Chlamydia pneumoniae pneumonia : An evolving clinical spectrum

I 1986 GRAY STON AND COWORKERS ISO LATED A NEW CHLA MY dia spe cies (1) which was sub se quently named C pneu mo niae (2). The ini tial clini cal de scrip tion of res pi ra tory dis ease due to C pneu mo niae was that of pneu mo nia of mild to mod er ate se ver ity af fect ing young adults with ei ther spo radic or epi demic in fec tion in closed popu la tions (3). It was also noted that C pneu mo niae could un dergo re ac ti va tion in older adults and in such in stances it was of ten a co patho gen (4). It ac counts for 6 to 10% of cases of com mu nity ac quired pneu mo nia re quir ing ad mis sion to hos pi tal (3,4). Since 1986 our knowl edge of the spec trum of ill ness at tributed to C pneu mo niae in fec tion has in creased. We pres ent two cases that il lus trate the spec trum of C pneu mo niae in fec tion and briefly re view the clini cal as pects of C pneu mo niae in fec tion. SE VERE PNEU MO NIA DUE TO C PNEU MO NIAE Case pres en ta tions – Case 1: A 40yearold fe male was ad mit ted to the Cal gary Gen eral Hos pi tal on Sep tem ber 15, 1994 with rap idly pro gres sive pneu mo nia. She had been well un til one week be fore ad mis sion when she noted my al gias, mal aise and a rash on the ab do men. These symp toms re solved within 24 h but the next day the pa tient de vel oped a se vere leftsided head ache that per sisted de spite an al ge sia with aceta mino phen and co deine. A non pro duc tive cough be gan two days be fore ad mis sion and 24 h later was fol lowed by pro gres sively wors en ing dysp nea. The pa ti ent’s fam ily had also noted that she was mildly con fused. Past his tory in cluded one un com pli cated vagi nal de liv ery and oc ca sional mild ex er tional asthma. She had no known al CASE RE PORT

ler gies and was an Alberta-born Cau ca sian.She had returned to Cal gary two weeks be fore ad mis sion from a driv ing trip to Idaho, Utah, Ne vada and Cali for nia.She stayed in hotels, not in camp grounds.While in Los An ge les, she briefly vis ited an ex otic pet shop but had no sig nifi cant con tact with any ani mals or birds.She was a former 15 pack-year smoker and con sumed al co hol only on oc ca sion.There was no known prior ex po sure to tu ber cu lo sis and no ap par ent risk of hu man im mu no de fi ciency vi rus in fec tion.She had not had any con tact with per sons suf fer ing from res pi ra tory ill ness nor any rec og nized mouse ex po sure.
At pres en ta tion, she ap peared ill and in res pi ra tory distress.She was tachyp neic at 26 breaths/min, even with supple men tal oxy gen.Blood pres sure was 120/75 mmHg and pulse was 110/min.Tem pera ture was 39°C.Chest ex ami nation re vealed coarse crack les that were worse on the left.The re main der of the physi cal ex ami na tion was un re mark able apart from a grade I/VI sys tolic ejec tion mur mur.Ini tial in ves tiga tions in cluded he mo glo bin 109 g/L, to tal white blood cell count of 9.9x10 9 /L and a plate let count of 213x10 9 /L.The differ en tial white blood cell count re vealed toxic granu la tion and a marked left shift.Elec tro lytes, cre ati nine and liver en zymes were nor mal.Se rum lac tate de hy dro ge nase was ele vated at 468 IU/L.There was no evi dence of a co agu lo pa thy and urinaly sis was nor mal.
