O RIGINAL ARTICLE

Risk factors for breakthrough Pneumocystis carinii pneumonia

on aerosol pentamidine prophylaxis

RA M CIVOR MD FRCPC MRCP, A R RACHLIS MD FRCPC, P BERGER MD CCFP, LR LEE PACK,

CK CHAN MD FRCPC FCCP FACP

Department of Medicine, The Wellesley and Sunnybrook Hospitals, University of Toronto, and The Toronto Central Aerosol Pentamidine Clinic, Toronto, Ontario

RA MC IVOR, A R RACHLIS, P BERGER, LR LEE P ACK, CK CHA N. Risk facto rs fo r breakth rough Pneumocystis carinii pneumonia on aerosol pentamidine prophylaxis. Can Respir J 1995;2(1 ):49-54.

O BJECTI VE: To identify base li ne character ist ics of human immunoJcficiency virus (HI Y)-i nfec tcd indi vi duals on ae rosol pcntamiJinc for P11c111110c_1 ·s1i.1· carinii prnphyl,1xi~ that an: predictive of subsequent breakthrnu /! h l'11t' 11111 o r _1·.1-

1is rnrinii pne umonia (PC P ). D ESIGN: Nested case-control study assemblcJ from a rn­hort ()f patients cnrnlled in the Toronto aerosol pentamidinc progra m. METHODS: Subjects wne se lected fro m a cohort o f HIY-in­l'cctcd in lividuals were enroll ed in a community based ae roso l pcntamidinc program bet ween May 1989 an J M ay 1992 in Toronto. Onta rio. Cases - ind ividua ls who had breakthrou gh PC P were matched with up to two controls enroll ed in the same week. Risk fac to rs examined fo r deve l­opment of PCP for both primary and secondary prophy laxis inc luded age. sex. smoking hi sto ry. evidence of bron­chospasm during aerosol pcntam idinc admini stration (fall o C forc ed expiratory volume !FEY I 15 °11! or mon:). admini ­stration o f sa lbutamol be fore aeroso l pentam idinc , pulmo­nary l"unl·tion te sts induJing lung volumes. flo w rates anJ diffusing capaL·ity for carbon monoxide . In the prima ry prophy la xis group. CD4 count at enro lment and in the sec,mdary prophylaxis group , lime f'rnm the most recent

episode o r PCP to enrolment for ae roso l pentamid ine and total time fro m the most recent episode o f PC P to break­through PC P were examined as addit ional ri sk fac tors. RESULTS: A to tal o r 1344 patients we re enro lled in the aerosol pcntamidine program. 78% for primary prophylaxis and 22'k for secondary prophylaxi s. At the time of census at the end o r 1992 there had been l)6 episodes or break­thro ugh PCP, .'1 % on primary prophy laxi s ,md 14 .Y,1' on secondary prophylaxi s. In the primary prophylaxis group, enrolment C D4 L'OUnt was signifi cantl y lmver in the cases dL've loping breakt hrough PC P: 11 6±74 rnmpared w ith 175±~5 ce ll s/mni3 in the control group ( P=0.00 I ). There was no difference in any other variable . In the secondary prophylaxis g rou p. time from the most recent cpisude or PC P to initiation or aerosol pentamidinc therapy was longer in the cases devel oping breakthrough PCP: mean delay 6 .1 ±6.6 months compared wit h 3.1 ±2.1 in cont rols (P=0.02). T here ,vas no difference in the o the r variables exam ined. CONCLUSIONS: The results of thi s study support immune augmentation for patients rece ivin g aerosol pcntamidi ne fo r primary prophyl axis. and aerosol pentamidine should he recommenced as soon as possible fo llowing an episode of PCP, fnr secondary proph ylaxis . (Po/Ir n ;.,./lnll\ 1•,,i,- /)(1.t;<' 50)

Key Words: ;k 1111i,.,,,I i11111111 11<1rl<'/icin11y s_r11,lro1111· /1\!DSJ. l/11 -

1111111 11111111 11 w d ,:fi"1·ic'11n· 1·im.1· ( Ill \!). / '1'll/<1111idi11 C'. Pneumocyslis

cari nii 1>11c11111 011iu

C"rrC'.\j}(!lt d,·111· ,, uwl U'/!ri111s: /) ,- CK Chun. Th,· W<'llnk_1· l/ns1>i111/. / (J(/ \\!cl/C'sle1· St/'l'el L11.1"/ , #2-12 }0 11 ,,.,. Hui!rli11g. Toro1110. 0 11/ario M-11 IJ.i

