Figure 1

Figure 1. Meningococcal disease in Kingdom of Saudi Arabia, by month, 1995–2000. Cases of meningococcal disease with dates converted from Islamic calendar months. The period of the Hajj pilgrimage for each year is...

From 1995 through 1999, the median annual number of meningococcal disease cases in Saudi Arabia (population 20 million) was 42 (range 20–107) with a resulting national annual meningococcal disease incidence of 0.2 cases/100,000 population (Figure 1). From 1995 to 1998, a median of 10 cases (range 4–20) occurred within 1 month of the Hajj. Most cases were serogroup A or W-135 disease; however, in 1998 a cluster of 20 cases of serogroup B meningococcal disease was identified. In 1997, a total of 72 cases of meningococcal disease, predominantly serogroup A, were reported in association with Umrah before the Hajj.

Serogroup W-135 has been present to a notable degree in Saudi Arabia at least since 1990. During 1995 through 1999, serogroup W-135 disease accounted for 13% of all meningococcal disease in Saudi Arabia (Figure 1). Saudi serogroup-specific surveillance data for 1990 through 1994 are available only by Islamic calendar year and not by month; during this time, serogroup W-135 accounted for 1.5% to 54% of annual meningococcal disease with the peak (24 cases) occurring in 1990–1991.

Figure 2

Figure 2. Meningococcal disease during the 2000 Hajj: Jeddah, Mecca, and Medina, January 24–June 5, 2000. 
The number of cases of serogroup-specific meningococcal disease is shown by date. The duration of the 2000...

In the year 2000, retrospective review identified 264 suspected cases of meningococcal disease in Mecca, Medina, or Jeddah. Of these, 253 (96%) were laboratory confirmed with 179 (71%) positive by CSF or blood culture and 74 (29%) negative by culture but positive by CSF latex agglutination. Seventy patients died, for a case-fatality rate of 28%. Cases increased during the month preceding the Hajj (Figure 2), peaking just after the Hajj ended; the last case was identified on June 5. The median age of patients with confirmed meningococcal disease was 40 years; most were male (Table 1). Overall, 56% of patients were Hajj travelers. Persons identified as Hajj travelers were older (median age 50 years vs. 5 years, p<0.001), more likely to be male (OR=1.9, p=0.02), and more likely to have a chronic illness (OR=7.8, p<0.001) than residents.

A serogroup was identified for 161 (64%) of the 253 confirmed cases. Ninety-three cases (37% of all confirmed cases) were attributed to serogroup W-135 and 60 (24%) to serogroup A. Both serogroup A isolates from the 2000 outbreak were confirmed as subgroup III (ET-734, ST-5 with PFGE patterns characteristic for the “first pandemic wave” (14); serogroup W-135 isolates from the 2000 outbreak belonged to the ET-37 complex, as defined by MLEE, and were designated as the (W)ET-37 clone (29). Serogroup W-135 case-patients had a median date of admission 2 weeks later than for serogroup A patients (p<0.001) (Table 1). The diagnosis for most serogroup A patients was made in Mecca; serogroup W-135 cases were diagnosed in patients in both Mecca and Medina. Rates of meningococcal vaccination did not differ between serogroup W-135 and serogroup A case-patients (67% vs. 59%, respectively; p=0.35); however, among Hajj travelers, patients with serogroup W-135 were more likely to have received meningococcal vaccine than were those with serogroup A disease (93% vs. 77%, p=0.05). The calculated attack rates of serogroup W-135 and serogroup A disease were 8.9 and 5.8 cases/100,000, respectively. During the month when the outbreak peaked, weekly serogroup W-135 attack rates remained <1 case/100,000 persons. Multivariable modeling for risk factors for serogroup W-135 disease showed that, after age was controlled for, patients with cases diagnosed in Medina were at increased risk for serogroup W-135 compared with all other cases with known serogroups (OR=6, 95% confidence intervals [CI] 2.2 to 15.5, p<0.01). While no regional group was at increased risk for serogroup W-135 compared with serogroup A disease, serogroup A disease was more likely to occur in travelers arriving from Southwest Asia than serogroup W-135 disease (OR=2.6, 95% CI 1.1 to 5.6, p=0.02);