Ini tial ar te rial blood gases dem on strated hy poxe mia with PO 2 of 31 mmHg and an oxy gen satu ra tion of 58%.A chest x-ray re vealed a sig nifi cant left lower lobe in fil trate (Fig ure 1).De spite an ti bi otic and oxy gen ther apy and sup por tive manage ment the pa tient con tin ued to de te rio rate and only 4 h after ad mis sion had to be trans ferred to the in ten sive care unit where she was in tu bated and ven ti lated.A re peat chest ra diograph at that time dem on strated ex ten sion of her left-sided pneu mo nia and the ap pear ance of a new right up per lobe in filtrate (Fig ure 2).While ven ti lated with 100% oxy gen her satura tion was only 85%.
Af ter ar ri val in in ten sive care she was con sid ered too un -sta ble to un dergo bron cho scopy or lung bi opsy.She was treated em piri cally with in tra ve nous ce fu rox ime and eryth romy cin as well as ri fampin via a na so gas tric tube.Over the sub se quent three days she sta bi lized but still re quired ven ti lation with 60% oxy gen.Her fe ver re solved.Ini tial blood and urine cul tures were nega tive as were cold ag glu ti nins.Sputum col lected via the en do tra cheal tube re vealed a few white blood cells on stain but only nor mal oral flora on cul ture.Legionella se ro logi cal stud ies and cul tures were nega tive.Vi ral, myco plasma and chla my dial stud ies of res pi ra tory se cre tions were not ob tained.Acute se rum was sent for chla my dia se rology.
By the fourth hos pi tal day it was ap par ent that her ini tial improve ment was mod est at most and had pla teaued.She remained se ri ously ill from a pul mo nary per spec tive.At that point in tra ve nous doxycy cline was com menced, the ri fampin was stopped and the ce f u rox ime and eryth ro my cin con tin ued.There af ter the pa tient im proved stead ily and was ex tu bated two weeks af ter ad mis sion.She re ceived 10 days of ce fu roxime and eryth ro my cin.The doxycy cline was to be dis con tinued af ter 10 days of ther apy, but af ter the re sults of acute and con va les cent (drawn on days 1 and 6 of hos pi tali za tion) se rology were re ported, it was con tin ued for an other two weeks (Ta ble 1).The pa tient was dis charged 18 days af ter ad mis -

Fig ure 1) Chest ra dio graph of case 1 at ad mis sion. Note the ex ten sive left lower lobe opac ity. There is a barely visi ble opac ity on the right
Fig ure 2) Chest ra dio graph of case 1.This ra dio graph was taken about 4 h af ter the one shown in Fig ure 1.Note there is more ex ten sive in volve ment of the right lung sion with reso lu tion of all res pi ra tory symp toms and a marked im prove ment of the pneu mo nia opac ity on chest ra dio graph.
Two months later she was seen in follow-up and was entirely well.Her chest ra dio graph was nor mal.The re sults of se ro logi cal tests are shown Ta ble 2. Case 2: A 40-year old male un der went re pair of a right in gui nal her nia on No vem ber 24, 1994.Post op era tively he de vel oped a mass in his right groin along with fe ver, chills and sweats.A wound in fec tion was di ag nosed and he was treated with ciprofloxa cin 250 mg bid orally for 10 days.The swel ling de creased but since in flam ma tion was still pres ent a fur ther seven-day course of cipro floxa cin was given.The in flam ma tion re solved but a small fluid col lec tion re mained in the right groin.
On De cem ber 23, 1994 he de vel oped a cough pro duc tive of clear spu tum.This cough per sisted over the next week and he felt un well but he did not have fe ver or chills.His spu tum be came green in col our and wheezes were heard on aus culta tion of his chest.Ther apy with eryth ro my cin 250 mg qid orally was be gun.He con tin ued to cough and the wheez ing be came more pro nounced.Ven to lin and be clovent were ini tiated.On Janu ary 8 (day 16) he noted a rash on his hands.This was non pru ritic and looked pur pu ric.By Janu ary 11 (day 17) his rash was worse and he had de vel oped pain and swelling of the left an kle.
He had a past his tory of asthma trig gered by ex po sure to hay, grass and pol lens.He had de vel oped a rash when he was given peni cil lin in the re mote past.