Can Respir J Vol 2 No 1 Spring 1995 49

MCIVOR ETAL

Facteurs de risque pour l'apparition d'une pneumonie a P11eumocystis carinii pendant une prophylaxie a la pentamidine en aerosol

O DJECTIF : IJcntifier les caractfristiques Jc base des inJiviJus infcctes par le virus de l' i111munodaicie 11 c:c humai 11e (V IH) ct traitcs e n prnphylaxic awe J e la prntam idi ne e11 afroso l cont re le P11 ew11oc1·stis rnri11ii. e t qui sont predictivcs pour le dcvcloppc­mcnt d'unc p11e L1monic a l'111·11111on·,1is rnrinii (PPC) subsequente. MODELE : t tuJe cas/tcm oins cmbo'ites rca lisee it part ir d'une cohnrte de patients recrutcs da11 s le programme de pe ntam idinc c 11 aeroso l de Toronto. ME."fHODES : Les .,ujc ts ont etc choisis dans unc cohorte J ' indi ­vidu s inf'cc tes par le YIH qui avaicnt ete recrutcs pour un pro­gra m me Jc pc11la1nidinc en ae roso l base dan s la comm unaute c ntre mai 1989 ct mai 1992 a Toron to. en Ontario . Les cas -inJ ividus qui Ont Jeve loppe une PPC- ont ete apparies avec un ()U

deux sujcts contro les n:c rutcs Jans la meme semainc. L ' ana lysc des fac tcu rs de ri sque pour k developpcmcnt d'une PPC au cours des deux types de pruph y l;1 xic. primaire ct scco ndairc. comprc n­aie nt l'f1gc, lc sexe. le tabag isim· , la presence J ' un bronchospasme !ors Jc l\ 1d111 inis tration de la penlamid inc en aeroso l (chute du vo lume ex piralo ire max ima l/seconde I Y EMS I de I 5 'k o u plus) , !'admin istratio n de salbutamo l avant la pcntamidine en ae rosol. les tes ts de fonction pul n1o nairc. nota rnmen l !cs volumes pul mo­naires. Ies debits el la capaci te Je Jiffusion du monoxyde de carbone . Un autrc· fac tcur de ri ·que analyse \'.' tail, pour le g roupe soumis a unc prnphylaxie primaire. la numeration C D4 au mo ment

PNEUMOCYS l'/S CAl<.IN/1 PNEUi'vlONli\ (Pl' l' 1 REMAINS T HC

most prevalent infec tious rnmpl iL·ation o f AIDS in North America. PCP in Ontario still rcprt:sen ts the itH.k x di sease in approximatel y SJ% of cases ( 1 ).

As the human immunode fic iency virus (HIV ) epidemic dl'velops into a chronic illnl'ss in thl' I L) lJ()s, the foc us nf treatment has changed towards prophylax is rather than acutL~ sal vage therapy for both PCP and many other opportuni .st ic infections that were lethal in the early 1980s.

Trimethoprim-sulfamdhoxawlc (T MP-SMX) remains the ·go ld' standard prophylax is against PCP in the I LJ90s.

This has been rnufirmecl in recent trials o f both primary and secondary PCP proph ylaxis (2 -J ). Approxi mately 30Clo o f HI V individuals are intole rant to long term T MP-SM X. and for these individuals aerosol pentamidine remains a strong and proven second-line alte rnative (2-3) . T hus. evc11 w ith early diagnosis and therapy directed towards reversal or tlw underl ying imn1t1ne dys function, there is still a substant ial pool of patients whu requ ire aerosol pent amidine prophyl axis over many months or years.

In the late 1980s, two main aerosol pcntamidine prophy­laxis regimens were validated in cl inical trials and are st ill widely used in the ILJ90s (4 ). Some centres have adopted the jc t nebuli zer Respirgard II system, using 300 mg o f pe n­tamidinc monthly to minimize the number o r clinic vi sits (5) . Ult rasonic nebulizcrs such as Fisoneb, Porta-sonic and Ae rosonic. using pentamidi ne at 60 mg every two weeks, arc be ing used to reduce the amount and cost o f drug used (6 ).

