Disseminated gonococcal infection (DGI) and gonococcal arthritis (GCA): I. Bacteriology, epidemiology, host factors, pathogen factors, and pathology

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Seminars in Arthritis and Rheumatism VOL. X, NO. 3

FEBRUARY

1981

Disseminated Gonococcal Infection (DGI) and G o n o c o c c a l Arthritis (GCA): I. Bacteriology, Epidemiology, Host F a c t o r s , Pathogen Factors, and Pathology BY Barry I. Eisenstein and Alfonse T. Masi

I S S E M I N A T E D gonococcal infection (DGI) and gonococcal arthritis (GCA) are increasingly important illnesses produced by Neisseria gonorrhoeae, a microbe having the distinction of producing the most commonly reported communicable infections in the United States) T h e characteristic symptom produced by this organism, venereal urethral discharge, was recognized in Biblical times, but it was not until the early 1500s that Pierre Van Forest described a patient who developed arthritis of the knee in association with urethritis. In 1879, Neisser described diplococci in smears of purulent secretions of patients with gonorrhea and conjunctivitis and, in 1892, Lindemann recovered these same organisms from a joint of a patient with septic arthritis. Vidal in 1833 was the first to recognize the typical skin lesions associated with gonococcal arthritis. 2 The present treatment of choice became established in 1945 with Davis' cure of.gonococcal endocarditis with parenteral penicillin) Our present understanding of disseminated gonococcal infection is that certain strains of N. gonorrhoeae a~'e more likely to cause DGI than others, that the disease can present in several major patterns, and that amongathose afflicted, a small subset of individuals are at an immunologic disadvantage. These three aspects of this disease, as well as our current Views of its epidemioiogy, pathology, diagnosis and treatment, will be covered in this series of 2 reports.

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BACTERIOLOGY

Classification The gonococcus belongs to the genus of bacteria called Neisseria. named i n honor of the Seth[hats in Arthritis and Rheumatism. Vol. 10. Na. 3 (Febr~arvL I g81

German physician Albert Ludwig Siegmund Neisser who, in 1879, first observed the causative agent in urethral exudates.4 This genus consists of 6 species of'gram negative cocci with a characteristic morphology of kidney beanshaped pairs (Fig. I). The present taxonomic classification includes N. gonorrhoeae, N.

meningitidis, N. flavescens, N. sicca, N. subflava, and N. mucosa) The first 2 species are characteristically pathogenic for man. Organ isms within this group are usually aerobic but occasionally facultatively anaerobic. They are nonmotile, nonspore-forming, and eatalase- and oxidase-positive. The latter characteristic, which is demonstrated by the colonies turning purple after the application of tetramethyl-phenylenediamine, is one of the major tools for distinguishing the gonococcus from other bacteria seen on culture plates. The genus Neisseria belongs to the family Neisseriaceaa, which now includes Front the Department of Medicine. Division of Infectious Diseases, University of Tennessee Center for the Health Sciences, Memphis. Tenn. and Department of Medicine, Division of Rheumatic Diseases, Peoria School of Medicine, University o f Illinois. Peoria, IlL Dr. Eisenstein is the recipient of a Clinical Investigator Award (AM-OO686)from the National Institute of Arthritis. Afetabolism, and Digestive Diseases of the National Institutes of Health, and is Associate Professor of Medicine, Department of Medicine, University of Tennesse. Dr. Masi: Professor.and Head, Department of Medicine, Peoria School of Medicine, Supported in part by AAf-12049 Address reprint requests t o Dr. Burr). L Eisenstein, Department of Medicine, Division of Infectious Diseases, University of Tennessee Centerfor the tl~alth Sciences. 956 Court Avenue. Room 3H!6. Memphis, Tenn. 38163. © 1981 by Grune & Stratton. Inc. 0049-0 i 72]81/!003--000! $02,00/0 155

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EISENSTEtN AND MASI

Fig. 1. Gram steirl of urethral discharge from a male w i t h gonorrhea. Note the kidney bean-shaped diplo(~occi w i t h i n a polymorphonuclear leukocyte.

the old Mimeae family, ,of which the genus Acinetobacter (formerly Mima and Herella) is a par t, but does not include the anaerobic family of Veillonellaceae.~ The 2 major pathogenic species, Neisseria gonorrhoeae and Neisseria meningitidis, are distinguished from their nonpathogenie relatives by their inability to grow at 22°C. Further differentiation of the meningococcus and the gonococcus typically depends on sugar utilization reactions, serologic reactivity, and colonial morphology. The gonococcus utilizes glucose but not maltose, rarely reacts with antiserum directed against meningococcal polysaccharide, and typically produces colonial varia',!s on special agar plates (see below). The menivgococcus, in contrast, utilizes both glucose and maltose, usually can be serogroupcd on the basis of its specific reactions to polysaccharlde antisera, and does not form gonococcal type colonies on agar. These organisms are relatively fastidious in that they require approximately 5% carbon dioxide for optimal growth and are easily outgrown on nonselective agar plates by commensal bacteria. Therefore; to help isolate these bacteria from hardier competitors, agar containing vancomycin, nystatin and colistin (Thayer-Martin) was devised to inhibit selectively the non'neisseriat organisms obtained from culture specimens with mixed bacteriology (see Diagnosis).