When ex am ined on Janu ary 12, 1995 crack les were present on aus cul ta tion at the left base and in spi ra tory wheezes were heard through out both lung fields.The left an kle joint was tender, slightly ery the ma tous and an ef fu sion was present.A macu lo papu lar rash was pres ent on the trunk and extremi ties, es pe cially his hands.These le sions were pur pu ric and some were tar get le sions.There were no mu so cal lesions.A chest ra dio graph showed a re ticu lonodu lar in fil trate at the left base (Fig ure 3).He mo glo bin was 138 g/L, white blood cell count 9.5x10 9 /L, plate let count 354x10 9 /L.Ther apy was be gun with doxycy cline 100 mg bid orally for 10 days.When seen in follow-up on Janu ary 27, 1995 (day 35) he had im proved con sid era bly.The rash had dis ap peared and his cough had de creased mark edly in fre quency.On aus cul ta tion of his chest there were no crack les and only a few wheezes.
Other in ves ti ga tions in cluded posi tive cryo globu lins, (4+ im mu no globu lin [Ig] M and 1+ kappa and lambda).The cryopre cipi ta ble pro tein was 654 mg/mL.Rheu ma toid fac tor was nega tive, and the lev els of the third and fourth com po nents of com ple ment were nor mal.Coombs' test (anti-C3D) was positive.No an ti bod ies to DNA were de tected.His C pneu mo niae IgG ti tre by mi cro im mu no fluo res cence rose from 1:64 on day 20 to 1:256 on day 35 of his ill ness.An ti bod ies to Chla my dia psit taci and Chla my dia tra cho ma tis were not de tect able at a di lu tion of 1:16.Myco plasma pneu mo niae an ti body ti tres were less than 1:32 as tested by a com ple ment fixa tion technique.

DIS CUS SION
C pneu mo niae ac counts for 6 to 10% of cases of com munity ac quired pneu mo nia (3).The ma jor ity of C pneu mo niae in fec tions are mild up per res pi ra tory tract in fec tions in volv ing the throat, nose and ears (5-7).How ever, as il lus trated by the pre sented cases, pneu mo nia may range from mild to very severe.It is also ap par ent that C pneu mo niae pneu mo nia may be ac com pa nied by ex trapul mon ary mani fes ta tions as in case 2. This pa tient had a re ac tive ar thri tis and ery thema multi forme.Braun et al (8) de scribed five pa tients with acute re active ar thri tis af ter an in fec tion with C pneu mo niae.Three of these pa tients had a res pi ra tory tract in fec tion (pha ryn gi tis 1, Fig ure 3) An tero pos te rior chest ra dio graph of case 2. Note the dif fuse in crease in in ter sti tial mark ings CAN J INFECT DIS VOL 6 NO 4 JULY/ AUGUST 1995 bron chi tis 2) one to three weeks be fore on set of ar thri tis.The re main ing two had no res pi ra tory tract symp toms.The du ration of the ar thri tis was two days to two months.All five had knee in volve ment (one had both knees af fected); el bow and wrist were other af fected joints and one pa tient had in volvement of the achil les ten don.These five pa tients also dem onstrated C pneu mo niae-sp ecific syno vial lym pho cyte pro lif era tion.Case 2 had mild oli goar thri tis in volv ing an kle and el bow.He also had ery thema mul ti forme.This con di tion has not been pre vi ously as so ci ated with C pneu mo niae in fec tion.Erythema mul ti forme has been as so ci ated with a wide va ri ety of in fec tious agents includ ing C psit taci and lym pho granu loma ve nereum in fec tion (9).Ery thema mul ti forme can also be due to a va ri ety of drugs, so we can't be sure that it was due to C pneu mo niae in our pa tient.Case 2 also had evi dence of cir culat ing im mune com plexes in the form of posi tive cryo globulins.It is pos si ble that these com plexes con trib uted to the ar thri tis.