Aerosol pe ntamidine is c learly not 100% e ffect ive. and as

50

du recru tcmc nt tand is que po u1· le g rou pc soumi , i'1 une prnpl1y­l,1 xie sccondai rc. lcs f'al'leurs de ri squc aJ d iti onnc ls comprenaiC" nl !'interval It; de tem ps e nt re !' episode le plus recent de PPC ct la date d u rcc ru tcmcnl pour le trai tc ment a la pc ntamiJi ne en ac'roso l ,·t l' inte rva llc de temps entrc !' episode de PPC le plus reccnljusqu ·,1 unc rec idive de PPC. R f:SULTATS : Au to ta l, 1344 patic'nts ,mt c te rc·c-rutcs dans k progra lll me de pcnta n1idine en ac' roso l dunt 78 r;,;. pour unc pro­phylaxie primairc et 22 % pou r une prophylax ic scconJairc. Au moment du rccensemcnt /1 b fin Jc 1992, on a denombrl' 96 episodes de PPC sous prophy laxic. so it 5 % des cas J c prophy lax ic· primaire et 14.5 •,0 des cas de prophylaxic sccondairc . Dans le g roupe so umi · ii une prnphy lax ic prinw irc, la numeration (04. au moment du rccru temcnt , e tail nctlc rncnt inffricurc chc, lt;s cas d vc loppanl unc· PPC : 116±74 ccllulcs/mm3 comparati ve nicn l a 175±85 ccllules/mni3 J ans le groupc contri'llc ( P=OJlO I). II n'y ava il aucunc d iffen:ncc J ans !cs aut rcs va riables. Dans le g roupc soum is a une prophy laxic sccondairc. l'intc·rvallc de temps e ntrc !' episode le plus recc.nt de PPC cl le debut Ju traite mcnt ~1 la pc ntamid ine en aeroso l e tait pl us long chcz Jes ca~ prcscnlant unc rccid ivc de PPC : retard moycn 6. 1 ±6.6 mo is corn parat ivcmcnt a 3. 1 ±2, I chcz Jes sujcts cont ro les ( P=0.02 ). A ucunc autrc Jif­f.:rcnce n · a e tc obscrvcc pour !es au trcs variables. CONCLUSIONS : Les rcsultats de cettc e tucle appuil'nl !' utili sat ion cl ' im mu nostim ulants chcL. les patients rcccvant de la pcntami cl inc e n aerosol pour unc prophylaxie primairc. De plus. on J cvrait recom mcncer le plus t6t poss ible a aJmini strcr la pe ntami d inc en aeroso l i;1 la suite d'un episode de PPC. pour unc prophylaxic scconda ire .

time passes we are faceJ wi th increasing numbers o f episodes of breakthrough PCP (7-9).

In an e ffort to id ntify risk factors for breakthrough PCP. with an emphas is on pulmonary func tion abnormali ties , we carried o ut a nested case-con trol study in a large cohort of patients followed for three-and-a-half years in a centra l aero­sol pentamidine program in To ronto.

PATIENTS AND METHODS Aerosol pentamidine program clinic population: Indi­vi duals were enrolled in the aerosol pe ntamidinc program for primary ()rophylaxis if they had CD4 counts be low JOO ce lls/mm3

. Primary prophylax is was al so commenced for HIV-infec ted ind ividuals with const itutional sy mptoms, eg. unexpla ined persistent fever (greate r than 37. 8°C ) fo r two weeks or more, or oropharyngea l cancl icl iasis (unre lated to antibio tic or corticoste roid therapy ). regard less o f the CD4 count.

Senmdary prophyla xi s was initiatL·d as srnln as pPssihlc follow ing comple ted therapy for one or more acute episodes of PCP.

In all cases, HIV status was n mfirmed by holh the e nzy me-l inked immu11osorbent assay (ELISA) and Western hlut methods. Aerosol pentamidine protocol: All patients rece ived 60 mg pentamid ine e very two weeks via Fisoneb (Fisons Corp, New York ) fo llowing a loading period of five closes over a two­week period according to the Canadi an multi centrc study protocol (h). Patients were monitored for cough :tnd pen-

Can Respir .I Vol 2 No 1 Spring 1995

Breakthrough PCP on aerosol pentamidine prophylaxis

TABLE 1 Primary prophylaxis

Cases Mean ± SD n::53 ~ ntrols Mean ± SD (n=~ P value

Baseline characteristics

Age (years)

T4 (cells/mm3)

First treatment to breakthrough PCP or last treatment (months)

Smokers

Spirometry and bronchodilator use

% Fall in FEV,

Fall of ~15% FEV1

Regular bronchodilator before aerosol pentamidine

Baseline pulmonary function tests

rotal lung capcity (% predicted)

Forced vital capacity (% predicted)

FEV1 (% predicted)

DLCO (% predicted)

39 .8±8

116±74

16.7t9.1

43%

-9.4c 11

26%

68%

86+14

90±13

87j_ 14

81±22

41.6±9

175±85

20.5±8.6

54%

-9.5±9 5

26%

54%

88+15

93±14

90±13

84±20

0.14

0.001

0 .016

0.28

0.96

0.84

0.28

0.5

0.09

0.12

0 .37

DLCO Single breath diffusion capacity for carbon monoxide: FEV1 Forced expiratory voume m 1 s; PCP Pneumoncystis carinii pneumonia

1amidi11e-i11duced bronchospasm during aerosol pentamidine therapy with pre- and postspirometry. Prophylactic salbuta-· 1t1lll w.is administered 20 mins hcfore aerosol penlamidine ir a fall in forced expiratory volume in I s (FEV 1) nr l 5'lr· llr more occurred between pre- and poslacrosol pentamidine therapy. Salbulamol was also available for individuals who experienced cough, wheeze or chest tightness hut did nlll have a reduct ion in FEV I or 15 Yc> or more.

