the of commensal of neisseria - journal of clinical …genus neisseria is considered to contain only...

J Clin Pathol 1983;36:213-223

The pathogenic potential of commensal speciesof NeisseriaAP JOHNSOON

From the Division of Communicable Diseases, MRC Clinical Research Centre, Watford Road, Harrow,Middlesex, HAl 3UJ

SUMMARY Although Neisseria species other than N gonorrhoeae and N meningitidis normallycomprise part of the commensal bacterial flora of the oropharynx, they may occasionally act asopportunistic pathogens. Infections in which these organisms have been implicated include cases ofendocarditis, meningitis, septicaemia, otitis, bronchopneumonia and possibly genital tractdisease. In this paper, the clinical and pathological features of such infections are described,together with a discusssion of factors that may contribute to their development.

In most textbooks of medical microbiology, thegenus Neisseria is considered to contain only twopathogenic species, namely, N gonorrhoeae andN meningitidis. The other members of the genus aregenerally regarded as harmless inhabitants of theoropharynx. There is ample evidence in the liter-ature, however, that these normally non-pathogenicspecies are capable of producing infection in a varietyof anatomical sites including the heart, nervoussystem, bloodstream, respiratory tract and possiblythe genital tract. Although the pathogenesis ofgonococcal and meningococcal infections has beeninvestigated extensively and is well documented,' 2there is little collated information concerning infec-tions produced by other Neisseria spp. This article isan attempt to remedy this deficiency.

Classification of the genus Neisseria

Any review of Neisseria infections is complicated bythe fact that the classification of the organismscomprising the genus has undergone a number ofchanges over the years. A detailed discussion of theevolution of the taxonomy of the genus is beyond thescope of this article, but a brief ojitline, whichconveys some idea of the degree of change ispresented below. In the early part of this century,Gram-negative cocci were allocated a variety ofgeneric and specific names including Micrococcus

Accepted for publication 20 October 1982

catarrhalis, M cinereus, M flavus, i, ii and iii,M pharyngis siccus, Diplococcus mucosus andD crassus. In an early review, Wilson and Smith3considered the classification of these organisms to beunsatisfactory and suggested that apart from themeningococcus, all Gram-negative cocci found in theoropharynx should be classified as a single groupcalled either D pharyngis or N pharyngis. Thissuggestion was not, however, generally adopted. Inthe 7th edition of Bergey's Manual of DeterminativeBacteriology4 published in 1957, the genus Neisseriacomprised 10 species (Tables 1 and 2). On the basis ofsubsequent studies of genetic homology betweenorganisms,5 6 however, several of the species werereclassified, and the 8th edition of Bergey's ManuaPpublished in 1974, lists only six main species (Tables 1and 2). The former species N flava and N perflavahave been incorporated into the species N subflava,while the former species N catarrhalis andN haemolysans have been transferred to the generaBranhamella and Gemella respectively. In addition,10 species are mentioned, but because of the lack ofrelevant genetic data they are currently listed asspecies incertae cedis (Table 1).

In this review no attempt has been made toreclassify organisms described in early papers interms of the currently used taxonomic scheme.Rather, the specific names used in each paper aregiven. However, the reader must bear in mind thatthe specific names used were determined by theclassification scheme in vogue at the time each paper

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Table 1 Species ofNeisseria listed in the 7th (1957)4 and8th (1974)1 editions ofBergey's Manual ofDeterminativeBacteriology

1957 classification4 1974 classification7

Ngonorrhoeae NgonorrhoeaeN meningitidis N meningitidisNflava NsubflavaNperflava NsiccaNsubflava NmucosaN sicca NflavescensN catarrhalisNflavescensN haemolysansN caviae Species incertae cedis

N animalis N canisN caviae N cinereaN cuniculi N denitrificansN elongata N lactamicusNovis Nsuis

was published, and that different authors who appearto be discussing the same species may not necessarilybe referring to identical organisms.