We also evaluated clinical characteristics of identified case-patients and found that approximately half were first seen by a clinician <1 day after symptom onset; at that time, 62% of case-patients were semicomatose, comatose, or dead. Only 9% of case-patients had sepsis without evidence of meningitis. Patients with serogroup W-135 compared with those with serogroup A were more likely not to have meningitis (OR 3.6, p=0.02) and to be admitted to intensive care (Table 2). Case-fatality rates did not differ by serogroup; patients with chronic illness had a higher case-fatality rate (50% vs. 19%, p=0.0003). For residents and Hajj travelers with serogroup W-135 disease, case-fatality rates were 12% and 46%, respectively (p<0.001). In a multivariate model controlling for age, factors associated with increased risk for fatal disease were the following: admission to intensive care (OR 15, 95% CI 5 to 45), chronic illness (OR 3, 95% CI 1 to 8), and being seen by a clinician <1 day of symptoms (OR 2.5, 95% CI 1 to 6); cases diagnosed in Medina were less likely to be fatal (OR=0.2, 95% CI 0.05 to 0.5). In this multivariate model, serogroup was not found to be a significant risk factor for fatal disease. A separate multivariate model for risk factors for severe illness, after age was controlled for, identified serogroup W-135 disease compared with all other cases of known serogroup (OR=2.0, 95% CI 1.2 to 5.2) and being seen by a clinician after <1 day of symptoms (OR=2.4, 95% CI 1.2 to 5.1) as associated with increased risk. In this model, persons with a history of chronic illness were at increased risk for severe illness, although this association did not reach statistical significance (OR 2.4, p=0.09).

The meningococcal outbreak during the 2000 Hajj was unusual because it consisted of two concurrent outbreaks, one caused by serogroup A and one caused by serogroup W-135. Both outbreaks were detected because the surveillance for meningococcal disease in Saudi Arabia, particularly during the Hajj, is extensive. In the African meningitis belt, serogroups are commonly identified on the basis of analysis of isolates early in the outbreak with little subsequent serogroup evaluation. If this practice had occurred during the 2000 Hajj outbreak, it would likely have been misidentified as an outbreak of solely serogroup A disease; the serogroup W-135 component would have been missed. Longitudinal serogroup-specific surveillance is especially essential for outbreak control with serogroup-specific vaccines.

Although isolates from Saudi Arabia before the 2000 outbreak were not available for analysis, other studies have found that the (W)ET-37 clone caused disease decades before the 2000 outbreak (29). Since serogroup W-135 disease appears to have been endemic in Saudi Arabia for at least the last decade, the (W)ET-37 outbreak strain was likely present in Saudi Arabia before the 2000 Hajj, and this outbreak was probably not due to introduction of a new clone. The (W)ET-37 clone probably not only caused invasive disease but also circulated in the population through nasopharyngeal carriage. In 2001, one study found rare serogroup W-135 carriage in returning pilgrims (31); another study found higher rates of carriage (32). However, the absence of carriage data from Saudi Arabia from 2000 or preceding years makes drawing conclusions about the complicated relationship between carriage and epidemic meningococcal disease in this setting difficult.

