Moraxella catarrhalis: Pathogenic Significance in Respiratory Tract Infections Treated by Community Practitioners

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632 Mraxella catarrhalis: Pathgenic Significance in Respiratry Tract Infectins Treated by Cmmunity Practitiners Gillian M. Wd,* Barbara C. Jhnsn, and Jseph G.

1 632 Mraxella catarrhalis: Pathgenic Significance in Respiratry Tract Infectins Treated by Cmmunity Practitiners Gillian M. Wd,* Barbara C. Jhnsn, and Jseph G. McCrmack Frm the University fqueensland Department fmedicine and Department finfectius Diseases, Mater Misericrdiae Hspital, Suth Brisbane, Queensland, Australia We prspectively studied the pathgenic significance f Mraxella (Branhamella) catarrhalis islated frm 212 patients f cmmunity practitiners in Australia. This rganism was mst cmmnly islated during winter and early spring, and 92% f islates were p-iactamase prducers. On the basis f predetermined clinical and micrbilgical criteria, 42% f the islates were definitely pathgenic, 7% were prbably pathgenic, 21% were f indeterminate pathgenicity, and 30% were nnpathgenic. Factrs assciated with pathgenic significance included pneumnia r brnchitis (87% f patients), predispsing respiratry r systemic cnditins (62%), islatin frm sputum, and pure islatin. Thirty-six percent f patients were <5 years ld, but nly 9% f islates frm these patients were pathgenic r prbably pathgenic, a finding that reflects the fact that nasalswab and naspharyngeal-aspirate sampling is a cmmn practice. Islates frm lder patients were mre likely t be pathgenically significant. An assessment f the pathgenic significance f M. catarrhalis islated frm a patient in a cmmunity practice shuld take int cnsideratin factrs such as the patient's age, clinical illness, and underlying cnditins; the presence f ther rganisms; and the surce f the islate. Mraxella (Branhamella) catarrhalis was nce cnsidered a nnpathgenic cmmensal f the upper respiratry tract (RT). Hwever, ver the past 10 years it has gained respect as a ptential pathgen [1]. The three clinical cnditins mst cmmnly assciated with this rganism are titis media (in children), acute brnchitis r pneumnia (in adults with chrnic bstructive pulmnary disease), and sinusitis [2]. It can als cause a wide range frt and systemic infectins. The apparent increase in pathgenicity has cincided with an increase in the number f,b-iactamase-prducing strains. Prir t 1980, < 10% f islates were,b-iactamase-psitive, while mre recent reprts suggest a 90% psitivity rate [2-4]. M catarrhalis is als a cmmn clnizing agent f the upper