Infections produced by Neisseria organisms

HEART INFECTIONSRecorded cases of endocarditis produced byNeisseria organisms together with their clinical andpathological features are presented in Tables 3 and 4

respectively. A variety of Neisseria spp aredocumented as having caused endocarditis, althoughthere are no recorded cases involving Nflavescens orN lactamica, despite the fact that these organisms cancause meningitis and septicaemia (discussed below).As with endocarditis produced by other micro-organisms-for example, Streptococcus viridans-patients generally presented with fever and malaise.Cardiac murmurs were nearly always present and thediagnosis was established by the repeated isolation ofthe micro-organism from the blood stream. Manypatients developed petechiae, splinter haemorrhagesand Osler's nodes (small tender nodules mostfrequently found on the finger or toe pads) whichwere probably manifestations of allergic vasculitis.Embolic episodes involving the right brachial andfemoral arteries," the brain,"8 20 1 and the toe,"5 werealso noted. Some patients exhibited haematuriawhich may have been due to renal emboli, focalembolic glomerulitis or diffuse glomerulonephritis.

Several of the patients had a history of underlyingheart disease. Rheumatic fever was a commonfeature,8 1128 but patients with ventricular septaldefect'0 and Marfan's syndrome2' have also beenreported. Four patients had previously receivedprosthetic heart valves,3 16 18 23 a procedure which isnow known to predispose towards the developmentof bacterial endocarditis. One patient developed

Table 2 Characteristics used to differentiate Neisseria species in the 7th and 8th editions ofBergey's Manual ofDeterminative Bacteriology4'

Edition of Differential characteristicsBergey (year) Species listed

Acidfrom Pigment Capsule Growth at22°C Polysaccharidefrom 5% sucrose

G M F S

7th (1957) Ngonorrhoeae + - - - - ND - NDNmeningitidis + + - - - ND - NDNflava + + + + ND + NDNperflava + + + + + ND + NDNsubflava + + - - + ND + NDNsicca + + + + - ND + NDN catarrhalis - - - - - ND + NDNflavescens - - - - + ND + NDNhaemolysans + + + + - ND + NDN caviae - - - - + ND + ND

8th(1974) Ngonorrhoeae + - - - - - - 0Nmeningitidis ++-- - V - 0Nsubfava + + V V + + d dNsicca + + + + d V d +Nmucosa + + + + - + + +Nflavescens - - - - + - + +

G = glucoseM = maltoseF = fructoseS = sucroseND = not discussed0= no growth on medium with 5% sucroseV = character inconsistent and in one strain may sometimes be positive, sometimes negative.d = some strains positive, some strains negative

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The pathogenic potential ofcommensal species ofNeisseria

Table 3 Cases ofendocarditis caused by Neisseria organisms

Organism Patient Author(s) YearpublishedAge (yrs) Sex

Nflava 20 F Connaughton and Rountree8 193914 F Matlauge et a n n 19505 F Scott" 1971

Nperflava 45 M Major and Johnson" 194544 M Breslin et ar2 196747 M Clark and Patton'3 1968

Nsicca 12 M Shaw'4 194960 F Gay and Sevier"5 197821 M Ghoneim and Tandon'6 1979

N calarrhalis 15 F Clarke and Haining'7 193621 M Clarke and Haining'7 193669 F Pollock and Holzmann'8 197645 F Douer et al9 1977

Nmucosa 9 M Brodie etalP° 197119 M Dowling et all' 197454 M Drapkin22 197740 M Hennessey et a!3 1981

Npharyngis 21 F Goldstein24 193426 M Shilingpm 193921 F Hudson'" 195715 M Linde and Heins27 1960

Micrococcus 27 M Graef et a!8 1932pharyngis siccus 14 F Weed et a!9 1943

Micrococcuspharyngitidis-siccae 25 M Schultz3' 1918

Unidentified 45 M Coulter3l 191525 M Shiling'2 193966 M Dammin'' 1941

Table 4 Clinical andpathologicalfeatures ofendocarditis caused by Neisseria organisms

Clinical orpathological Clinical orpathologicalfeature reported Reference feature reported Reference

Fever 8,9,10,11,12,13,15,16,17,18,19,20,21, Abdominal pain 9,10,13,17,24,25,2822,23,24,25,27,28,29,30,31,32