TA BLE 1 Se ro logi cal stud ies (com ple ment fixa tion) in ca se 1 with an ti body ti tres shown a s the re cip ro cal of se rum di lu tion
As is the case for M pneu mo niae, the spread of C pneu moniae may oc cur within a fam ily unit (10)(11)(12)(13).
Of much more im por tance clini cally is the as so cia tion between C pneu mo niae lower res pi ra tory tract in fec tion and reac tive air ways dis ease (19).Hahn et al (19) noted that three of 19 pa tients with acute C pneu mo niae in fec tion wheezed at en rol ment into their study and five more de vel oped wheez ing dur ing the course of their ill ness.
The symp toms and signs of lower res pi ra tory tract in fection due to C pneu mo niae are not dis tinc tive and clini cally can not be dis tin guished from those due to a va ri ety of other res pi ra tory tract patho gens (4,20).Like wise the ra dio graphic mani fes ta tions of this in fec tion are non spe cific.McCon nell et al (21) noted that in pri mary in fec tions uni lat eral al veo lar opaci ties were most com mon while those with re ac ti va tion of in fec tion were more likely to have in ter sti tial opaci ties.This group was also more likely to have bi lat eral opaci ties.Pleu ral ef fu sions were com mon and rarely the ra dio graphic ap pearance was that of non car dio genic pul mo nary edema.
The labo ra tory di ag no sis of C pneu mo niae is de tailed by Peel ing (22).These two cases pre sented il lus trate some of the cur rent dif fi cul ties in ob tain ing an early labo ra tory di ag nosis that may be use ful for man age ment of C pneu mo niae infec tions.In case 1, the pa tient had a four fold rise in IgG an ti body ti tre by com ple ment fixa tion to a genus-specific chlamy dial an ti gen by day 6 of hos pi tali za tion, but a sig nifi cant C pneu mo niae-sp ecific an ti body re sponse could not be dem onstrated un til day 23 by mi cro im mu no fluo res cence.The an tibod ies de tected in the com ple ment fixa tion test are an ti bod ies to chla my dial lipo poly sac cha ride, which are usually seen early in in fec tion (21).In this par ticu lar case, the com ple ment fixa tion ti tre was use ful in the de ci sion to continue tet ra cy cline ther apy.But case 2 is more typi cal of the se -rol ogy seen in the ma jor ity of in fec tions in adults.The com ple ment fixa tion test re mains nega tive even when a fourfold rise in C pneu mo niae IgG an ti body ti tre can be dem onstrated by mi cro im mu no fluo res cence.For adult in fec tions, se ro di ag no sis us ing IgM an ti bod ies is in sen si tive be cause pri mary in fec tions oc cur in early teen age years and IgM an tibod ies are rarely pro duced in re in fec tion.Mo lecu lar meth ods such as po lymerase chain re ac tion or di rect fluo res cent an tibody as says may pro vide a more rapid labo ra tory di ag no sis, but these tech niques are, at pres ent, costly and not widely avail able.Care fully done labo ra tory stud ies show that about 41% of pa tients with pri mary C pneu mo niae in fec tion have a sec ond res pi ra tory patho gen pres ent and 18% of pa tients with re cur rent in fec tion have an other patho gen as well (21,23).
Ham merschlag (24), in a re view of the an ti mi cro bial suscep ti bil ity and ther apy of in fec tions caused by C pneu mo niae, con cluded that two to three weeks of doxycy cline or eryth romy cin (2 g/day) or azithro my cin 1.5 g over five days is ap propri ate ther apy of this in fec tion in adults while eryth ro my cin or clarithro my cin was ap pro pri ate in chil dren.
It is evi dent from the cases pre sented and the lit era ture cited that the spec trum of ill ness as so ci ated with C pneu moniae in fec tion is just be com ing ap par ent and it is likely that, with the wide spread avail abil ity of di ag nos tic serv ices for this in fec tion, we have not yet fin ished de fin ing its clini cal spectrum.