During the 9-year surveillance period, 4,896 confirmed cases were noted. Of these, nine cases could not be used because of recording errors (Table 1). The dataset was made up of 250 different meningococcal serosubtypes, of which 42 were seen in 20 or more cases (4,189/4,887 = 86% of all strains), while 99 serosubtypes were only connected to one case (Table A1).

The observed background value of cases in temporal and spatial proximity to an index case being of the same serosubtype is 12.0%. When random labeling was used, this percentage was 9.7%. We observed that 15.1% of the first nearest-neighbors were of the same serosubtype, an excess probability or secondary case percentage of 3.1% (CI 2.1%–4.1%). As most nearest-neighbors are coincidental, little difference was seen in the mean temporal and spatial distance between nearest-neighbors of the same serosubtype (6.1 km [range 0–44 km] and 13.2 days [range 0–63 days]) and those of different serosubtype (7.6 km [range 0–49 km] and 14.3 days [range 0–380 days]). The probability of the second, third, fourth, and fifth nearest-neighbors being of the same serosubtype did not differ significantly from background values (this difference was 0.6%, 0.3%, 0.8%, and 0.4%, respectively). For serogroup B, the excess probability was 3.1% (CI 2.0%–4.3%, n = 4,035) for the first nearest-neighbor. For serogroup C, the excess probability was 3.5% (CI 1.6%–5.3%; n = 728), and for serogroup W135 no excess probability was found (n = 59). Seven different serosubtypes, accounting for 14% (694/4,887) of all cases, showed significant excess probability (Table 2): B:1:P1.4 (12%), B:1:P1.16 (10%), B:4:P1.5 (20%), B:4:P1.10 (5%), B:nt:P1.nt (11%), B:15:P1.7 (11%), and B:15:P1.7,16 (7%).

The Municipal Public Health Services identified 40 field clusters involving 21 different serosubtypes: 11 primary school clusters (range 2–5 cases), 7 daycare center clusters (2–3 cases), 1 swimming pool cluster (4 cases), and 21 household clusters (2–3 cases). The cases all occurred within 21 days from the first case, and 78% (32/41) occurred within 8 days.

Six serosubtypes were identified by both methods as serosubtypes with clustering, 15 were identified only in field clusters, and 1 in statistical clustering only. Most field clusters consisted of only two cases (75%); this result is consistent with the results of our statistical approach.

Our results suggest that in the context of current public health efforts, clustering of meningococcal disease is rare in the Netherlands and other Western countries. Our nearest-neighbor analysis provided a useful method of assessing the phenomenon of meningococcal clustering by taking random variance into account. Cases of the same serosubtype appeared beyond the expected background rate and were only seen in the first nearest-neighbor, which implies that only secondary cases occur in excess of chance (3.1%). Connections of more than two cases could not be demonstrated beyond chance. Throughout the year, invasive disease appears mostly as isolated cases. This limited clustering may reflect the positive effect of the prophylactic rifampicin policy; however, household field clusters are still reported, which possibly shows the constraints of this prevention policy. This paucity of real secondary cases is consistent with findings from other studies. A Belgian study found 4.4% secondary cases (range 2.0%–5.2%) in 1,913 cases of invasive meningococcal disease from 1971 through 1976 (7). In France, 37 (4.5%) co-primary and secondary cases were found in 814 reported cases from 1997 to 1988 (8). A Dutch study reported 1.4% co-primary and secondary cases among 507 cases from 1989 to 1990 (9). In England and Wales, 17 (0.5%) secondary cases were found among 3,256 cases from 1984 through 1987 (10). In a Danish study published in 2000, 1.2% secondary cases were observed in 172 cases of meningococcal disease (11).

Apart from proper prophylactic treatment, no additional measures could prevent further cases, since excess clustering only occurs in the first nearest-neighbors, while a cluster is only identified after at least two connected cases. The field cluster analysis confirms this assessment, since most new cases occur within a short period (78% within 8 days), occur geographically close to each other (patients are in the same household, daycare center, or primary school), and occur mostly in pairs (75%). These findings are consistent with observations in field cluster studies showing that secondary invasive disease most likely occurs nearby, within the next few days. In a Belgian study, 83% of 63 secondary cases occurred within 8 days of identifying the index case (7); in a French study, 31 (82%) of 38 secondary cases occurred within 8 days (8). Almost all (94%, 29/31) of the secondary cases occurred within 8 days in a study in the United States from 1980 to 1993 with eight school and university clusters (12). Five secondary cases occurred within 8 days in a school outbreak of six cases with serogroup B meningococcal disease in the United States (13).

Space-time clustering methods, e.g., those using the spatial scan-statistic (14–17), have been used for surveillance purposes with the objective of identifying outbreaks. However, to our knowledge, such methods have not been used to explore the existence of, and quantify, the phenomenon of clustering in a specific infectious disease. For this purpose the Ederer-Myers-Mantel procedure has been used (18,19); however, since this method requires separating space and time (e.g., into provinces and years), we considered it inappropriate for our purposes. Instead, we adapted the concept of nearest-neighborship to the two dimensions of space and time simultaneously (5,6).

Our study has several constraints. As many serosubtypes were rare, their individual clustering behavior could not be fully ascertained. We used place of residence as our geographic parameter, which could underestimate clustering, since transmission might occur at locations outside place of residence (such as work, school, and sport clubs). Most cases are found in children, who often spend time in daycare centers, schools, and other places outside the home. Since these places tend to be located in the same area as their homes, this factor likely did not affect our results. The extent of clustering was possibly overestimated because of imprecise geographic coordinates since our statistical method used the center of the municipality or postal code area, but no more precise alternative is available. Since only phenotypic strain typing was conducted (serogroup, serotype, and subtype) and not the more sensitive porA-genotyping method that would have identified spurious clusters, background rates of clustering may have been overestimated. However, this method is unlikely to have affected the excess probability (3.1%) of clustering, since this rate is probably a result of direct transmission. Our method for calculating background value was chosen to be as realistic as possible; however, our results do not appear to be sensitive to the choice of 6th to 10th nearest-neighbors as a reference. For instance, results from 3rd to 10th nearest-neighbor or 7th to 10th nearest-neighbor, as a reference, were virtually identical.

We believe that our low observed incidence of secondary cases partly reflects the general inability to link cases connected by chains of transmission. As disease develops in only a few of the links in a chain of transmission, connected cases are unlikely to be still temporally and spatially close, which obviates detection. Not surprisingly, we found three times as many serosubtypes among reported field clusters (21 serosubtypes) than assessed with nearest-neighborship analysis (7 serosubtypes), which confirms that field clusters may be spurious. Although field clusters have low specificity, their sensitivity is presumably high. Genotyping can identify those clusters brought about by direct transmission; nevertheless, the value of cluster surveillance as a means of prevention is uncertain. Apparent clusters are not valuable to guide additional intervention efforts, since these would prevent few additional cases. Our method of space-time nearest-neighborship analysis provides a sensitive novel approach to the epidemiology of meningococcal disease and possibly even other infectious diseases.