Headache 9,10,12,14,17,20,21,24,29,30 Splinter haemorrhages 9,11,16,29Chills 10,11,13,17,19,21,22,23,24,25,29,31,32 Osler's nodes 16Vomiting 8,9,20,28,29,31 Janeway's lesions 22Muscular aches 8,9,24 Embolic episodes 15,16,18,20,21,25,26Enlargement of heart 8,10,11,17,24,25,28,31,32 Clubbing of fingers 14,25Heart murmurs 8,9,10,11,12,13,15,17,19,20,21,22,25, History of rheumatic fever 8,11,28,32

28,29,30,31,32Conjunctival petechiae 8,9,10,11,13,20,28,29,30,32 Pre-existing heart valve abnormality 10,14,21Petechiae on skin 11,14,16,17,24,28,30,32 Intracardiac prosthesis 13,16,18,23Haematuria 8,10,13,15,18,19,21,22,25,28,29,30,32 Recent history of dental procedure 8,18,21,26Arthralgia/arthritis 8,9,15,22,24,31 Patient died 8,17,18,24,25,28,30,31,32

early onset endocarditis"3-that is, onset within twomonths of valve replacement-while the other threepatients'6 18 23 developed late onset disease.

Although the portal of entry for the initiatingepisode of bacteraemia which resulted in infection ofthe endocardium was often not apparent, it wasthought that the oropharynx was the source ofinfection in a number of instances. In four patients,endocarditis developed after dental extrac-tions,8 18 2126 and in one patient, bacteraemia wasbelieved to have occurred following the use of an oralirrigation device.22 In at least two other patients poororal hygiene was noted.10 32 It was suggested that in

one patient the source of bacteraemia may have beena genital tract infection,9 while in another patient thedevelopment of endocarditis was thought to bepossibly related to a prior gynaecological operation."9

In addition to endocarditis, one case of purulentpericarditis due to a Neisseria organism (N mucosa)has been described.33 A 51-year-old man with chronicrenal failure developed purulent pericarditis andN mucosa was isolated from pericardial tissue andfluid.

MENINGITISDocumented cases of meningitis produced by

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Table 5 Cases ofmeningitis caused by Neisseria organisms

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Organism Patient Author(s) Yearpublished

Age* Sex

Nflava 8 days M Noguchi et aP4 1963Nperflava 31 M Sophian35 1944Nsubflava 7 months M Benson et aP' 1928

7 months F Lewin and Hughes37 196621 F Lewin and Hughes37 19669 months F Lewin and Hughes3' 1966

Nsicca 61 M Bansmer and Brem38 1948Organism resemblingNcatarrhalis 45 F Newing and Christie39 1947N catarrhalis 21 M Pfister et aP° 1965

14 months F Cocchi and Ulivelli4l 196836 M Elston et ap2 19703 M Arora and Chitkara43 1973

Micrococcus catarrhalis 3 months - Wilson' 19085 F Garland45 192331 F Moersch46 1928

Nmucosa 5 F Berger et a'7 1974Diplococcus mucosus - - Cowan48 1938

29 M Bray and Cruickshank49 19433 months F Bishop and Randelln5 1947

N lactamica 7 months F Lauer and Fisher51 19766 M Hansman52 1978

Nflavescens - - Branham53 193010 M Prentice54 1957

Unidentified 7 F Reimann and Koucky55 193931 M Edwards. 194425 F Christie and Cook57 19474 M Kippax et a58 1968

*Age in years unless stated otherwise.

Table 6 Cases ofmeningitis caused by Neisseria organisms reported in languages other than English

Organism Patent Author(s) YearpublishedAge Sex

Nflava 10 months F Kostmann* 193921 M Hillemand et al* 1951

Ncatarrhalis 6 months - Mayerhofer-Lateiner*t 1918- M Cot and RoberttW 192135 M Gaupp and Axen*t 1933- - Zoeller et al*t 19334i M Zinke*t 193611 M Zinket 1936S months F Bergqvist*t 19404 F Savim*t 19575 F Savini*t 195713 M Bentegeat et al* 1960- - Cassoute and Gibaudt 19207 weeks - Neal* 1922

Nmucosa 12 F V6ronetal§ 19616 months - Sirot and Cluzelf 19723 - Sirot and Cluzel 1972