.'lntibiotic Resistance Gonococcal strains preserved from tile proantibiotic era and tested later for antibiotic resistance were tmiformly sensitive to penicillin, tetracycline and streptomycin ("wild" phenotype). ~ Since the introduction and widespread clinical use of these antibiotics, a slow, progressive increase in the proportion of strains with drug resistance has been f o u n d . 7 A recent epidemiologic study of resistance patterns noted a high association among certain individual drug sensitivities;8 strains possessing low level resistance to penicillin were also relatively resistant to tetracycline. In contrast to the multiple and additive small-step increments in drug resistance devel~pcd towards penicillin, absolute resistance to streptomycin a~d its clinically more important relative, spectie,omycin, occurred as separate singlc-~tep mutations unrelated to penicillin susceptibilityfl In addition to these chromosomal mutations, an altogether different type of drug resistance, the R-factor (plasmid)-mediated production of penicillinase has been acquired by several gonococcal strains and noted since 1976.j°'~ This specitic/3-1actamase, which hydrolyzes penicillin, typically renders such strains resistant to even heroic doses of the drug. The therapeutic importance of these Various mutations is considerable in thai treatment failure rates are directly

DISSEMINATED GONOCOCCAL INFECTION (DGI) I

propordomtl to the degree of antibiolie resislance among strains recovered] The genetic analysis of antibiotic rcsisrmee in Neisseria gonorrhoeae has been facilitated by the classic tools of tnmsfonnation ~2and conjugation. ut6 Spading and coworkers have demonstrated that low-level (non-penieillinase mediated) resistance to penicillin is due to the additive effects of at least 3 chromosomal genes, designated pen A, mtr, and pen B) 7"1"Tile increments in resistance contributed by each serially inserted gene are two-to-fourfold. The mtr gene also causes an increased resistance to many other antibiotics (e.g., tetracycline, erythromycin), detergents, and dyes, due to decreased envelope perlneability) 9 Hence the earlier epidemiologic finding of multiple-drug resistance was explained by a single mutational event; Although the emergence of low-level drug resistance among gonococcal strains has driven the required dosage of penicillin in maximal Single-session amounts, the remarkable discovery that almost all DGI isolates are penicillinsensitive 2° has prompted a new, low-dose approach to the treatment of that syndrome (see Part ll---Treatment). Whereas only 35 of I l l non-DG1 strains had minimal inhibitory concentrations (MICs) _< 0.3 pg/ml, 32 of 38 DGI organisms were this sensitive. An obvious, but unproven, conclu;don is that mutations to lowt.vel antibiot;~ resistance in N. gonorrhoea,, diminish the invasiveness of the mutant (see Virulence Factors). Unfor!unately, several reports ,tow indicate little, if any, change in local bacterial virulence associated with acqaisiton o f Table 1. Phenotypic Charactefistics of Gr~nococcat ~w~.ins That are Probably Import~]nt for Pathogenicity

Factor

Role in Infection

Pill (colony types I, ll) Lipopolysaccharide (endotoxin) "'LA factor'" Capsule (?) Excreted proteases

Adherence, colonization, resistanc~ to

R-factor (rare strains) Cytotoxin (?distinct from e n d o toxin)

p,hagocytosis Adherence (?), serum resistance (see "Fable 2} Resistance to phagocytosis Resistance to phagocytosis (?) Cleaves lgAt --- resistance m humeral immunity (?) High level resistance to penicillin interferes with routine thffrapy Damages mucosal surfaces without the absolute r0quirement for bacte2 rim adherence

157 Table 2. Characte,istics of Gonococcal Strains That are Particularly Associated With the Ability to Cause Bacteremia

FBcto~ Antibiotic sensitivity

Serum resistance

Avid iron acquisition I?)

Cornmetlts "Wild-type" characteristic. Mutations to low-level drug-resistanCe decrease invasiveness for t~lknown reasons. Provides resistance to the compMment-dependent bactericidal system found in the bloodstream. Probably mediated by a geneiicallydetermined form of lipopotysaccharide that binds eithur ,blocking" or bactericidal antibodies. Needed for survi~a| in blood

(?) "Light" colony coloration

Arg" H y x Ura" auxotype

Found most often during menses; more virulent in attintal mooel. Morn often associated with asymptomatic carriage --~ greater tendency to dis* semination (?)

the high-level resistance (penicillinase) piesmid. '~''~ The relative propensity of such organ~,,1, to cause DGi has not yet been resolved (~ce Part II---Treatment). VIRULENCE FACTORS (Tables I and 2)

Bacterial pathogenicity d,:i~c~-'ts ;~pon a number of pte,nertics that are requn-c~ at vari,~us stagc~ h~ the development of disclose. As ~'~dJ m a n y bacterial infections, that produce,i by N. gonorrhoeae begins with symplomatic or ;.,s~ mptomatic mucosal colonization, procecd.~ to ]o~,d tit,sue penetration, and, in the case ot DGI, to bloods~,ream invasion. Ac,:ordingiy, the organism must adhere to local ti,;su,_" cells in ~he mucous membranes while avoiding the host c,~earanee mechanisms; cv"~de the eellm~r and humeral hnmunc systems; scavci~ge for nutrients while in a hostile environment; ~ i d . finally. ~in the Case of gonococcal arthritiS, must find a saf e nich' h~ or near the svnovium, where ISacterial cells: c a n replicate and produce iissue injury. Although t h e full understam~ing of pai.h0genesis awaits further study, enouehis presently known to eotnment on some:* ~ O~hc f ibaeter.;a]: factors

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EISENSTEIN AND MASI

Fig. 2. Electron micrograph of a gonococcus with multiple pill. x32.350.

important in each of these sequential, occasionally overlapping, stages.

Mucosal Adherence: ('olont' 7)'pes atut Pill Much has been learned about basic virulence factors in the gonococcus in the past 15 yr of investigation. The first major advance was the discovery that colonies of/V. gonorrhoeae grown on specific complex media could be separated into 4 different morphological types. :~':~' Types I and 2, later shown to consist of bacteria containing surface hairs, or pili '7"'~ (Fig. 2), were the only variants isolated from patients and the only ones capable of inducing infection in volunteers. In contrast, colony types 3 and 4 were nonpiliated, nonpathogenic, and found to emerge during nonselective serial subculturing in the laboratory. The necessity for pili in disease probe,bly results primarily from their role in bacterial-host cell adherence. Pili mediate bacterial attachment to epithelial cells,2.~" sperm, ~j and erythrocytes. 3~The importance of attachment in the pathogen,:sis of gonorrhea has been shown by Watt and Ward? 5 Electron microscopy showed that exfoliated urethral epithelial cells had adherent bacteria, many aggregated on the cell surface in clusters. Buchanan and co~vorkers~ba7 have extended t h e binding studies by an organelle-specific approach. They have isolated and purified gonococcal pili and subjected the preparation to a

nunaber of biochemical and physiologic studies. Pill consist of aggregated and uniform polypeptide subunits that are composed of a high proportion of hydrophobic residues, which probably bind to uncharged regions on cell membranes, overcoming negative charge repulsion between bacterial and human cell surhlces. Pili demonstrated high binding altinity to buccal and cervical epithelial cells. The binding was temperature-dependent and blocked by anti-pilus serum. Preliminary data suggested that the pilus receptor may be a gangliosidelike substance.

