to the high flow of patients and the quick turnaround time, only 500 patients were screened and had the questionnaire data completed. All 500 samples and questionnaires were included in this study. In total, 54 (10.8%) samples were positive and 446 were negative for viruses. Over half of the patients (52.8%) were male, and 47.2% were female. Only 25 patients were below 10 years of age, and the majority were 20 to 40 years old (Table 1). Of the 54 positive samples, 27 (50%) were influenza B, 3 (5.6%) were influenza A, 4 (7.4%) were parainfluenza, 7 (13.0%) were RSV, and 13 (24.1%) were HSV (fig.). Of the patients with positive cultures, only four had received the influenza vaccine that season, and, of those, one was positive for influenza A. Of the whole population studied, only 22 (4.4%) pilgrims received the influenza vaccine that year, and 17 pilgrims did not know whether or not they had received the vaccine. Of the culture-positive pilgrims, 9.3% were smokers, while 11.9% of culture-negative pilgrims smoked. Most of the culture-positive cases were found among the Saudi Arabian pilgrims, followed by Egyptian pilgrims. Among the different age groups, the most positive yield was from the 20- to 40-year-old age group.among the 25 children under 10 years of age, five (20%) infections were detected: one influenza A infection, one parainfluenza infection, and three HSV infections. Among the 78 pilgrims over 50 years of age, six (7.7%) were culture positive; one influenza B, two RSV and three HSV. Of the three influenza A patients, one was a 25-year-old from Sudan without fever but with sore throat and cough, one was a 47-year-old Egyptian female with fever and sore throat, and one was a 3-year-old Saudi child with fever and sore throat. None of the samples was positive for enteroviruses or adenoviruses. Table 2 Presenting Symptoms in Culture-positive and Culture-negative Pilgrims Culture Positive Culture Negative (54) (446) Symptoms No. % No. % Fever Throat pain Fever and throat pain Cough Sputum Chest pain Headache Sneezing Runny nose Myalgia Arthralgia p-value insignificant for all variables.

4 Balkhy et al., Influenza a Common Viral Infection among Hajj Pilgrims 85 Symptom Analysis Of the culture-positive pilgrims, 18 (33.3%) were febrile,43 (79.6%) had a sore throat,and 33 (61.1%) had a cough (Table 2). Statistical Analysis Data were analyzed with Epi Info statistics software, version 6.04 (CDC, Atlanta, GA). Univariate analysis was done, and statistical significance (p.05) was determined by a Fischer exact test or Student t-test, as appropriate. None of the symptoms was statistically significant among the culture-positive group. When we compared the presence of symptoms between the culture-positive and culture-negative groups, again none was statistically significant. Among the demographics collected, the presence of a positive culture among Egyptians was statistically significant when compared to other nationalities. Discussion Since more than two million people gather in a confined area for the Hajj pilgrimage in Mecca on a yearly basis, we wanted to identify the importance of the influenza virus as a cause of illness among the pilgrims of the Hajj and provide a crude estimate of influenza vaccine utilization. Of the 54 viruses isolated from 500 symptomatic pilgrims, 27 (50%) were influenza B and 3 (5.5%) were influenza A. Only one pilgrim had received the influenza vaccine. Our general impression when interviewing the pilgrims was major ignorance of the vaccine, whereas almost all were aware of the meningococcal vaccine that they had received. When we simply applied these percentages to the total two million pilgrims, we estimated that at least 400,000 pilgrims would develop URTI symptoms and 24,000 would develop influenza. In a study published in 1998, pilgrims with URTI symptoms from two consecutive Hajj seasons were tested for a variety of pathogens. 6 Viruses were present in 148 samples, with influenza A and adenovirus being the most common. In our study, only three were influenza A, and no adenovirus was isolated. Given that viral culture is relatively insensitive for detecting both enterovirus and adenovirus, and since our samples were stored for some time at 80 C, we believe that we are presenting an underestimate of the role of influenza and other viruses in causing URTI in the Hajj.In another study by Qureshi et al.,54% of 2,070 Pakistani pilgrims received the influenza vaccine prior to the Hajj pilgrimage. 7 They were compared with those who were not vaccinated with regard to vaccinepreventable symptoms. The authors concluded that those who were vaccinated had fewer symptoms than those who were not. Unfortunately, the study did not include any virologic data. Periodically, novel influenza viruses emerge and spread rapidly through susceptible populations, resulting in worldwide epidemics or pandemics, with the Spanish flu pandemic of 1918 being the most famous. 8 It is reasonable to assume that future influenza pandemics will occur, given historical evidence and current understanding of the influenza virus. 9,10 Because it is impossible to predict when the next pandemic will occur, contingency plans must be put in place now, during the inter-pandemic period. These plans must be flexible enough to respond to different levels of disease In 1993, the GrIPPE working group in the United States of America was founded with the aim of preparing for an upcoming influenza pandemic, and identified surveillance as a key activity. 15 Financial limitations and shortage of personnel were identified as obstacles to this. 16 We believe that these obstacles are the reasons why so little surveillance is done for viral diseases in large gatherings of people in general,and in pilgrims to Saudi Arabia in particular. In addition, a surveillance study that is not capable of studying the antigenic properties of the influenza virus and linking that information to the yearly manufactured vaccine will be of limited value. The WHO Influenza Program has 112 NICs (Saudi Arabia is not one of them), and four worldwide collaborating centers that are responsible for identifying the antigen and genetic make-up of newly isolated influenza virus from NICs. 17 Such information allows for close monitoring of antigenic changes in the circulating influenza virus, which are taken into consideration when designing the yearly influenza vaccine. The first cases of severe acute respiratory syndrome (SARS) caused by the new virus arising from China were reported less than 2 months after the Hajj pilgrimage had ended. There were no links found between the SARS cases and the returning pilgrims. 