Considerazioni generali

- Non è possibile definire un valore della colonizzazione alla luce del rischio di patologia invasiva da Nm

- Ruolo di N.lactamica ( altre N.spp) cross-reagenti nel fornire stimolo alla produzione anticorpale

- Stagionalità ???

- Omotipia tra ceppi isolati e ceppi produttori di malattia

- Ruolo di Mycoplasma pn. ? alterazione dell’epitelio e conseguente penetrazione di Nm ? ruolo del fumo ambientale ?

- Il maggior rischio è a carico dei soggetti non portatori

- Immunità di breve durata (sia naturale che indotta)

- Ruolo delle comunità chiuse

Nm carriage vs. disease

Analisi della letteratura

[D.A.A. Ala’Allden, K. R. Neal. 2000. Dynamics of meningococcal long-term carriage among university students and their implications for mass vaccination. J. Clin. Microb. 38: 2311-2316.]

[2] [Gold R., Goldschneider I., Lepow M.L. 1978. Carriage of Neisseria meningitidis and Neisseria lactamica in infants and children. J. Infect. Dis. 137:112-121. ]

- Currently, meningococcal disease is endemic in many parts of the world, with relatively large-scale outbreaks occuring in many countries. It is interesting that the highest attack rates of invasive meningococcal disease in the United Kingdom are in the first year of life (50/10*5) and among teenagers (5/10*5), whereas the highest carriage rate

(5 to 15%) is found among teenagers and young adults.

- 13 serogroups of N.meningitidis have been identified.

- It is now increasingly clear that capsular expression is phase variable, and loss of capsule is believed to enhance the organism’s ability to colonize the nasopharynx.

- University students are considered to be a population at increased risk of invasive meningococcal disease. They originate from various parts of the country and abroad, and carriage strains isolated on the first day(s) of the academic year constitute a representative sample of the prevalent strains in the country.

- 2453 students were screened over 4 consecutive days. The carriage rate rose rapidly in the first week of the term. By November, the carriage rate was 31.0% and in December it had reached 34.2%, in March, the rate was 28.0%.

- 30.5% of the isolates belonged to the more virulent serogroups B and C; 25.6% belonged to the apparently less virulent serogroups 29E, H, W135, X, Y and Z; and up to 43.9% of isolates were NG.

- One hundred twenty-four (55.9%) index carriers apparently cleared the organism by the end of the autumn. Twenty-five of these were re-examined in March, and four (19%) were found to be recolonized, indicating that the individual remain susceptible to subsequent meningococcal carriage despite eradication following an episode of colonization. In all, 68 index carriers were rescreened at 6 months and 28 (41.2%) were still carriers.

- Of the students who entered the university as noncarriers, 344 were re-examined in autumn and spring; 268 (77.9%) persisted as noncarriers in autumn; 76 (22.1%) became colonized in autumn, and another 47 (13.7%) became colonized by March. Two hundred twenty-one (64.2%) were apparently persistent noncarriers.

- Almost a third of the autumn-round isolates expressed the same capsular serogroup as their paired index isolates, but only six of these expressed matching serotypes and subtypes antigens. The rest either expressed different type and subtype epitopes or were NT and NST. Thus, based on serological markers alone, only six pairs of the sequential isolates can be considered highly likely to be the same.

- In total, 904 meningococcal isolates were obtained; almost a third belonged to the more virulent serogroups B and C, and up to 43.9% were NG.

- Group C stains are more likely to switch off their capsular expression than group B ones. This may be due to greater pressure on serogroup C strains, generated by their more immunogenic capsule, compared with serogroup B.

- Conventional capsular polysaccharide vaccines against serogroup C appear to have little impact on nasopharyngeal carriage of the organism.

- From the serological markers alone, it appears that virtually all of the phenotypically distinct strains, which were found in October, continued to be represented, although to varying ratios, throughout the academic year. The proportion of the individual capsular groups, types and subtypes fluctuated only marginally during the course of the academic year.

- Some strains (clones) are capable of displacing others in the carried meningococcal population.

- Nasopharyngeal carriage of N. meningitidis or N. lactamica will not necessarily protect against invasion even by the same meningococcal strain.

- It has been suggested elsewhere that individuals acquiring new strains are at greater risk of invasive meningococcal disease and that carriage of Neisseria spp. Protects against disease. [2]

[R. Townsend, L. Goodwin, T. Stevanin.2002. Invasion by Neisseria Meningitidis varies widely between clones and among nasopharyngeal mucosae derived from adult human hosts. Microbiology 148:1467-1474].