Npharyngas 22 M Engel and L6fgren' 194149 F Engel and Lbfgren' 1941

Diplococcu pharyngisfkavus II 52 F Emile-Weil et al* 1933Diptoocu pharyngis

ocus III 20 M Brunel and D6robeit* 1937'Meningococctslike' organism 8* M Reusst 1922Ncapsulata - - Courtoiseta41 1954

'For reference see Noguchi ;t al.34tFor referene see Benson etal.36:For reference see Garlanid.For reference see Berger et al.47or reference see Kippax etal.ss



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Table 7 Clinical andpathologicalfeatures ofmeningitis caused by Neisseria organisms

Clinical orpathological Clinical orpathologicalfeature reported Reference feature reported Reference

Fever 35,36,37,38,40,41,42,43,44,45,46,47,49,50, Maculo-papular or purpuric rash 49,52,5751,54,57,58 on skin

Headache 38,45,46,49,55,57 Neck stiffness 35,38,40,41,42,45,47,49,52,54,55,58

Vomiting 36,37,38,39,41,44,45,46,47,54,55,58 Positive Kernig's sign 35,36,38,40,41,45,54,55,57,58

Lethargy/drowsiness 37,38,39,40,43,45,47,51,52,57,58 Positive Babinski's sign 35,47Altered state or loss 37,39,40,42,43,57 Positive Brudzinski's sign 35,36,40,41,47

of consciousnessConfusion 35,39,49,57 Positive Oppenheim's sign 35Convulsions 37,40,43,44,58 Positive Gordon's sign 35Bulging fontanelie 36,44,50 Cloudy cerebro-spinal fluid 35,36,38,39,40,41,44,45,46,

49,50,51,55Inflammation or infection 36,37,38,39,41,42,45,47,49,51,56,57 Cerebral-spinal fluid under 35,38,39,45,49,50,57,58

of upper respiratory tract increased pressurePetechiae on skin 35,37,40,41,44,47,49 Patient died 35,36,37,39,44,45,46,56,57

Table 8 Pathologicalfindings in cerebro-spinalfluid from patients with meningitis caused by Neisseria organisms

Organism Findings in cerebrospinalfluidNo of Glucose Protein Gram-negative Author(s) Yearpublishedinflammatory cells (mmoUll) (gil) diplococci seen(cellsllitre) in smear

Nperflava 1-5 xlO10 NR NR + Sophian35 1944Nsubflava 4.8 x109 0.17 1.9 + Lewin and Hughes3 1966

1-9 x 109 0-22 1-4 + Lewin and Hughes37 19664.0 x 106 1.7 0.4 + Lewin and Hughes37 1966

Nsicca 4-2 x 109 4-6 0-8 - Bansmer and Brem3 1948Ncatarrhalis 3.0 x 109 NR NR + Pfisteretal' 1965

1-2 x 109 1.7 0-7 + Cocchi and Ulivelli4l 19687-6 x 109 2-1 3-5 + Elstonetal'2 197010-12 HPF 1.4 0.7 + Arora and Chitkara4'3 1973

Mcatarrhalis 1.5 x 109 1.9 increased + Garland45 1923Nmucosa 2.3 x 109 Normal Normal - Bergeretal47 1974(D mucosus) 3-3 x 108 NR 2-4 + Bray and Cruickshank49 1943

2-0 x 108 1-9 1-9 + Bishop and RandaliO 1947Nlactamica 1-3 x 1010 Not detected 2-5 - Lauer and Fisher5l 1976Nflavescens 2-6 x 107 4.4 0-5 + Prenticem 1957Undescribed 2-9 x 108 Not detected 2.0 + Christie and Cook-7 1947

1-1 x 108 4-3 0-3 NR Kippaxeta18 1968

HPF = high power field.NR = not reported.