RT. Clnizing rates f 54%-78% have been reprted with regard t children [5, 6], whereas significantly lwer rates (2%-3%) have been reprted fr adults [7, 8]. Clnizatin f the upper RT ccurs mst cmmnly in winter [9] and in titis media-prne children [5]. Investigatrs using an in vitr Received 23 March 1995; revised 13 Nvember Findings f this study were presented in part at the annual scientific meeting f the Australasian Sciety fr Infectius Diseases, held in Canberra in March Financial supprt: Gillian M. Wd was a recipient f a Natinal Health and Medical Research Cuncil Schlarship. The study was partly funded by a research grant frm SmithKline Beecham. Present address: Directr f Micrbilgy, Prince Charles Hspital, Chermside, 4032, Queensland, Australia. Reprints r crrespndence: Dr. 1. G. McCrmack, Department f Medicine and Infectius Diseases, Mater Misericrdiae Hspital, Suth Brisbane, Queensland, 4101, Australia. Clinical Infectius Diseases 1996;22: by The University fchicag. All rights reserved /96/ $02.00 rpharyngeal cell assay have shwn that adherence f M. catarrhalis t epithelial cells is increased in the winter [10] and in the elderly, especially thse with underlying disease [11]. It is likely that clnizatin and adherence precede and facilitate infectin in the upper and lwer RT. We have previusly examined the pathgenic significance f islates f M catarrhalis recvered frm hspitalized patients [3]. We nw reprt n a prspective study f the clinical and epidemilgic characteristics and the pathgenic rle f this rganism in cmmunity practice. Our aim was t identify factrs that wuld assist a clinician in determining the likelihd that islatin f M catarrhalis frm any given patient is clinically significant. Methds Our study chrt cnsisted f cnsecutive patients frm whm M. catarrhalis was islated, as reprted by a single labratry t cmmunity practitiners. Specimens were prcessed accrding t the standard labratry practice apprpriate fr the specimen type. Fr this study, nly sputum samples f high bacterilgic quality were analyzed. A specimen was cnsidered adequate if it cntained < 10 epithelial cells and >25 neutrphils per lw-pwer field and if mderate t numerus gram-negative diplccci were seen n the gram stain; a sample was cnsidered apprpriate nly if it cnsisted f material frm the infected site [12]. All islates were cultured n either 5% hrse bld agar r chclate agar. They were identified n the basis f typical clnial mrphlgy, gram-stain appearance, xidase and butyrate esterase psitivity, and failure t prduce acid frm glucse, maltse, sucrse, and lactse [2, 13].,B-Iactamase testing