- During non-epidemic periods, the baseline prevalence of nasopharyngeal carriage of meningococci is 5-10% but it is considerably higher in certain population such as military personnel, and in households of cases of smokers.

- The precise site within the nasopharynx that N. meningitidis colonizes and invades is not known, but during natural carriage, the organism can be isolated both from the nose and from the throat, and can be observed by immunofluorescense deep within tonsillar tissue.

- It is possible that N. lactamica displaces N. meningitidis from the nasopharynx in childhood and produces natural immunity against invasive menigococcal disease as a consequence of immunogenic epitopes shared between N. lactamica and N. meningitidis.

- Meningococci attach selectively to non-ciliated columnar cells, and during this process microvilli of non-ciliated cells elongate and surround the organism. Meningococci appear to undergo parasite-directed endocytosis and are observed in subephitelial tissues adjacent to lymphoid tissue after prolonged incubation, though this is observed in a minority of explants.

- One remarkable finding was the very wide variation in the recovery of meningococci from nasopharyngeal explants derived from different humans, which was initially apparent in experiments investigating differences between Neisseria species and clonal groups.

- As the experimental methodology was uniform across the 40 individuals studied, the variation that was observed was likely due to genetic or environmental influences upon the host tissue. All the individuals who donated tissue in this survey were suffering from non-allergic nasal obstruction, mainly due to septal deviation. None were receiving intranasal topical steroids, though clearly we cannot exclude the influence of disease comorbidities secondary to the upper respiratory tract obstruction. Other possible environmental influences that could explain this variation include recent respiratory tract infection, though there was no correlation with season. It is unlikely that anti-meningococcal antibody present in the mucosae was responsible for the variation observed, as the tissue employed is not lymphoid, and we have not detected antibody to common viruses in tissue homogenates.

- We conclude that the distinctive colonization and disease potential of Neisseria spp. may be partially a consequence of their ability to invade and survive within human nasopharyngeal mucosa, but that this is influenced greatly by host or environmental factors.

[P. Krizova, J. Kalmusova, M. Musilek.2004. Study of long term and multiple carriage of Neisseria meningitidis in a healty population using molecular biology methods. Epidemiol. Mikrobiol. Imunol. 53:25-36].

- Multiple carriage of different clones of N. meningitidis is rare and usually of short-term duration. The colonization of upper respiratory tract by a single clone of N. meningitidis does not protect from colonization by other clone.

[M.I. Marks, C.E. Frasch, R.M. Shapera.1979. Meningococcal colonization and infection in children and their household contacts. Am. J. Epidemiol. 109:563-71].

- Infants and children with proven meningococcal infection, or asymptomatic meningococcal nasopharyngeal carriage, and their household contacts, were studied in Canada. N. meningitidis was present in 30 (2.4%) of the nasopharyngeal cultures from 1238 asymptomatic infants and children in this civilian population during a non-epidemic period. Meningococcal carriage was not found in 278 subjects 1-60 days of age; there was no difference in carriage rates between the sexes and between hospitalized and non-hospitalized children in all age groups.

- Duration of nasopharyngeal carriage was longer (mean 15.2 weeks) in disease-free families than in families of ill patients (mean 5.5 weeks).

[P.S. Moore, J. Hierholzer, W. DeWitt.1990. Respiratory viruses and Mycoplasma as cofactors for epidemic group A meningococcal meningitidis. JAMA. 264:1271-5].

- Case patients were more likely than controls to have nasal colonization or infection with respiratory viruses and Mycoplasma species.

- In controls, the presence of respiratory pathogens increased the risk of upper-respiratory-tract symptoms but did not significantly increase meningococcal carriage.

[D.S. Stephens, A.M. Whitney, M.A. Melly.1986. Analysis of damage to human ciliated nasopharyngeal epithelium by Neisseria meningitidis. Infect. Immun. 51:579-85].

- Encapsulated, viable meningococci damaged ciliated epithelium of nasopharyngeal organ cultures, whereas Neisseria subflava, a commensal species, did not.

- Meningococcus-induced ciliary damage was due to loss of ciliated cells to which meningococci were not attached.

- Meningococcal viability was a requirement for both ciliary damage and interactions of meningococci with microvilli of nonciliated epithelial cells.

- Damage to nasopharyngeal ciliated epithelium by N. meningitidis may be an important first step in meningococcal colonization of the human nasopharynx, but meningococcal lipopolysaccharide does not appear to be directly responsible for this toxicity.