Neisseria spp other than the gonococcus and themeningococcus are listed in Tables 5 and 6. Mostpatients presented with meningeal symptoms such asheadache, vomiting, lethargy, neck stiffness, andpositive Kernig's and Brudzinski's signs (Table 7)which are common to many types of meningitis.Interestingly, several patients had a petechial,maculo-papular or purpuric rash (Table 7) which is afeature commonly associated with cases of menin-gococcal meningitis. Gram-negative cocci werefrequently seen in smears of cerebrospinal fluid(CSF) (Table 8) and in all cases the diagnosis wasconfirmed by isolation of the organisms from the CSFand occasionally from the blood.The findings in the CSF were generally consistent

with those seen in other forms of bacterial meningitis

(Table 8). The white blood cell count was commonly,though not invariably, greatly than 1.2 x 109/1 with a

predominance of polymorphonuclear leucocytes. Inthe cases where glucose and protein concentrations inCSF were recorded, about half the patients hadglucose concentrations <1-7 mmolIl, and about halfhad protein concentrations >1 5 g/l.SEPTICAEMIAThe clinical and microbiological features of docu-mented cases of Neisseria septicaemia are shown inTable 9. It must be remembered, however, thatinvasion of the blood stream by bacteria occurs alsoin cases of endocarditis and meningitis (see above),and that there is an overlap with regard to the clinicalfeatures of these conditions. In all the reported cases

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Table 9 Clinical andpathologicalfeatures ofsepticaemia caused by Neisseria organisms

Organism Patient Clinicalfeatures Bacteriologicalfeatures Author(s) Yearpublished

Age* Sex

Nsubflava 3 months M History of coryza and cough 1 wk prior to Bacteria isolated from blood Lewin and 1966admission, fever, loss of consciousness, Hughes37generalised petechial rash, pupils unresponsive tolight, deep tendon reflexes absent, right upperlome pneumonia, patient died.

Nsubflava 2 F History of coryza and cough 1 wk prior to Bacteria isolated from blood Lewin and 1966admission, fever, generalised petechial rash, Hughes37tonsillar fauces inflamed, haematuria, patientrecovered.

Nsubflava 10 M Fever, nausea, stomach ache, mild pharyngitis, Bacteria isolated from blood Muchmore and 1968macular-purpuric skin rash, patient recovered. Venters5

N catarrhalis 6 months M History of fever and vomiting 2 days before Bacteria isolated from blood, Feigin et aP°" 1969admission, sudden onset of purpuric lesions, few CSF and bone marrowspontaneous movements, pupils sluggish to light,CSF clear and colourless, patient recovered.

N catarrhalis 8 M History of immunosuppressive therapy for acute Bacteria isolated from blood. Burnett et ap1l 1975lymphoblastic leukaemia, fever, malaise, nausea, Bacteria seen in Gram-stainabdominal distension, purpuric rash, pain and of material obtained byswelling in both knees, extensive oropharyngeal needling from cutaneousulceration, patient died. lesions

Npharyngis 24 F Patient collapsed at work. Bacteria isolated from blood Thomson and 1973Evidence of disseminated intravascular and from heart swab taken at GopauI62coagulation. Patient died. autopsy

N lactamica 23 months F Patient had chromosomal defect and suffered Bacteria isolated from blood. Wilson and 1976from patent ductus arteriosus with pulmonary Bacteria seen in Gram-stain Overman63hypertension. of fluid from middle ear.Patient found lifeless in bed but resuscitated.On admission, patient had inflamed and dullright tympanic membrane.

Nflavescens 20 F Fever, chills, headache, vomiting, myalgia, Bacteria isolated from blood. Wertlake and 1968arthralgia, maculopapular and pustular skin Bacteria seen in Gram-stain Williams64lesions, third right metacarophalangeal of pustular skin lesion, butjoint inflamed, CSF clear, patient recovered. cultures were negative.

*Age in years unless otherwise stated.

of Neisseria septicaemia organisms were isolatedfrom the blood, but additionally in one case,organisms were isolated from the CSF and bonemarrow,60 while in two other cases organisms wereseen in Gram-stained materials from skin lesions.6164The cases described here are of particular interest inthat they resemble the clinical picture generally seenin meningococcal septicaemia, with the developmentof a maculo-papular, petechial or purpuric rash.Other similarities include fever,37 59 60 6164 joint in-volvement,61 64 and, in one patient, evidence ofdisseminated intravascular coagulation.6"

In some of the patients, septicaemia may havefollowed an upper respiratory tract infection. Threepatients had a history of either coryza and cough37 60(although relevant microbiological data were notavailable) or pharyngitis,59 and in one patient,organisms were detected microscopically in fluidfrom the middle ear.60 One other patient waspredisposed to infection as a result of receivingimmunosuppressive drugs.6'