CID 1996;22 (April) M catarrhalis Respiratry Infectins 633 was carried ut by means fthe standard chrmgenic cephalsprin test (Nitrcephin; Oxid, Melburne, Victria, Australia).

2 CID 1996;22 (April) M catarrhalis Respiratry Infectins 633 was carried ut by means fthe standard chrmgenic cephalsprin test (Nitrcephin; Oxid, Melburne, Victria, Australia). Antibitic susceptibilities were determined with use f the disk diffusin methd f the Natinal Cmmittee fr Clinical Labratry Standards. M catarrhalis islates recvered by a large private pathlgy service between May 1992 and Octber 1994 were included in the study. The pathlgy service's catchment area includes the Brisbane metrplitan area and mst f Suthern Queensland and nrthern New Suth Wales. Mst f the micrbilgical investigatins carried ut were bacterial cultures. This is cnsistent with the usual practice f cmmunity-based dctrs, wh d nt rutinely lk fr evidence f "atypical" rganisms such as Chlamydia species. Infrmatin n the age f the patient, date f the specimen, specimen type, micrscpic findings, presence f ther rganisms in culture,,8-lactamase prductin, and susceptibility patterns was cllected. The lcal dctr wh initiated the testing was cntacted by phne t btain infrmatin abut the patient. Symptms, signs, presumptive diagnsis, results f ther tests perfrmed, antibitic( s) used, and whether the patient was hspitalized were all dcumented. The lcal dctr was als questined abut whether the patient's cnditin imprved with initial treatment r whether administratin fa different antibitic was required. The fllwing factrs were cnsidered the criteria fr determining the pathgenic significance f an islate: (1) psitive clinical evidence f infectin, cnsistent with the disease spectrum assciated with M catarrhalis (e.g., a histry f recent cugh with sputum prductin, sinusitis, r titis media); (2) M. catarrhalis as the predminant ptential pathgen islated frm an apprpriate and adequate specimen; and (3) subsequent clinical respnse t treatment with an antibitic t which the islate was susceptible. The pathgenicity f M catarrhalis islates was cnsidered t be significant if criteria 1, 2, and 3 were present; prbably significant if criteria 1 and 2 were present but criterin 3 was unknwn (usually because the patient was nt seen again by the lcal dctr and was therefre presumed t be cured r t be feeling better); indeterminate if criterin 1 was present but 2 was nt, irrespective f whether 3 was present; and nt significant if criterin 1 was nt present. In rder t minimize subjectivity the data were cllated independently by ne authr (B. 1.), and the decisin t allcate an islate t a specific pathgenic categry was made independentlyby anther authr (G. W.) but was discussed with the third (1. McC.) when any dubt arse. Statistical analysis was carried ut by regressin analysis and calculatin f the standard errr f differences f prprtins. Results Over the 30-mnth study perid, 212 M catarrhalis islates were recvered frm 212 patients. One hundred and eleven (52%) were frm males and 101 (48%) were frm females., O~~I.A MJJASONDJFMAMJJASONDJFMAMJJASO Mnth andyear Figure 1. Mraxella catarrhalis islates, as a percentage f ttal respiratry tract islates, recvered frm patients fcmmunity practitiners in Australia ver the 30-mnth perid f study. Peaks were bserved during Australia's winter and early spring mnths. lactamase prductin was nted in 194 f the 212 islates (92%). Susceptibility fthe islates t the fllwing cmmnly tested antibitics was determined: erythrmycin (97%), trimethprim-sulfamethxazle (93%), tetracycline (98%), and ceftriaxne (100%). The 30-mnth study perid included three winters. As expected, submissin rates fr RT specimens were higher during the winter mnths than at ther times. Hwever, the islatin rates fr M. catarrhalis as a percentage f the ttal number f specimens received by the labratry were als higher during winter and early spring (figure 1). With use f the criteria defined abve, 90 (42%) f the 212 islates were judged t be significant; 14 (7%), prbably significant; 45 (210/0), f indeterminate significance; and 63 (30%), nt significant (table 1). A ttal f 63 patients (61%) amng thse whse islates were f significant r prbably significant pathgenicity (14 with pneumnia, 45 with brnchitis, and 4 with brnchiectasis) had an underlying predispsing cnditin, as listed in table 1. Ofthe 104 patients with significant r prbably significant islates, 91 (87%) had either brnchitis r pneumnia. Hspitalizatin was a mre likely utcme fr patients whse islates were significant r prbably significant than fr ther patients (29/104 [28%] vs. 11/108 [10 % ] ; P <.01). N patient required prlnged hspitalizatin. Other than patients wh had a chrnic lung cnditin such as chrnic brnchitis r brnchiectasis, nbdy had a chrnic r prlnged cugh. Mixed rganisms (;:::2 islates) were recvered frm 58 f the 212 patients (27%). Hwever, f the 104 patients infected with significant r prbably significant rganisms, islates were recvered frm a mixed grwth fr nly 19 (18%); in all except tw f these, M catarrhalis was the predminant pathgen. In these tw cases M. catarrhalis was grwn in equal prprtin