Despite previous circulation of the (W)ET-37 outbreak strain, the outbreak described here was the first large W-135 outbreak reported worldwide (33); the attack rate was 9 cases/100,000 population. Although the 2000 serogroup W-135 outbreak was larger than the 2000 serogroup A outbreak, this comparison must be put into the context of other outbreaks. During the 1987 Hajj, 1,841 laboratory-confirmed cases of serogroup A disease (16) were identified in Saudi Arabia among approximately 1.5 million Hajj attendees (34), for an incidence of 120/100,000. The N. meningitidis serogroup A isolates from the 2000 and 1987 Hajj outbreaks are members of the same serogroup A subgroup III, and yet the magnitude of the 2000 outbreak was less than one tenth that of the 1987 outbreak. The requirement for meningococcal vaccination was enacted in Saudi Arabia only after the 1987 Hajj. We found vaccination coverage in the 2000 outbreak case-patients in Saudi Arabia (59% to 67%) similar to coverage reported previously in Mecca residents (16); substantial blunting of serogroup A outbreaks elsewhere has been associated with similar levels of vaccination coverage (5,18). This finding suggests that the potential impact of the serogroup A outbreak during the 2000 Hajj may have also been markedly blunted by vaccination. However, since most vaccination for the Hajj is performed with bivalent, not quadrivalent, vaccine, vaccination coverage for serogroup W-135 during the 2000 Hajj was probably low (35). Therefore, the 2000 outbreak could be interpreted as representing the full outbreak potential of the (W)ET-37 clone within the context of the Hajj—much as the 1987 outbreak represented the unblunted impact of serogroup A subgroup III. Given that the 2000 serogroup W-135 outbreak was very small in comparison to the 1987 serogroup A outbreak, and weekly attack rates associated with the 2000 Hajj outbreak were substantially below the thresholds used to identify meningococcal outbreaks in Africa (19), within the context of the Hajj, the (W)ET-37 clone would appear to be less likely to cause outbreaks with incidence as high as those associated with serogroup A subgroup III. Clearly, this hypothesis is difficult to prove, since a constellation of host, environmental, and pathogen-specific factors in Mecca during the 2000 Hajj likely contributed to propagation of the outbreak strain; we were unable to identify the specific causative factors for this outbreak. A more recent (W)ET-37 outbreak in Burkina Faso, which had epidemiologic features typical of a serogroup A epidemic, may also have been caused by one or more of these factors (36).

Since 1987, a core component for preventing meningococcal disease during the Hajj has been mandatory vaccination of pilgrims and Saudi residents. In 2000, most vaccinated pilgrims received the bivalent vaccine. Given the large number of 2000 Hajj pilgrims and the estimated 85% to 95% vaccine efficacy against serogroup A disease (37,38) (and based on the assumption that reported Hajj pilgrim vaccinations are accurate), the 35 persons who reported having serogroup A disease despite having recently received meningococcal vaccine would be expected vaccine failures. Vaccine failure may have also led to the single primary case of serogroup W-135 disease (39) that occurred among the 11,000 Hajj pilgrims returning to the United States, where quadrivalent vaccine is used. In contrast, 10 primary cases of serogroup W-135 disease were reported among the 10,300 pilgrims returning to the United Kingdom, where bivalent vaccine is used (p=0.01) (20). Since no modifiable risk factors for disease have been identified for the 2000 serogroup W-135 outbreak, quadrivalent vaccine should be used to reduce the risk for serogroup W-135 disease. Given the high overall case-fatality rate of 28% for the 2000 Hajj outbreaks and our finding that chronic illness was a risk factor for severe illness and death, use of quadrivalent vaccine for older and chronically ill pilgrims is a priority. Strategies should also target this population for frequent evaluations for symptoms of disease.

Since 2002, Saudi Arabia has required quadrivalent vaccine for all pilgrims participating in the Hajj (40). However, the higher cost of this vaccine, as well as inadequate global vaccine supply, makes implementing this strategy difficult. If the (W)ET-37 clone continues to cause outbreaks in sub-Saharan Africa, as it did in Burkina Faso in 2002 (36), quadrivalent vaccine would be urgently needed for outbreak management. While empiric use of quadrivalent vaccine for outbreak response in Africa is not warranted at this time, heightened surveillance for serogroup W-135 disease, particularly in the Eastern Mediterranean region and the African meningitis belt, will be essential in designing and assessing future control and prevention strategies for this emergent epidemic disease.