RESPIRATORY TRACT INFECTIONSAlthough Koch's postulates have not been fulfilled,the isolation of Neisseria organisms in pure culture

from the heart, CSF or blood (organs and tissueswhich are normally sterile) provides strong cir-cumstantial evidence that these organisms are theaetiological agents in the cases of endocarditis,meningitis and septicaemia described above. Withregard to respiratory tract infections, however, theinterpretation of bacteriological findings is moredifficult as Neisseria organisms are known to exist asharmless inhabitants of the upper respiratory tract.With this proviso in mind, there is, nevertheless, anaccumulating body of evidence which suggests thatoneparticularspecies-namelyNcatarrhalis(recentlyrenamed Branhamella catarrhalis)-can cause infec-tions in both the upper and lower respiratory tract(Table 10). There is only serological evidence tosupport an aetiological role forN catarrhalis in somecases of sinusitis,60 but the evidence for it causingotitis media in children is stronger, the organismshaving been isolated in pure culture from middle earexudates and having been seen associated withpolymorphonuclear leucocytes in Gram-stainedsmears.,*-70 Moreover, it is unlikely that these isolateswere simply contaminants from the oropharynx,since other organisms also found normally in theoropharynx were not isolated. In a study of acute



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Table 10 Evidencefor aetiological role ofNeisseria catarrhalis (Branhamella catarrhalis) in respiratory tract infections

Infection Evidencefor aetiological role of Predisposing host Author(s) YearN catarrhalis (Branhamella catarrhalis) factor published

Maxillary Complement-fixing antibodies present in sera of ND Brorson et all 1976sinusitis some patients.Otitis media Organisms isolated in pure culture from middle ear ND Coffey etap6 1966

exudate; Organisms seen in association with PMN Coffey et alP 1967leucocytes in middle ear exudate; antibodies detected Kamme et ap8 1971in serum and/or middle ear fluid of patients from Lee et aP9 1981whom organisms were isolated. Leinonen etafll 1981

Laryngitis Organisms isolated as sole pathogen from nasopharynx None Schalen et al71 1980in 55% of patients studied.

Bronchitis or Predominant organisms in sputum. All patients had chronic Johnson etaP 1981pneumonia undferlying lung disease.Pneumonia Organisms isolated in pure culture from sputum and Patient received immunosuppressive McNeely et alP3 1976

transtracheal aspirate; organisms seen associated with therapy for multiple myoloma.PMN leucocytes in Gram-stained sputum andtranstracheal aspirate; positive correlation between One patient had chronic lymphocytic Srinivasan et aP4 1981disappearance of organisms and clinical improvement. leukaemia and another was an

alcoholic with chronic obstructivepulmonary disease.

Patients were miners with altered Ninane et al5 1977pulmonary function; they all suffered Ninane et aP76 1978from repeated respiratory tract Ninane et aFl 1978infections and many had receivedcorticosteroids.

ND = not done

laryngitis in non-compromised adults, B catarrhaliswas isolated as the sole pathogen in 55% of thepatients, a figure significantly higher than that for thecontrol group.7"There is also fairly convincing evidence that

N catarrhalis may cause bronchopneumonia, theseorganisms having been isolated in pure culture frombronchial secretions obtained by transtracheal punc-ture,72"-` which is widely accepted as the procedure ofchoice for collecting uncontaminated material fromthe lower respiratory tract. Moreover, in the studiesreported by Ninane and colleagues,76 transtrachealaspirates containing epidermoid cells were discardedthus reducing the possibility that the aspirates werecontaminated with oropharyngeal secretions.

Further evidence for the pathogenic role of Ncatarrhalis in cases of pneumonia was a correlationbetween the disappearance of the organisms and theresolution of clinical symptoms. Generally, treat-ment with ampicillin or other antibiotics resulted inthe disappearance of the organisms and clinicalimprovement.76 However, in some patients treatedwith ampicillin or amoxycillin, the organisms per-sisted as did signs and symptoms of infection.' 75 76Laboratory investigation showed the persistentstrains to produce ,-lactamase.n ' 6 When thepatients were treated subsequently with either cefur-oxime,75 76 (a cephalosporin active against,B-lactamase-producing organisms), tetracycline72 or acombination of amoxycillin and clavulanic-acid77(a f3-lactamase inhibitor) the organisms were elimi-nated and the condition of the patients improved.