634 Wd, Jhnsn, and McCnnack CID 1996;22 (April) Table 1. Clinical diagnsis at the time f islatin and clinical (pathgenic) significance f M. catarrhalis. Assessment f pathgenic significance (n.

3 634 Wd, Jhnsn, and McCnnack CID 1996;22 (April) Table 1. Clinical diagnsis at the time f islatin and clinical (pathgenic) significance f M. catarrhalis. Assessment f pathgenic significance (n. f islates) Diagnsis Ttal n. f islates Significant Prbably significant Indeterminate* Nt significant Pneumnia 23 t Brnchitis 82 t Brnchiectasis Sinusitis Cnjunctivitis Otitis media Upper RT infectin Viral lwer RT infectin Other \1 10# Ttal (%) (42) 14 (7) 45 (21) 63 (30) * Eleven specimens were inadequate; the remainder were inapprpriate. tin 14 (70%) f the 20 cases invlving significant r prbably significant islates, infectin cmplicated chrnic bstructive pulmnary disease (COPD; 3), asthma (2), cardiac failure (2), prednisne therapy (1), recent surgery (1), lymphma (1), lung carcinma (1), r disseminated carcinma (3). tin 45 (63%) f the 71 cases invlving significant r prbably significant islates, infectin cmplicated COPD (25), asthma (8), lung carcinma (2), disseminated carcinma (2), IgA deficiency (1), aplastic anemia (1), myasthenia gravis (l), systemic lupus (l), lymphma (l), r chrnic lymphcytic leukemia (l). All had a psitive ELISA fr respiratry syncytial virus. \I This patient had mastiditis. #These patients had titis extema (2), impetig (2), blcked tear duct (1), pertussis (1), heart blck (1), esphageal reflux (1), pstperative atelectasis (1), r laryngeal spasm (1). t the ther RT pathgen fund. The prprtin f cases with mixed grwth was higher in the indeterminate and nnsignificant pathgenicity grups (36% and 38%, respectively; P <.01). Haemphilus injluenzae and Streptcccus pneumniae were the dminant rganisms fund in the mixedgrwth cases, accunting fr all but 10 f these 58 cases. There was a strng representatin in this study f children <5 years ld: 76 fthe 212 patients (36%). Hwever, fr nly seven (9%) f these patients was the islate cnsidered t be significant r prbablysignificant. T a large extent this reflects the frequency with which nasal swab specimens and naspharyngeal aspirates are btained frm patients in this age grup wh are treated in cmmunity practices. In cntrast, all 16 islates (100%) frm patients aged years were significant r prbably significant. M catarrhalis tends t be f greater pathgenic significance in lder children r adults (figure 2). As shwn in table 2, sputum was cnsidered a valuable specimen: 77% f islates frm this surce were cnsidered significant r prbably significant. Nasal swab specimens and naspharyngeal aspirates were nt useful as indicatrs fpathgenic significance. In this study, as in cmmunity practice in general, these were ften the nly samples available frm children. Sputum samples fgd bacterilgic quality are difficult t btain. The numbers f ther samples were t small t enable us t draw meaningful cnclusins. Brnchscpic washings were available frm nly ne patient. Discussin When a physician receives a reprt frm a micrbilgy labratry indicating grwth f M catarrhalis frm a clinical specimen, it is ften unclear what this means and hw it shuld be dealt with. Is the islated rganism clnizing r pathgenic? Is it clinically significant? Shuld changes in antibitic therapy be based n this islatin? We attempted t answer these questins with regard t hspitalized patients in an earlier study [3] and nw prvide sme data t assist such decisinmaking in cmmunity practice. M catarrhalis islatin rates were higher in winter and spring in cmmunity practice (figure 1), just as they are. in hspital practice [3]. The winter f 1993 was particularly mild in Queensland and nrthern New Suth Wales, and the rates fislatin fm catarrhalis were crrespndingly lwer during this seasn than during the ther tw winters. A similar pattern has been bserved fr almst all RT pathgens in epidemilgic studies. While sme f the M catarrhalis islates may have been assciated with RT infectins fundetermined cause, there was n particular identifiable utbreak in this part faustralia during the three winter perids studied. Our study shws that in 49% fpatients M. catarrhalis can be cnsidered a significant r prbably significant pathgen (table 1). Thirty percent f ur islates were nt clinically significant, while in 21% fcases it was impssible t decide. In brad terms, therefre, fevery 10 islates, 5 will be pathgens, 3 will be clnizers, and 2 will be f undeterminable pathgenic significance. In ur study f hspitalized patients [3], we cnsidered 50% f ur islates t be pathgens and 50% t be cmmensals; we did nt include an indeterminate categry. In that study, ne-thirdfthe islates were assciated with nscmial infectin and 18% were assciated with intubatin [3]. Obviusly, there were n such cnditins in this study fcmmunity infectins. By far the cmmnest diagn-

em 1996;22 (April) M catarrhalis Respiratry Infectins 635 100 -c CO 80 (,) :;: '2 00) G)'- _0.!!~ 60 0-,_ -- 0"c CO... "c 00 ce. G)- 40 -- (,)0 G)c Q.