[J. M. Griffis, R. Yamasaki, M. Eastbrook.1991. Meningococcal molecular mimicry and the search for an ideal vaccine. 85 Suppl 1:32-6].

- The carbohydrates expressed on the surface of meningococcal strains of groups B and C mimic those commonly found on human cells and thus are not functionally antigenic in infancy.

- The surface polysaccharides can theoretically present conformationally different epitopes, some of which might be recognized as antigenic by the host.

- Precursors of the surface lipooligosaccharides may be unable to mimic human antigens, and so may be potential candidates for vaccine development.

- Natural immunity to some strains of meningococci develops in young children who are colonized with strains of Neisseria lactamica.

[G. Paret, N. Keller, A. Barzilai.1999. Invasive meningococcal disease: patient and strain characteristics set new challenge for prevention and control. Infection. 27:261-4].

- All hospitalized patients in six major hospitals in central Israel with a verified meningococcal disease during 1990-1994 were included (n=66). Meningococci were isolated from both blood and CSF, from blood alone, and from CSF alone in 60.6%, 18.2%, and in 21.2% of the cases, respectively.

- The highest proportion of isolations were from infants < 1 year (34.8%), followed by children aged 1 to 5 years (25.8%).

- Serogroup B prevailed in 62.1%. while groups C and W135 accounted for 28.8% and 9.1%, respectively.

- Serogroup B predominated in children < 1 year, while in patients aged 5-22 years, C strains were the major pathogen.

- Serogroup B accounted for 93% of the cases of meningitis, 58% of meningoccemia and 42% of fulminant meningococcemia, while group C strains were the major cause of fulminant meningococcemia (50%).

[M. van Deuren, P. Bradtzaeg, J.W.M. van der Meer. 2000. Update on meningococcal disease with emphasis on pathogenesis and clinical management. Clin. Microb. Rew. 13:144-66].

- Strains of serogroups B and C cause the majority of infections in industrialized countries. Strains of serogroups A and, to a lesser extent, C dominate in third world countries. In this region, meningococcal disease caused by serogroup A occurs in yearly recurrent waves. The disease attack rate rises at the end of the dry season and declines rapidly after the beginning of the rainy season. During epidemic peaks, the disease incidence may approach 1000/100000 inhabitants.

- In most industrialized countries, serogroup B strains have prevailed the last 30 years north-western Europe, hyperendemic infections with an attack rate of 4 to 50/100000 have prevailed since the mid-1970s. this persistent relatively high attack rate is caused mainly by serogroup B strains belonging to the ET-5 complex or lineage III. This strain circulates slowly through the population with a low transmissibility but a high degree of virulence.

- In parts of the United States, serogroup Y strains belonging to the ET-508 and related clones emerged in the mid-1990s as an important cause of endemic cause clusters.

- During periods of endemic infection, approximately 10%of the population harbors meningococci in the nose. However, 9 0f 10 strains isolated from carriers are considered non-pathogenic because the are not associates with the clones cultured from patients with invasive meningococcal disease.

- In three different cross-sectional studies in Norway and the United Kingdom, the carriage rate in children younger than 4 years was < 3%. The carriage rate increases with age to a maximum of 24 to 37% at 15 to 24 years, and decreases to < 10% at older ages.

- The carriage rate of meningococci is higher in lower socio-economic classes, probably because of crowding, and under conditions where people from different regions are brought together, as for military recruits, pilgrims, boarding school students, or prisoners.

- Colonization takes place both at the exterior surface of the mucosal cell and intra- or subepithelially. Damage to the nasopharynx ciliated epithelium may be the first step in colonization. Physical damage by active or passive smoking increases the risk of carriage and invasive disease, as do stressful events and preceding viral infections which either alter the integrity of the mucosal surface or influence local or systemic immunity.

- Frequently, invasive disease is preceded by Mycoplasma pneumoniae or viral upper respiratory tract infections; it is assumed that this preceding infection promotes invasion.

- The initial defence is dependent primarily on elements of the innate response.

- Deficiency of one of the terminal complement factors increases the chance for invasive disease, mainly by uncommon groups. Deficiency of protein C leads to extensive diffuse intravascular coagulation and necrosis.