Mucosal Adherence: Other Gonococcal Stufface Antigens The pilus, while necessary for gonococcal virulence, is not sufficient fi~r it, since several nonpathogenic ncisserial species contain typical pill when examined by electron microscopy.~ Moreover, pill-mediated adherence is certainly not the only mechanism by which gonococci adhere to host cells. Nonpiliated bacteria, though typically less adherent than piliatcd ones, demonstrate moderate attachment to a variety of human cells, including tissue culture cells, sperm and epithelial cells, j~'3'~ The adherence advantage seen for pillared organisms in some cell systems is not seen in others, such as the epithelial surfaces of guinea pigs, the bronchial mucosa of humans ~° or human leukocytes.39"~1-43Watt and coworkers~ have demonstrated that pill, though

DISSEMINATED GONOCOCCAL INFECTION (DGI) I

important, are not essential for attachment to organ cultures of human fallopian tubes. Moreover, they provided evidence that sugar residues on gonococcal surfitce lipopolysaccharide (LPS) are involved in adherence.~4 Other laboratories have investigated specifically nonpilus structures and their involvement in adherence. Swanson s~ has presented evidence that the attaclunent of gonococci to human leukocytes is mediated by so-called "LA factor" on the bacterial surface which is distinct from pilus protein, lie found that this determinant is destroyed by trypsin, chymotrypsin, heat or gluteraldehyde at doses that do not affect pill. Otherwise identical strains with or without LA factor were different in their surface protein structures: I.A bacteria exhibited the presence of a protein band on electrophoresis (approximate molecular weight of 29,000 daltons) not seen with the LA- strain. (Another group of surface proteins that are related to colonial coloration or "opacity," and which may affect mucosal adherence, will be discussed below.) Lastly, an unrelated surface structure long known to be a virulence factor in other organisms, the polysaccharide capsule, has been tentatively identified on several gonococeal strains by three independent groups, ~~-~7although a fourth group, employing high resolution electron microscopy, questioned its existence. 48 Except for the observation that putative gonococeal. capsule ma)' interfere with pilus-mediated adherence, ~ its contribution to gonococcal virulence can only be inferred from what is already known about capsules in other pathogens. For example, the pneumococeal capsule, one of the best studied of all bacterial structures, interferes with phagocytosis by host leukocytes. Antibody to a given capsular type promotes bacterial phagocytosis and protects against infection with pneumococcal strains having homologous capsular polysaccharide.4~ Likewise, the capsule found on the related meningococcus has antiphagocytic 5° and antigenic properties, permitting the development of a polysaccharide vaccine for protection against group A and C meningococci. 5~ Unfortunately, not all capsular polysaecharides make effective vaccines; meningococcal group B polysaccharide stimulates effective opsonic, but not bactericidal, antibodies and is

159

not protective in a model infection system'" (see Host Defense Mechanisms). These studies suggest that the attachment of gonococci to eukaryotic cells involves the participation of two mechanisms: piIi- and nonpilimediated adherence. Which mechanism is dominant probably depends on the particular gonococeal variant and the particular host Cell. Moreover, non-specilic factors may be contributing in wlriable degrees to modify specific attachment mechanisms. Surface charge, steric interference, pit and others 44 may be important modulators. In this regard, nothing is known about the synovial tissue-gonocoecal interaction. Virulence Factors Unrelated(?) to Adherence: Tissue Penetration and Cytotoxicity Although adherence is presumed to be a necessary factor in colonization and tissue tropism, it alone is insultieient for disease production. Watt et ai, using an explanted fidlopian tube as a human organ model, demonstrated that penetration into organ cells by adherent bacteria was an important determinant of cytotoxicity.~ In natural infection gonococci have been observed by electron microscopy within cervical epithelial cells.~4 The preserved integrity of the host-cell's plasma membrane, as shown by thorium-colloid exclusion, suggested that gonococci were being actively phagocytosed. Synovial nlembranes are probably analogous to fallopian tubes ill that pathogen specificity for arthritis production suggests an important role for adherence, and the early intracellular location of bacteria within the synovial cells53'54 suggests the importance of intracellular penetration or phagocytosis. A complementary model of cytotoxicity has been proposed recently by McGee's group. Employing fallopian tube organ cultures, they found evidence for a soluble toxin that was excreted by gonococcal cells. This toxin produced marked cellular damage to ciliated cells prior to bacterial adherence to the mucosa. s5 Although ciliated cells were more susceptible to the toxic action, the nonciliated, mucoussecreting cells were much more susceptible to attachment a n d penetration by gonococci,s~ Thus, adherence, penetration and eytotoxicity

160

might be independent events that require unrelated ell'ectors.

Ftlclors Promolitlg Bloodslream ]nvasiveness: Colony Coloralion (Op~wity F~wtor) Certain phenotypic variables of the bacteria that modify pathogenicity have been discussed, including piliation, encapsulation and LA positivity. Recently, Swanson and coworkcrsJ~ have presented data that another phenotypie attribute, recognized by colonial coloration and demonstrated to be associated wilh a spccilie protein component in the outer membrane, results in altered leukocyte binding, independent of piliation of I.A positivity. These results were corroborated by Lambden and co-v~orkers,5b who demonstrated that variation in colonial coloration was associated with variation in a cell wall protein (designated protein 11) extracted from the bacteria. Depending on the specific variant of protein isolated, cells displayed altered antibiotic resistance, adhesion to human buccal epithelial cells, red cells or leukocytes, and resistance to the bactericidal action of serum. It is yet to be shown that the altered protein II is actually responsible for these phcnotypic properties since pill. as welh have been found to vary biochemically ~7 and functionallys~ among the colonial variants. Regardless of the exact mechanism of phenotypic alteration, it is most interesting that infected women, when cultured during the time of menses, give rise to transparent (light) cok)hies but. when cultured during midcycle, give rise to opaque (dark) colonies of N. gonorrhoeae, s9 Since DGI and GCA occur most often near menses, tllese findings may indicate a difference in the ability of these variants to disseminate. This hypothesis was supported by studies performed by Salit and Gotschlich60 using a chick embryo model. When gonococci from light or dark colonies were inoculated by intravenous challenge, bacteria from light colonies were enormously more virulent than those from d a r k colonies, independent of encapsulation and piliation. It "is not yet known what association these in vivo results have with all the in vitro results described above, since different strains and a s s a y systems were employed. Phenotypic variations o f both pilus and outer membrane are likely to be critical determinants