Neisseria catarrhalis (occasionally producing13-lactamase) was also recorded as a respiratory tractpathogen by Percival and colleagues.78 Interestingly,these workers noted that although N catarrhalis wasthe sole pathogen isolated from some patients, it wasmore frequently isolated together with Haemophilusinfluenzae and pneumococci. All the patients fromwhom N catarrhalis was isolated were chronicbronchitics or had bronchiectasis.

In addition to N catarrhalis, three other Neisseriaorganisms have been reported as being associatedwith infections related to the respiratory tract.Neisseria sicca has been isolated in pure culture fromthe transtracheal aspirate of an elderly patientsuffering from pneumonia,79 and N mucosa has beenisolated from the pleural space of a patient sufferingfrom empyema a year after pneumonectomy.5'Neisseria lactamicus was isolated from the pharynx ofa man suffering from fever, chills, and pharyngitis,8"but the role that the organism played in the disease isquestionable sinceN lactamicus may be isolated fromthe healthy nasopharynx.n2

GENITAL TRACT INFECTIONSIt is frequently thought that the observation of Gram-negative diplococci in genital tract smears is evidenceof a gonococcal infection. However, as shown inTable 11, several species of Neisseria other than thegonococcus have been isolated from the genital tract.It should also be mentioned that meningococci havesimilarly been isolated.90While it is now clear that Neisseria organisms other

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Table 11 Occurrence ofNeisseria organisms in the genitaltract

YearOrganism Author(s) published

Nflava Carpenter83 1943Wax84 1950Wilkinson85 1952

N subflava Johnston86 1951Wax84 1950

Nsicca Wax84 1950Weaver87 1950Wilkinson85 1952

N catarrhalis Wax84 1950Wilkinson85 1952Graber et al 1963McCague et arl 1976Blackwell et alt 1978

N lactamicus Jephcott and Morton91 1972N lactamica Brunton et al2 1980Nflavescens Wax84 1950Aberrant strain ofNcatarrhalis orNgonorrhoeae Coleman93 1946

than the gonococcus may be isolated from the genitaltract, it is not clear whether these organisms cause

pathological changes. In some cases it was suggestedthat the organisms isolated were acting as pathogens,while in other instances the evidence suggested thatthey were not directly involved in the disease process.However, the results of these studies are difficult tointerpret for several reasons. Firstly, the isolation oforganisms from patients with no evidence of genitaltract disease does not negate the possibility that theorganisms may be pathogenic, as the gonococcus (aknown genital tract pathogen) frequently producesasymptomatic infections. Secondly and more impor-tantly, some of the patients described in the paperslisted in Table 11 may also have been infected withgenital pathogens such as Chlamydia trachomatis or

Ureaplasma urealyticum which would not have beendetected by conventional bacteriology. If non-gono-coccal Neisseria species are to be shown to bepathogenic for the genital tract, they must first beisolated from patients from whom no other genitalpathogens can be recovered. Until such studies arecarried out, the relevance of non-gonococcalNeisseria species to the aetiology of genital tractdisease will remain purely speculative.

Factors possibly influencing the development ofinfection with Neisseria organisms

From the epidemiological standpoint, most of thereports of non-gonococcal non-meningococcalNeisseria infection take the form of case historiesrather than reports of outbreaks (although one mildepidemic of meningitis due to N flavescens was