- In normal individuals, the incidence of meningococcal disease is reciprocally related to the titer of specific antibodies, with the highest incidence occurring from 6 to 24 months of age, when maternal antibodies have disappeared. Throughout life, specific antibodies are induced by the continuously repeated and intermittent carriage of different meningococci and N. lactamica. Certain enteric bacteria have a capsule that is structurally and immunologically identical to the capsular polysaccharide of meningococci (Bacillus pumilus and E. coli K1). It has been suggested that these bacteria contribute to the defence against meningococci by the induction of cross-reacting antibodies. On the other hand, it has been suggested that IgA antibodies, which do not activate complement, may adhere to important epitopes and block these epitopes for the bactericidal effects of complement-activating IgG and IgM antibodies.

[M. Bakir, A. Yagci, N. Ulger. 2001. Asymptomatic carriage of Neisseria meningitidis and Neisseria lactamica in relation to Streptococcus pneumonia and Haemophilus influenzae colonization in healty children: apropos of 1400 children sampled. Eur. J. Epidemiol. 17:1015-8].

- Meningococcus and N. lactamica carriage were detected in 17 (1.23%) and 245 (17.7%) of 1382 subjects, respectively. Number (%) of serogroups for meningococci was 1 (6), 5 (29), 0 (0), 1 (6), 1 (6), and 9 (53) for A, B, C, D, W135, and Y, respectively.

- Pharyngeal carriage of Streptococcus pneumoniae and Haemophilus influenzae were associated with carriage of meningococci, whereas age less than 24 month was associated with carriage of N. lactamica. There was a reverse carriage rate between N. meningitidis and N. lactamica by age which may suggest a possible protective role of N. lactamica against meningococcal colonization among pre-school children.

[2002. Weekly epidemiological record. 77:329-40].

- Humoral immunity is essential in the resistance to meningococcal disease, whereas the corresponding role of T-cell dependent immunity is poorly defined.

- Passively transferred maternal antibodies protect infants against meningococcal infections during the first few months of life, whereas high incidence rates are recorded in the age group 6-12 months.

- A progressive increase in the proportion of children with bactericidal antibodies in the age group 2-12 years coincides with a decrease in the incidence of meningococcal disease. The persistence of this protection may depend in part upon bactericidal antibodies induced by cross-reacting microbial antigens and occasional nasopharyngeal colonization by meningococcal strains. Protection is usually group-specific, and for serogroups A, C, Y and W135 protection appears largely to be due to antipolysaccharide antibodies.

[P. Mastrantonio, P. Stefanelli, C. Fazio. 2003. Serotype distribution, antibiotic susceptibility, and genetic relatedness of Neisseria meningitidis strains recently isolated in Italy. Clin. Infect. Dis. 36:422-8].

- In Italy there has been a clear predominance of serogroup B meningococci (74% vs. 24% for group C), but the proportion of group C isolates increases in cases of septicaemia and among teenagers and young adults.

- There is a moderate presence of meningococci with decreased susceptibility to penicillin lower than that reported in neighbouring countries, but with an increase in the MIC when compared with strains isolated in Italy in the 1980s.

[D.M. Patrick, S. Champagne, S. Goh. 2003. Neisseria meningitidis carriage during an outbreak of serogroup C disease. Clin. Infect. Dis. 37:1183-8].

- It has been reported that low prevalence of carriage of an N. meningitidis outbreak strain, together with a low prevalence of protective immunity within a student population, was associated with a high incidence of invasive disease among those who acquired the strain.

- The consistent finding of a low rate of carriage of serogroup C in the presence of heightened disease activity suggests that immunization has a particularly important role in preventing morbidity resulting from serogroup C disease.

[G.R. Jones, J.N. Williams, M. Christodoulides. 2000. Lack of immunity in university students before an outbreak of serogroup C meningococcal infection. J. Infect. Dis. 181: 1172-5].

- For the majority of persons, acquisition of meningococci does not cause invasive disease and merely results in colonization of the nasopharynx. Carriage of meningococci occurs in 10% of the population but is considerably higher in institutions, particularly military camps or other closed or semiclosed communities.

- It is generally accepted that there is a strong correlation between the presence in serum of complement-dependent bactericidal activity against meningococi and immunity of the individual to subsequent infection.

- In this study has been found a low prevalence of carriage of the outbreak strain together with a low prevalence of protective immunity within the student population. This was associated with a high incidence of invasive disease in those acquiring the outbreak strain.

- These conclusion contrast with the earlier studies on military recruits, which found both a high prevalence of carriage of serogroup C meningococci within the training camp and a high prevalence of protective immunity. The differences between these findings may be explained by a significant epidemiologic differences. The effects of changes in these epidemiologic factors on the development of natural immunity to meningococcal infection are unknown.