EtSENSTEIN AND MASt

of bacterial virulence. Moreover, it is conceivable that control of the synthesis of pilus and outer membrane proteins are coregulated through dependence on a genetic signal that provides advantages to the bacterium by coordinating its response to environmental pressures. Such genetic signals have been found in other bacteria (e.g., cyclic A M P) and have been shown to increase bacterial clliciency by coordinating synthesis of important proteins,

I'Jvading tiosl Defenses: Serum Resislatlce One aspect of DG! is the common lack of overt genital infection such as prostatitis or pelvic inflammatory disease (PID). This linding has led investigators to question whether those strains which produce DGI may be similar to those causing asymptomatic colonization but different from those that produce PID and urethritis (Table 2). Indeed, strains which produce either DGI or asymptomatie disease (that is, carrier States) are typically penicillinsensitive and often possess a unique nutritional requirement for arginine, hypoxanthine, and uracil ( A r g l t y x - U r a - a u x o t y p e ) ; 6u6' and strains producing DGI are able to evade the serum bactericidal system, in marked contrast to other strains. It was first shown, in 1937, that fresh defibrinated blood from healthy donors killed non-DGl strains more elliciently than DG! isolates. ~ Later, DG! strains, unlike urethritis strains, were found to be ahnost invariably resistant to the complement-dependent bactericidal activity of normal human serum. 64 The "'natural" or preimmune bactericidal antibody, elt'ective against non-DG! strains, is probably directed against gonococcal lipopolysaccharide (LPS) of a certain type 6~and appears to depend upon normal lgM activity? 6 In contrast, in one patient examined, the immune antibody that developed after an attack of DG! was of the lgG class, but also directed against the bacterial LPS, or endotoxin.07 In another study, DGI strains, in contrast to noninvasive ones, appeared able to bind blocking antibody of the lgG class to their surfaces,6~ possibly preventing the natural bactericidal antibodies f r o m attaching to bacterial receptor sites. Whether or not LPS from DGI strains differs from that of non-DGl strains as antigen for the

DISSEMINATED GONOCOCCAL INFECTION {DG|) I

natural or elicited immune response is yet to be determined. The virulent i)GI straihs are therefore both serum-resistant and antibiotic-sensitive, an association n o t unique to the gonococcus. Enteric bacteria that cause bacte'remia are more serumresistant than comparable, but noninvasive, strains recovered from urine, stool, skin, and mucous membranes. ~971 Antibiotic-resistant mutants of Salmonella, 72 NeL~'seria meningitidis, 73 and various grain positive cocci 7~ were less virulent when tested in the appropriate in vivo model, The precise mechanistns by which these mutations alter ~bacterial ability to produce infection and inwide the bloodstream are poorly understood. It is likely, however, that the bactericidal action of serum minimizes systemic invasion by limiting the proliferation of serumsensitive strains in the bloodstream. Mutations to antibiotic resistance may decrease virulence by also slowing bacterial growth; such an effect has been reported in gonococcal strains that had acquired low-level resistanceby genetic manipulation. 75 Lastly, the recent discovery that, unlike uonpathogenic neisserial species,76 strains of both N. gonorrhoeae and At. meningitidis excrete a protease that specil'ically cleaves imtnunoglobulin A (lgA), subclass 1,77and inactivates it, 7~ suggests that this enzyme is important in gonococcal pathogenicity at the mucosal (secretory) level. The further observation that both IgG and subclass lgA2 resist proteolytic attack is of unclear signilicance since the relative amounts and protective powers of lgG and the 2 igA subclasses at the genital mucosa are unknown.~6 As yet no distinction has been made between DGI and non-DGI strains in the efficacy of their proteases.

Evading ttost DeJenses: Leukoqvtes Although marked differences between the ability of DG! and non-DGI strains to avoid complement-mediated lysis exist (see above), no such difference has been demonstrated for leukocyte interaction. One inference is that avoidance of phagocytosis may not be relevant for bloodstream invasiveness. Nevertheless, this property may be important at the initial mucosal stage since not only do piliated organisms adhere better to epithelial cells, they adhere less well to

161

leukocytes (see above). More recently it has been shown that piliated organisms, even when they do attach to leukocytes, resist phagocytosis and intracellular lysis. 79

iron-Dependent Effects A recent series of experiments in Finkelstein's laboratory s°-s~ has shown that organisms that tend to produce septicemia, such as N. meningitidis; t l . htfluen:ae type b and Pseudomonas aeruginosa, when compared to less invasive species, such as Shigella and V. cholerae, a r e more lethal to chick embryos at low, but not at high, concentrations of iron. Of note strains of N. gonorrhoeae that produced DGI displayed similar iron-related effects as compared to non-DGl strains. The authors speculated that invasive bacteria might be more adept a t scavenging for iron, an element probably required for bacterial growth or virulence. The Nature o f the Target Cell as a Determinant of Bacterial l'athogenicity Cells obtained from various p a r t s of the human anatomy demonstrate markedly different propensities for gonococcal attachment: Epithelial cells from buccal mucosa bind piliated gonococci more avidly than non-piliated ones, whereas leukocytes do the reverse. 39 in fact leukocyte-bacterial association may depend more on a protein comPonent in t h e bacterial membrane than on pill pc1: se. ~9Cells from bronchial mucosa bind gonococci less well than cells from t h e cervix, which may help explain the rarity of gonococcal bronchitis. The mechanisms responsible for the extent of binding by a given cell are poorly understood, but m a y depend partly on the number of pill receptors on the cell surface. ~'~7 Adherence is probably mediated in various tissues byadditional ligands as well, such as LPS-sugar residues'u and LA factor, 39 making binding characteristics of different cell surfaces complex and dependent on multivalent affinities. As discussed above the ultimate outcome of tile bacterial-host cell interaction may involve intracellular penetration as much as surface attachment. Except for the work of Watt ~ or McGee, 5~ little is known about gonococcal penetration i n general and almost nothing abou t possible differences in thesusceptibilitY of various tissues. Unlike most other jzram negative bacteria, the