18,19 The fear, however, is that as we are approaching the yearly smaller pilgrimage known as the Umrah, which starts every year at the end of Ramadan (October 2004), people from around the world will again soon start to travel to Mecca and Medina. For the time being, not many medical preventative measures can be taken to prevent the spread of SARS,but strict infection control and quarantine measures need to continue, especially in countries where active disease transmission has been documented 20 (see also Memish et al,this issue). We still need to continue to emphasize the importance of annual vaccination with the current influenza vaccine.it may need to become a mandatory vaccine for all pilgrims, such as was done for the meningococcal vaccine. 1 The less invasive but pathogenic influenza strains H 5 N 1 and H 7 N 7 have emerged and represent a cause for concern for other influenza outbreaks. 21,22 Antiviral agents have not been widely used for either prophylaxis or treatment of annual influenza epidemics. 23

5 86 Journal of Travel Medicine, Volume 11, Number 2 However, new antiviral agents are effective against both influenza A and B, and are likely to be active against a new pandemic variant. Until definite therapeutic agents or vaccines are developed, pilgrims need to be advised about modes of disease transmission and the importance of hand hygiene in curtailing disease transmission. 1 It would also not be unreasonable to have pilgrims wear masks when in crowded areas while performing the Hajj rituals. In addition, local and global health organizations should make vaccination against influenza a prerequisite for performing the pilgrimage, and serious consideration should be given to prophylaxis with one of the neuraminidase inhibitors. In conclusion, it is recommended that all pilgrims be made aware of the potential of contracting influenza during their Hajj journey and be appropriately vaccinated, and that rapid testing for influenza be made available at the Hajj premises. Finally, it is recommended that routine surveillance take place in order to confirm suspected outbreaks, so as to assist health care personnel in utilizing antiviral agents when appropriate in order to prevent a possible wider outbreak or a pandemic. Acknowledgment We would like to acknowledge Dr Faten Gazzaz, Head of the Virology Laboratory at King Abdulaziz University Hospital in Jeddah, for her assistance in conducting the virologic testing. References 1. Memish ZA, Ahmed Q. Mecca bound: the challenges ahead. J Travel Med 2002; 9: Musher DM. How contagious are common respiratory tract infections? N Engl J Med 2003; 348: Voordouw BC, van der Linden PD, Simonian S, et al. Influenza vaccination in community-dwelling elderly: impact on mortality and influenza-associated morbidity. Arch Intern Med 2003; 163: Bridges CB, Harper SA, Fukuda K, et al. Prevention and control of influenza. Recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep 2003; 52:1 34; quiz CE1 CE4. 5. Reina JF-BV, Blanco I, Munar M. Comparison of Madin Darby canine kidney cells (MDCK) with a Green Monkey continuous cell line (VERO) and human lung embryonated cells (MRC-5) in the isolation of influenza A virus from nasopharyngeal aspirates by shell vial culture. J Clin Microbiol 1997; 35: El-Sheikh SM, El-Assouli SM, Mohammed KA, Albar M. Bacteria and viruses that cause respiratory tract infections during the pilgrimage (Haj) season in Makkah, Saudi Arabia. Trop Med Int Health 1998; 3: Qureshi H, Gessner BD, Leboulleux D, et al. The incidence of vaccine preventable influenza-like illness and medication use among Pakistani pilgrims to the Haj in Saudi Arabia. Vaccine 2000; 18: Potter CW. Chronicle of influenza pandemics. In: Nicholson KG, Webster RG, Hay AJ, eds. Textbook of influenza. Oxford: Blackwell Science, 1998:3. 9. Subbarao K, Katz J. Avian influenza viruses infecting humans. Cell Mol Life Sci 2000; 57: Dalton R. Feathers fly in Beijing. Nature 2000; 405: Fock R, Bergmann H, Bussmann H, et al. Influenza pandemic: preparedness planning in Germany. Eur Surveill 2002; 7: Desenclos JC, Manigat R. The European Union faces up to the threat of a pandemic:meeting at the DGV on the influenza A (H5N1) of the ad hoc group on communicable diseases Luxembourg 14 January Eur Surveill 1998; 3: Brotherton JM, Delpech VC, Gilbert GL, et al. A large outbreak of influenza A and B on a cruise ship causing widespread morbidity. Epidemiol Infect 2003; 130: Uyeki TM, Zane SB, Bodnar UR, et al. Large summertime influenza A outbreak among tourists in Alaska and the Yukon Territory. Clin Infect Dis 2003; 36: Gensheimer KF, Fukuda K, Brammer L, et al. Preparing for pandemic influenza: the need for enhanced surveillance. Emerg Infect Dis 1999; 5: Gensheimer KF, Fukuda K, Brammer L, et al. Preparing for pandemic influenza: the need for enhanced surveillance. Vaccine 2002; 20(suppl 2):S63 S WHO Global Influenza Programme. Survey on capacities of national influenza centres, January June Wkly Epidemiol Rec 2002; 77: Shortridge KF, Peiris JS, Guan Y. The next influenza pandemic: lessons from Hong Kong. J Appl Microbiol 2003; 94(suppl 1): Shortridge KF. SARS exposed, pandemic influenza lurks. Lancet 2003; 361: Dye C, Gay N. Modeling the SARS epidemic. Science 2003; 300: Update: influenza activity United States and worldwide, season, and composition of the influenza vaccine. MMWR 2003; 52: Quirk M. Avian influenza outbreak linked to eye infections. Lancet Infect Dis 2003; 3: Oxford JS, Bossuyt S, Balasingam S, et al. Treatment of epidemic and pandemic influenza with neuraminidase and M2 proton channel inhibitors. Clin Microbiol Infect 2003; 9:1 14.