4 em 1996;22 (April) M catarrhalis Respiratry Infectins c CO 80 (,) :;: '2 00) G)'- _0.!!~ 60 0-,_ -- 0"c CO... "c 00 ce. G) (,)0 G)c Q.c e :;: 20 '2 0) 'Ui Age (y) 80 O &.----L & 100 Figure 2. Regressin analysis shwed a crrelatin between patients' ages and the percentage f significant r prbably significant islates f Mraxella catarrhalis recvered (y = x; r = 0.77). Only 9% f islates frm children under the age f 5 years were significant r prbably significant. Fr lder children and adults the percentages variedbetween 33% (6-10 yearsld) and 100% (81 90 years ld). The majrity f islates frm children were btained frmnasalswabspecimens r naspharyngeal aspirates (81% f thse aged <5 years and 50% f thse aged 6-10 years). ses amngst the cases invlving significant r prbably significant islates in this study were pneumnia and brnchitis (87% f patients). The hspitalizatin rate f27% in this grup indicates the ptential severity f these infectins. We cnsidered all 48 islates frm patients with upper RT infectins t be nnpathgenic. These were patients with "clds," wh had n symptms r signs suggestive f extensin f infectin beynd the nse r naspharynx; the majrity f specimens were btained with nasal swabs. These infectins are usually caused by viruses, and the pathgenic rle f M catarrhalis in this setting is dubtful. While viral upper RT infectin may facilitate spread f M catarrhalis further afield in the RT r int the bldstream, this is prbably a rare event and certainly nt cmmn enugh t warrant antibitic therapy. Sinus aspiratin and tympancentesis are nt cmmnlycarried ut in cmmunitypractice in Australia. The high rate findeterminate islates assciated with cases f sinusitis (14 f 16) and titis media (15 f 17) reflects this, and while M. catarrhalis may have been pathgenic in sme f these cases, we felt unwilling t designate them as such (table 1). The majrity f ur patients (70% with pneumnia and 63% with brnchitis) frm whm significant r prbably significant islates were recvered suffered frm an underlyingpulmnary r systemic cnditin that predispsed them (t varying degrees) t M catarrhalis infectin (table 1). The presence f these cnditins may enhance clnizatin with and decrease clearance f M catarrhalis. The factrs that facilitate spread fm. catarrhalis rather than ther clnizing rganisms remain unknwn. In 27% f ur patients, M catarrhalis infectin was mixed (i.e., at least ne ther rganism was islated). It is difficult t decide in these cases if bth rganisms are pathgenic r if ne is a clnizing agent. One rganism may prmte pathgenicity in the ther (e.g., by cadherence) and may inhibit therapeutic respnses [14]. It is generally cnsidered likely that if ne rganism predminates in terms f grwth characteristics in the labratry, then it is mre pathgenic, but such a crrelatin has nt been validated. Often the nly means f determining relative pathgenicity is the selective use f antimicrbial agents and the mnitring frespnse, but the infrmatin thus prvided will always be retrspective. In ur study, mixed infectins ccurred less cmmnly in patients whse islates were significant r prbably significant (18%) than in thse whse islates were f indeterminate (36%) r nnsignificant (38%) pathgenicity (P <.01). Age was a critical determinant fthe pathgenic significance f an islate f M catarrhalis (figure 2). Althugh there was a strng representatin f children under the age f 5 years in ur study, the islate was cnsidered t be significant r prbably significant in nly 9% f these cases. With advancing age the pathgenic significance fthe islates became greater, culminating in 100% significance in the age grup f81-90 years. These data are affected by the greater difficulty in cllecting clinically relevant samples frm children, the higher clnizatin rates in children than in adults [5, 6, 7, 8], and the higher incidence f predispsing cnditins in adults (table 1). A similar trend (greater pathgenicity with advancing age) was bserved in hspitalized patients [3]. It is imprtant when assessing the pathgenic significance f an M. catarrhalis islate t take accunt f its rigin. Our study shws that sputum was a valuable specimen type, since 77% f islates frm such specimens were significant r prbably significant (table 2). Obviusly, sinus aspirate, eye-swab, Table 2. Pathgenic significance f Mraxella catarrhalis islates, as related t specimen type. Specimen type Sputum Naspharyngeal aspirate Nasal swab Sinus aspirate Eye swab Ear swab Brnchial washing Bld culture Ttal N. f islates N. (%) f islates significant r prbably significant 96 (77) 2 (100) 3 (75) 2 (33) 1 (100) 104 (49)

636 Wd, Jhnsn, and McCrmack cm 1996;22 (April) and bld culture specimens will als usually yield useful infrmatin n pathgenic significance, but few such specimens were available in ur study.