162

EtSENSTEIN AND MASI

gonococcus ahnost always clltlSeS arthr.'dgia when it invades the bloodstream. Therefore, it is likely that the synovium is interacting with the gonococcus in a-specific way.

Implications of the Recentl), Recognized R-Factor As yet the acquisition of t h e [~-Iactamase ph|smid, a classic R-factor, has not produced a demonstrable change in gonococcal virulence. Two eases of DG[ associated with ~3-1actamase producing strains' have been reported separatelyflJ::a Although the genetic acquisition of mutations coding for low-level resistance to penicillin probably reduces the capacity of the organism to disseminate, that of high-level resistance may not further limit such potential. However, the data are too limited for conclusions to be drawn at this time. HOST DEFENSE MECHANISMS (Table 3)

tluotoral lmmu/te Response The study of immunity to infection with Neisseria gonorrhoeae is complicated by the likelihood that host response to mucosal infection differs from the response to disseminated infection, and by the fact that the role of classic parasite-host interactions, such as complelnentdependent bactericidal antibody, opsonization, secretory antibody, and cellular immunity in these 2 syndromes, is not well-defined. For example, Kearns and associates found that in spite of a measurable immune response to one attack of urethritis, subsequent attacks of gonorrhea were not prevented.8J An immune response that is broadly protective may be impossible due to the marked heterogeneity of such antigenic components as pill,~4's~ outer m e m b r a n e proteinfl 6 and lipopolysacchaTable 3, Host Factors That Promote Gonococcal Dissemination Factor

Menstruation

Genetic def~ciertcy of C~, C,~, C~, or C,,

Comments r'hysical state or cervix (e,g., pH) may promote selection of invasive strains ("light" colonies). Breakdown of normal mucosalcapillary barriers, Patient's serut~nis unable to C ~ ~ plete cornplement-dep~Jndent killing of bacterial

uride. ~5'~79t A major obstacle to the use of purl'lied, isolated pill as a vaccine against gonorrhea has been the marked heterogeneity of pilus atdigens and the high specilieity of secretory antipi~ lus antibody capable of bloc~:ing mucosal attachmentfl~ Thus, immunity may be type- or even st rain-s peci fic~o.~t Except in rare instances, gonococcal infection begins with mucosal colonization, whether that surface be urethral, cervical, pharyngeal, anal, or conjunetival. Uncomplicated urethral disease in males9z and f e m a l e s 9~ elicits secretory lgA antibodies. Genital antibodies can inhibit the adherence of bacteria to epithelial cells in vitro ~4 but are active only against homologous strains. Although it is unknown whether parenteral immunization elicits secretory lgA, in chimpanzees it has been shown to elicit strain-specific bactericidal antibodies that were subsequently protective against urethrally challenged pathogens. 95 In this model, degree of protection was correlated with degree of strain-specific bactericidal antibody in the serum, h| contrast other investigators, studying natural infection in humans, have found serum bactericidal status of little protective value in the urethral syndrome: 4 of 13 males with urethritis had preexisting strain-specific antibody, yet still developed gonorrheafl6 However, controlled studies are needed to better evaluate the possible protective role of secretory and circulating antibodies in local and disseminated gonococcal infection.

Serum Complement Deficiencies In contrast to genital disease, the development of DG! invariably requires strain resistance to serum killing,z:'6: Occasionally this condition is met by the inability of the host to complete the requisite complement cascade initiated by bactericidal antibody. Several "'experiments of nature" have demonstrated the marked susceptibility to DGI of individuals lacking terminal components of complement. To date, homozygous deficiencies of C5, C~, C7 and C~ have been described, all with associated neisserial bacteremia. 9~71°°In each case, restoration of bactericidal activity against the infecting strain was accomplished by addition of the purified missing component to the patient's serum. The importance of serum bactericidal activity in protecting individuals from DGI is reminis-

DISSEMINATED GONOCOCCAL iNFECTiON (DGI) i

cent of the association of serum bactericidal antibody deficiel}cy and bacteremia due to Neisseria menhsgitidis. I°~a°~ The establishment of bactericidal antibody of the meningococcus (ill this case with polysaccharide vaccine) provides marked protection from bactcremia in the presence of a normal complement system, but only small reduction in mucosal colonization) °'~

163

O

GONORRHEA REPORTED TO CDC 1941-1978 CIVIUAN CASE RATES (INCIDENCE)BY VEAR

ee

Opsonization attd PhugocytosL~' Opsonic activity, unlike the bactericidal system, is not dependent on terminal complement components and, by itself, will not prevent gonococcal dissemination. 9~'99'~°4 Mucosal exposure to the gonococcus provokes detectable opsonic antibody) °s as well as enhanced lymphocyte res~ponsiveness to gonococcal antigens, s-' but the signifiea~Jce of these immune responses is unclear Since pillared organisms resist phagocytosis (see above) and the pathologic halhnark of gonorrhea is bacteria-laden leukocytes, opsonic antibody (possibly directed against pill) may be important in localized (e.g., urethritis, arthritis) immune response. (See Ptaut ~°6 for a recenl review of local immunity in gonococcal infections.)