Johnson

reported 50 years ago53) suggesting minimal person toperson transmission. As Neisseria organisms otherthan the gonococcus or meningococcus normallyexist as inhabitants of the oropharynx, developmentof disease is probably due in most instances, toendogenous spread of infection and probably reflectseither reduced resistance to infection on the part ofthe host or enhanced virulence of the infecting strain.In some of the reported cases it was evident that thepatients were prone to infection as a result ofimmunosuppressive therapy or because of chroniclung disease, but in the majority of cases theunderlying cause of disease was not known. In viewof our current lack of knowledge concerning thepathogenesis of these infections it must be stressedthat much of what follows is speculative.The first stage in the development of diseases such

as endocarditis, meningitis or septicaemia mustinvolve the haematogenous spread oforganisms fromthe oropharynx. Micro-organisms in the oropharynxenter the blood stream following oral trauma, whichmay be severe-for example dental extraction-orrelativelymild-forexampletoothbrushing,chewing.Micro-organisms that enter the blood stream areusually eliminated within a short time, but theisolation of Neisseria organisms from blood in casesof endocarditis, meningitis or septicaemia suggeststhat they may be resistant to the bactericidal activityof human serum. Strains of gonococci vary in theirsusceptibility to killing by serum when cultured invitro, with strains associated with disseminatedinfection being generally more serum-resistant thanstrains isolated from cases of localised infection.94 Itwould clearly be of interest to see if other species ofNeisseria isolated from blood were similarly serum-resistant in comparison with commensal strains of thesame species which appear to be serum-susceptible.95An alternative explanation for the ability of Neisseriaorganisms to survive in the blood stream is that thepatient's serum may be defective in killing micro-organisms. It is now known that deficiency ofterminal components of the complement systempredisposes to repeated systemic infection withN gonorrhoeae and N meningitidis.96 It would be ofvalue to know if such complement deficiencies arepresent in the sera of patients infected with otherNeisseria species.

After invading the blood stream, the micro-organisms must be capable of colonising appropriateanatomical sites such as the heart or nervous system ifthey are to produce infection. If they are to colonisethe heart effectively, for example, they must becapable of attaching to valve leaflets or other areas ofthe endocardium. Gould et aP reported that speciesof bacteria commonly associated with bacterialendocarditis adhered in significantly higher numbers



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to the endothelial surfaces of human and canineaortic valve leaflets in vitro, than did bacteria notassociated with this disease. In view of these findings,it would be of interest to determine if Neisseriaorganisms isolated from cases of endocarditis ad-hered to heart tissue more readily than organismsisolated from the healthy oropharynx. Attachmentwould also be an important prerequisite for thesuccessful colonisation of the genital tract, either asthe first step in the process of infection, or simply inthe establishment of a commensal genital tract flora.Once established at a potential site of infection,

Neisseria organisms must be capable of resisting hostdefences. As with gonococcal and meningococcalinfections, the host appears to respond to anopportunistic Neisseria infection with an acuteinflammatory reaction. The persistence of Neisseriaorganisms in the presence of large numbers ofpolymorphonuclear leucocytes implies either that thebacteria are capable of resisting to some extent thebactericidal activity of these phagocytic cells, or thatthe polymorphonuclear leucocytes from patientswith opportunistic Neisseria infections are defectiveat killing these organisms. This question could beresolved perhaps by performing in vitro phagocytosisstudies with polymorphonuclear leucocytes frompatients and from healthy donors, and by usingNeisseria organisms of apparently differingvirulence. Such studies have been reported pre-viously for N gonorrhoeae.

Conclusions

The great interest shown by researchers during thelast few decades in the study of gonoccoci andmeningococci has resulted in a steady increase in ourknowledge and understanding of the diseases pro-duced by these organisms. By way of contrastrelatively little attention has been paid to the otherNeisseria species, as they have generally beenregarded as harmless organisms of little clinicalimportance. While it is true to say that the latterbacteria do not rank among the major pathogensencountered in the field of infectious diseases, itwould appear that they may cause infections morefrequently than is commonly appreciated, and micro-biologists should guard against dismissing too readilyas normal flora, Neisseria species isolated fromclinical material.

Addendum After this paper was submitted forpublication, a report appeared in the literaturedescribing a case of osteomyelitis due to Nsicca.ReferenceDoern GV, Blacklow NR, Gantz NM, Avcoin P, Fischer RA,

Parker DS. Neisseria sicca osteomyelitis. J Clin Microbiol 1982;16:595-9.

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Requests for reprints to : Dr AP Johnson, Division ofCommunicable Diseases, Clinical Research Centre,Watford Road, Harrow, Middlesex HAl 3UJ. England.

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