5 636 Wd, Jhnsn, and McCrmack cm 1996;22 (April) and bld culture specimens will als usually yield useful infrmatin n pathgenic significance, but few such specimens were available in ur study. By cntrast, nasal swab specimens and naspharyngeal aspirates, the majrity taken frm children, were useless in determining the pathgenic implicatins f M catarrhalis islates. These samples are generally used fr ther diagnses (e.g., respiratry syncytial virus and pertussis infectins) but are f n clinical value fr diagnsis f M catarrhalis infectins. Our study demnstrates that M catarrhalis is a significant cause f lwer RT infectins encuntered in cmmunity practice, especially brnchitis and pneumnia. Islated rganisms are likely t be f pathgenic significance in adults and lder children, especially thse with underlying RT r systemic cnditins. Islates frm sputum are likely t be pathgenic, while thse frm nasal swab specimens r naspharyngeal aspirates are nt. In children under the age f 5 years and in patients with viral upper RT infectins, M. catarrhalis is unlikely t be pathgenic. The significance f an islate f M catarrhalis frm patients with sinusitis r titis media is difficult t determine, unless it is recvered frm a specimen btained directly frm a sinus r middle-ear cavity. These guidelines shuld prve useful t physicians in assessing the significance f M catarrhalis islated frm a patient. In view f the high,b-iactamase-psitivity rate bserved in ur study, antibitics such as penicillin r amxycillin are nt apprpriate fr treatment ifthis rganism is cnsidered t be the cause f infectin. Acknwledgments The authrs thank Dr. Michael Harrisn and the staff f the Department f Micrbilgy as well as Sullivan and Nichlaides and partners (Taringa, Queensland) fr their participatin in the study. They als acknwledge the time and effrt put in by the many dctrs wh allwed access t infrmatin regarding their patients and thank the Medical Graphics Departmentf the Mater Misericrdiae Hspital fr the figures, Helen Wds fr statistical assistance, and Mary Herwig fr secretarial assistance. References 1. Dern GV. Branhamella catarrhalis-an emerging human pathgen. Diagn Micrbi1 Infect Dis 1986;4: Catlin BW. Branhamella catarrhalis: an rganism gaining respect as a pathgen. Clin Micrbi1 Rev 1990;3: Byle FM, Gerghiu PR, Ti1seMH, McCrmack JG. Branhamella (Mraxella) catarrhalis: pathgenic significance in respiratry infectins. Med J Aust 1991; 154: Nictra B, Rivera M, Luman Jl, Wallace RJ Jr. Branhamella catarrhalis as a lwer respiratry tract pathgen in patients with chrnic lung disease. Arch Intern Med 1986; 146: Faden H, Harabuchi Y, Hng JJ, TnawandaIWilliamsville Pediatrics. Epidemilgy f Mraxella catarrhalis in children during the first 2 years f life: relatinship t titis media. J Infect Dis 1994; 169: Ejlertsen T, Thisted E, Ebbsen F, Olesen B, Renneberg 1. Branhamella catarrhalis in children and adults. A study f prevalence, time f clnisatin, and assciatin with upper and lwer respiratry tract infectins. J Infect 1994;29: Di Givanni C, Riley TV, Hyne GF, Ye R, Cksey P. Respiratry tract infectins due t Branhamella catarrhalis: epidemilgical data frm Western Australia. Epidemil Infect 1987;99: Jusimies-Smer HR, Savlainen S, Ylikski JS. Cmparisn fthe nasal bacterial flras in tw grups f healthy subjects and in patients with acute maxillary sinusitis. J Clin Micrbi11989;27: Van Hare GF, Shurin PA, Marchant CD, et al. Acute titis media caused by Branhamella catarrhalis: bilgy and therapy. Rev Infect Dis 1987;9: Mbaki N, Rikitmi N, Nagatake T, Matsumt K. Crrelatin between Branhamella catarrhalis adherence t rpharyngeal cells and seasnal incidence f lwer respiratry tract infectin. Thku J Exp Med 1987; 153: Carr B, Walsh JB, Cakley D, Sctt T, Muhihill E, Keane C. Effect f age n adherence f Branhamella catarrhalis t buccal epithelial cells. Gerntlgy 1989;35: Gleckman R, DeVita J, Hibert D, et al. Sputum gram stain assessment in cmmunity-acquired bacteremic pneumnia. J Clin Micrbil 1988;26: Dem GV, Mrse SA. Branhamella (Neisseria) catarrhalis: criteria fr labratry identificatin. J Clin Micrbi11980; 11: Sung BS, Chnmaitree T, Bremeling LD, et al. Assciatin frhinvirus infectin with pr bacterilgic utcme f bacterial-viral titis media. Clin Infect Dis 1993;17:38-42.

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