Other Factors The role of cellular immunity is poorly understood in gonococcal infection, although it is known that H LA B-27 histocompatibiJity locus does not predispose individuals to D G I ) °7 EPIDEMIOLOGY

Incidence of Uncomplicated Disease (Fig. 3) After World W a r I! and the widespread use of penicillin for gonococcal infection, the annual number of new reported cases (incidence) of gonorrhea in the U.S. decreased from an early peak of over 300 cases/100,000 population in 1947 to a low of 100 cases/' 100,000 in 1957. The rate stabilized at this level until the mid-1960s, when a marked increase began) °~ By 1976 the annual number of reported cases had reached more than one million, with the estimated unreported cases bringing the total close to two million) °~ I n 1973, programs were implemented to control gonorrhea, and in 1977, the reported cases decreased below 1976 (0.2%), t h e first decrease in 16 yr.

C)

1940 45

50

55

60

65

70

75 80

CALENDAR YEARS Fig. 3. Reported incidence of' gonorrhea by y~ar ( 1 9 4 1 - 1 9 7 8 ) . Civilian case rates snd numbers of cases. Adapted from HEW Publication No. (CDC) 79,8241 (p. 26},

Based on the reported cases, the Center for Disease Control made several observations about the epidemiology of this disease: (1) gonorrhea was reported most frequently from large urban are~,.s, with the highest incidence in the southcast; (2) sexually active adults between ages 20 and 24 yr had the highest age-specific case ra~e, followed by teenagers 15-19 yr of age: (3) males constituted 60% of the reported cases; (4) pelvic inflammatory disease (Pll)), an important cause of sterility, ectopic pregnancy, and hospitalizatiers, occurred in 17% of all women known to have gonorrhea (229.000 cases of gonococcal P I D / y e a r ) ) °9 The annual cost, extrapolated from data from one city hospital, has been estimated to be greater than 200,000.000 dollars nationally) ~° The progressive increase in incidence has b e e n ascribed to greater sexual permissiveness coinciding wit!~ the introduction of oral contraceptives in the early 1960s. izl'~-' One measure of the effect of promiscuity is the observation that ~male incidence of infection multiplied 20-fold among, those with five or more sexual partners compared to those with only o n e . 1~.

Prevalence o f Asymptomatic Disease The factor contributing most t o the epidemic of gonorrhea is the large reservoir of untreated asymptomatic individuals. T h e m a g n i t u d e of this population is denaonstrate d by results :of large scale bacteriologic screening o f more than

164

nine million women during 1976. The overall prevalence of positive gonococcal cultures front these asymptomatic individuals was 4.3%, with ranges from 1.6% among private family planning groups to Iq% in venereal disease clinics) °~ htcrcased risk has been associated with women who were young, single, nonwhite, and of low socioeconomic status)C~ l}ariser has estimated that 90% of all culture-positive females were asymptomatic carrjers,t in contrast to 10% of positive n:ales) ~4 More recently, llandstield and associates ~1~ found that 66% of infected U.S. servicemen were asYml)tOS)lalic, some for as long ~s 5 rod, bringing into question the older concept that ascribed the vast proportion of the covert reservoir to females) t.a An addititmal subset of great epidemiologic importance is made up of individuals with phuryngeal infection or colonization. Women and homosexual mete, particularly those practic-. inl? fellatio, are at great risk of devel6ping this conditio~,i. Wiesner reports that the prevalence t~f po~fi ve cull ures from |he tbroals of t:omosexuai men may be as high as 25%, with the pharynx being the only positive site in about 5% of the tt~tul infected group. |~ Tlae importance of gonococcal pharyngeal disease is multiple: (I} it is el'ten a.,;ymptomatic; ~7'tts (2) i t is dillicult to treat: 1~ and:(3) it may be an iniporlant source for gonococcal bacteremia) ~'tz° Thus, carriers of either sex ate now thought to be important in the transmission chain. For this reason most workers in the [ield emphasize the need for "'epidemiologic treatmenr' directed at those individuals with or without symptoms recently exposed sexually to others with proven gonorrhea. "Frot2smis.~iot~

In the best controlled study of risk of male acquisition of gonorrhea via coitus with infectic,us prostitutes. Holmes et al. estimated a 20% r a t e a f t e r a single sexual act) 2~ Other, unpublished, reports put t h e r i s k at only 5%) Is The prevalence of positive cultures from named contacts,: male or female, of known infected ind;.viduals is about 4 0 ~ - - 5 0 0 ~ . t!'IA21'122 Rein argues that ~ince this prevalence rate is similar tbr both sexes, and since the total male-female ratio approaches unity when thorough contact tracing is pursued, the ease of transmisskm is probably similar in either direction) |~ One exception is pharyngeal disease, where the rate

EISENSTEIN ANt) MASt

of genital-oral transmission is higher with fcllatio than with cunnilingus, lt~ Nonvenereal transmission in adults is a rare, but reported, event, t~s'J~3 In addition there exists at least one unpublished case of a laboratory technician who developed gonococcal bactcremia after a pipettia~g accident (P.F. Sparling, personal communication, 1976). (See Israel ~2~for a review of childhood disease.I

DISSEMINATION FACTORS S e x Risks

The incidence of DG1 among all patients will} symptomatic gonorrhea was estimated to be 1%3% in 1929. ~:s tn the antibiotic era, a report from Sweden calculates a 3% rate for females and 0.7% for males) '6 If the denominator consists of all gonococcal infections, including asymptomatte ones, the frequency calculation drops to 0.3-0.1% primary infections) ~7 Of particular note is the marked change in sex ratios over the last 50 yr. Wehrbein's study or 610 cases of gonococcal arlhritis in 1929 included only sevel: females; ~'s 8 yr later Keefer and Spink reported a 3:1 naale-female ratio) 2s Interpretation of these older studies is clouded by the inability to exclude nudes with Rotter syndrome, the low percentage of delinitive cases (delined as isolation of gonococci front either blood or joints), and the bias against diagnosing disease in females due to the relative ease of idenlifying organisms |Yore male genital exudates. W h e n the epidcmiology of DGI has been reexamined over the last 20 yr, these sex ratios have been reversed) '~ 14° Age Risks

The age-specific incidence of DGI parallels the age-specitic incidence of gonorrhea, with only rare cases above the age of 60. TM Occurrence of dissemination is uncommon, but well reported, in neonates z~-' and children :~a44 where the course of the illness is similar to that in adults except, perhaps, l\~r a higher incidence of septic arthritis ~4~and lower incidence of dermatitis) 4z Of historical interest is a 1927 report of a large nosocomial outbreak affecting 44 infants in a hospital nursery, where 75% developed polyarthritis but few had oermanent residua. Menstruation atul Pregnamg' Risks

Episodic host factors, particularly menstruation a n d pregnancy, are itnportant as well. ~a6

O)S,SEM!NAIED GONOCOECAL INFECTION (DGI) I

ltohne~ lound that 71% of females altlicted with DGI were either in the lirst week of the menstrual cycle, pregnant or postpartum, m More recent reviews corroborate this striking finding. ~~'~4~'~ itohnes speculates that tile decreased risk of bactcremia during the third week of the menstrual cycle is related to local host factors that defend against the parasite; during this period endocervical shedding of organisms is mirfimal, peroxldasc-mediated bactericidal activity of tile mucous is maximal, and cervical p l l is least conducive to gonococcal growth. ~3.s

Portal (~ Ento' of lnfectiot~ Location of initial parasite cokmization on mucosal surt,tces may also inlluencc the likelihood of subsequent dissemination, in a study of 60 patients with I)GI, Welsher et al. isolated gonococci from the pharyr~× in 10, of whom live had the pharynx :is the sole primary site of recovery. ~t~ ()f partictdar interest was the 40% prewdence of pharyngeal infection among the 15 heterosexual men in this group, in comparison only three of 95 infected heterosexual men without DGI had positive throat cuhures (p < ,001). Hands!ield, utilizing a larger data base from the same institution, also suggested that pharyngeal infection might be a risk factor for I)GI. t4° Without prospective analysis, though, one cannot include the less likely possibility that the pharynx becomes secondarily infected from a bacteremia arising from an undetected locus.

,,lsymptomatic ItV~ection Of perhaps greater importance than primary localization is the frequent lack of mucosa} symptoms in disseminated infection in both males and females, ~°J3s'~5 even with an infected intrauterine device, in9 Furthermore, pelvic inltammatory disease and DGI rarely coexist, x~9 The pathogenesis of dissemination From a covert focus is unknown, but several alternatives are possible. The simplest model is that the likelihoed of a patient developing DGI is directly related to the length of time of mucosal coloniz~tion, and a patient with syraptomatic infection will tend to be treated sooner than one with asymptomatic carriage. Thus, length of risk for dissemination would be more important than degree of risk per unit time. Alternatively, the combination of host and

IB5

parasite factors that result in acute inflammatory response and focal symptomatology may contMn tile organism at the site of primary colonization. Crawford and associates ¢~° have recently shown that strains recovered from patients with asymptomatic urethral disease have nutritional requirements for arginine, hypoxanthine, and uracil ( A r g ' , H y x ' , Urn", auxotype), similar to strains associated with DG1. ~9 This observation supports the epidemiologic association between these two conditions but does nut elucidate a causal mechanism. At variance, at least conceptually, with these results are those of Catlin and Pace :~° who find that strains recovered from throats of asymptomatic clinic patients are not typically of that auxotype. Further insights into DGI pathogenesis may require controlled experiments utilizing an appropriate model s~stem of infection.

Other Factors The risk of prltr~ary g,onococcal infection progressing to dissemination is not the same in all situations. Previous mentioi~ of strain-specific virulence factors and of isolated examples of conaplement component deticiencies in the host has been made in this review. Mention has been made (above) of tile association of specific "coloration" types of bacteria with the menstrual cycle. PATHOLOGY OF GONOCOCCAL ARTHRITIS AND DER MATITIS

Three major subgroups of patients with DGI have been described, based on clinical and bacteriologic data: ( l ) bacteremic stage--positive blood cultures, characteristic dermatitis, migratory arthralgias; (2) septic joint stage~oligoarthritis with positive joint culture; (3) indeterminate---variable presentation, u9 Whereas some patients present within one of the above groups, others progress from the bacteremic to the septic joint stages over several days. ~3S Frequently the gonococcus cannot be recovered from any of the involved regions, a problem that led early investigators to postulate hypersensitivity reactions as the cause of much of the observed pathology. ~ More sophisticated methods o f recovering organisms m a n d antigenic products !'6"~ in tissues, including tile use of hypertonic media for culturing L-forms, tsz havesubsequently proven the infectious nature of the typical lesions of

166

EISI~NSTE|N AND MASI

Fig. 4 (A-D), Various superficial and papulonecrotic lesions of a 48,yr-old divorced woman who had painful skin ulcers and migratory arthritis of 2 w k prior to hospital admission, After examination of t h e skin lesions further probing of her personal history revealed that silo was divorced and had several sexual encounters with a "particular m a n " over the past several m o n t h s . The patient had noted increased vaginal discharge f o r the past month w i t h o u t dysurie. N. 9onorrhot~ae was cultured from the endocerviK, The palmer surface of her hand revealed several superficial healing lesions at the base, a pustule on the ring finger, an ulcerated pustule on the index finger, and an ulcerated lesion of the thumb, which was biopsied (A}. The dorsum of the hand showed a necrotic pustule on a purpuric base at the distal interphalangeal joint of the ring linger (B|, L o w - p o w e r (60 ×| microscopy of the thumb biopsy showed a superficial ulcer with pure pus formation and diffuse inflammation in the dermi s and subcutaneous areas, including involvement of vessels of varying size (C). High-power (240 × | shows thrombus formation and necrosis of vessels with polymorphonuclear leukocyte infiltration of wBtls (D). lower right).

arthritisand dermatitis. These pathologic, mani, festations represent tissue d a m a g e resulting from infection and secondary inflammation, at least in the localized joint infection.

Skin Lesions (Fig. 4A-D) The dermatitis is characterized by the evohltion of acrai macules to papules and vesiculopustules on an erythematous base. Individual lesions are usually about 5 mm in diameter ~'~3but may also appear as large hemorrhagic pus: tules 1*9"l~ or even hemorrhagic btillae) ~J In a careful hi~lopath0!ogie study o f g0noc0ceal derm~4titis in 12 patients, Shapiro and c0-work ers found:t!lemost:Significant changes iln the eutis./with sec0ndai'y epidermal pathology.! s4 speeifiC~di~C, lihere ; w a s m a r k e d small vessel ~

vaseulitis and perivaseular inflammation consisting mostly of polymorphonuelear angiitis. Gonococcal dermatitis, unlike leukocytoclasie angiitis, was marked by: "'inlra-epidermal neutrophilie pustules, involvement of the deep as well as superficial vessels, pronounced hemorrhage, and microthfombiY Features occasionally seen in leukocytoclastie angiitis b u t m o r e typical of gonococcal dermatitis were t h e admixture of mononuelear inflammatory cells• and the pre. senee of inflammatory Changes beyond the blood vessels. These observers, 1~4 as well as others,133'139 felt that the pathogenesis of these lesions Wereseptic infarcts of the skin, Proving the direct presence of organisms in tissue has been difficult, though, since the inajority of gram stains and Cultures of

L~ISr'~.E.MINATEDGONOCOCCAL INFECTION (DGI) !

lhese lesions have been negative. ~"'ts~ Nevertheless, the concomitant gonococcal bacteremia. ~ the occasional recovery of organisms in the lesions, ('~ and positive fluorescent antibody response in the majority of skin biopsies )~'~6 are slrong arguments in favor of a septic rather than an indirect immunological etiology. Shapiro and coworkers ~= stressed the likelihood of a local Shwartzman phenomenon occurring once the fastidious bacteria die releasing endotoxin. In this regard, they pointed to similar dermatohistopathologic features of meningococcemia.

167

with the major differences being the greater degr~:e of hemorrhage (paralleling the clinically evident purpura) and higher recovery rate of live organisms in meningococcal disease, j~4 Several investigators have noted skin lesions more typical of immunologieally mediated disease in several patients with gonococcemia. In particular subcutaneous nodules resembling erythemia nodosum, t:6 urticaria, t~v generalized crythema, or erythema multiforme ~5~ have been observed. Whether or not immune complexes play a role in manifestations of DGI is a subject

!

Fig, 5. Photomicrographs of synovium from a patient with gonococcal arthritis. (A) Margination of polymorphonu* clear leukocytes in a subsynovial vessel (arrows) with synovial hypertroph Y (hematoxylin and eostn. >~=480). (B| Dipiocoocal forms (strews) in synoVial lin!ng cells.. {Gram stain~ × 1200). (Reprinted With permission from the J o u r n a l o f Infec-" tiOUS '

Diseases

13o(2tfs3-~as.J

1974;

i¸

168

o f d e b a t c , One groups found circulating complexes in the majority of studied with gonococcal seisticemia in contrast, with only l o c a l i z e d disease, Ls'~ but a slt|dy It~jdisputed these findings.

EISENSTEIIN AND MASI

immune patients to those separate

,4rticular Lesions (Fig. 5) 1"here is little doubt about the direct causal role of bacteria in .the typical septic joint° since bacteria can be readily isolated from purulent synovial effusions. !~° T h e proportion of positive cultures increases wilh the degree of synovial tluid leukocytosis and the duration of symptomsJ 40 T h e Pathological changes in the joint space are typical ,~.ro t h e r acute septic arthritides and vary in degree depending on the duration o f iullammalion, l)isease is limited to synoviai and tenosynovial tis~,ac early, with subsequent spread within the joht~ cavity to cartilage, which is irreversibly gestr~wcd i f the oroccss its not halted. Assoeiaied changes in ti~e s e q u e s t e r e d joint spat:: m a y themselves be important in the p r o g r e s s i v e j o i n t d e s t r u c t i o n qnd i n c l u d e increased pressure, lowered pll and glucose concentration, and activation o f proteo;ytic enzymes liberated from (lying polymorphonuclear neutrophils.l~! T i t u s , the p r e s e n c e o f m a r k e d s u p p u r a t i v e effusions in the joint space requires d r a i n a g e a s well as a.~,tibiotie therapy (see Part ! I ~ - T r e a t m e n t ) , In contrast to palients with septic joints, m a n y present with ~uigratory arthralgias, tenosynovitis or sterile synovial ell'u-

sions with little inllammatory reaction, and are cured with antibiotics alone,

Visceral Lesions in the pre-antibiotic era, some paticnls developed uremia a f t e r p r o l o n g e d gonococcal sepsis, "2 F u r t h e r m o r e , a small group o f patients devclbp evidence of myocarditis, which m a y lead to t h e erroneous diagnosis o f acute r h e u m a t i c fever, soj or hepatitis, mimicking a vir'al etiology. Although tile pathogenesis of these disorders is not well understood, some investigators tentatively ascribed the rheumat01ogic manifestations t o circulating immune complexes and the heart and liver abnormalities to the " t o x i c " Consc~ quences of bactcremia, t~4 Rarely the gonococcus can p r e s e n t with a fulminant W a i e r h o u s e Friderichseu syndrome typical or overwhelming meningococcemia and probably due, at least partially, |o massive release o f potent endotoxin into the circulationJ "'~ A m a j o r impediment to research involving the pathology and pathogenesis o1"gonococeal arthritis is the present lack of a suitable animal model. Although perihepatitis and endocarditis have been produced in a rabbit model employing a n intracRrdiac catheter and intravenous injection o f bacteria, "" neither a r t h r i t i s nor dermatitis resulted. ACKNOWLEDGMENT We thank Drs. P.F. Sparling and M. Miller for critical review, Drs. A. l|isno and G.F. Bale for pathological specimens, and S. White for secretarial assistance.

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DISSEMINATED GONOCOCCAL INFECTION (DGI) 1

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E|SENSTEIN A N D IMASI

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DISSEMINATED GONOCOCCAL INFECTION (DGI] I

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