All treatments were administered at a single out-patient treatment facility in Toronto. Selection of patients for the case-control study: The cases and control s were identiried from the cohort or all HIY ­inkcted patients enrolled in the aerosol pentamidine program between May 1989 and May 1992. All breakthrough cases occurring up to the date or census, December .11. 1992, were matched with up to two ui11trols. Selection of cases: Cases or PCP were defined as either: conrirmcd PCP episodes from cytopathologically prnvl'n samples obtained from sputum, brnnchoscopy m biopsy: or highly probable episodes or PCP without cytopath1>logical proof hut with clinical and radiological response lo a course of anti-PCP therapy, or cause or death directly allributed 10

breakthrough PCP. No cases or exlrapulinonary P ,·c1rinii infection were identiried. Selection of controls: Controls were individuals who had nllt developed breakthrough PCP and were selected rrom thl' longitudinal aerosol pentarnidine program database. They were matched to the cases for primary 1>r secondary prophy­laxis. All cases wnc also matched h1r date or enrolment with up lo twll urntrols enrolled in the aerosol penlamidinc pro­gram within one week or the case. Controls had no docu­mented episodes or breakthrough PCP or treatment ror presumed PCP. These criteria for control selcct1011 ensured comparable length or acnisol pentamidinc treatment a11d length of time at risk of breakthrough PCP afll'r initiation or aerosol pentamidine in lhl' two groups. Baseline risk factors: Risk factors examined were age. sex.

Can Respir J Vol 2 No 1 Spring 1995

smoking history. evidence of hronchospasm during aerosol penlamidine administration (foll of FEV 1 15c,4- or more), requirement for salbutamol before pcntarnidine administra­tion and baseline complete pulmonary !"unction, and all were recorded at patient cnrnlmenl. In the primary prnr,hylaxis group CD4 count was also reuirded al enrolment, before commencement of al'rosol pcntamidine. In the secondary prophylaxis group. the Lime rrom the most recent episode or PCP to enrolment in lhL' aerosol pentarnidine progrnm was also assessed, as was the total time from the most recent episode of PCP to either breakthrough PCP (cases) or the L'nd of the study pniod. Surveillance protocol for PCP: Baseline assessment al en­rolment and follow-up was coordinatl'd through the HIV primary care physicians who were responsible ror the pa­tients. The HIV r,rirnary care physicians we1-c prompted by the HIV Project Centre (Sunnybrook Health Science., Centre, Toronto) and were responsible for the completion of follow-up assessments al three- to six-month intervals. A team or three data collection nurse/monitors made regul,ir visits to the physicians· offices to cnwre adequate documen­tation on all patients in the aerosol prntamidine program. Data related lo investigation and treatment of PCP episodes were obtained and conrirmed from source documents in phy­sicians' offices. Pulmonary function tests: Complete pulmonary runction tests were perfonned by a single technician on a computcr­i1cd MMC HoriLon 4400 system (Sensori'Vkdics. California) and results exr,ressed :is r,ereentage predicted using Knudsen l l/83 values ( I 0). Complete pulmonary function tests in­cluded spirometry performed in accordance with American ThoraL·ic Society guidelines ( 11 ), lung volumes by nitrogen washout and single breath diffusion capacity for carbon mon­oxide (DLCO) corrected for hemoglobin ( 12). Baseline pul­monary function tests were performed on all patients bcl'orc commencement or aerosol pc11U1midinc therapy. Statistical analysis: Baseline results arc presented as the

51

MCIVOR ET AL

TABLE 2 Secondary prophylaxis

Cases Mean ± SD n=43 Controls Mean ± SD n=n) P value

Baseline characteristics

Age (years)

Latest PCP to first aerosol pentamidine treatment (months)

39. 8±8

6.1±6.6

40.0±9

3.1±2.1

0.45

0 .02

First treatment to breakthrough PCP or last treatment (months)

10.8±6 15.3±7 0.002

First episode of PCP to breakthrough PCP or last 14.8±6.5 17.9±8.2 0.04 treatment (months)

Smokers 42% 36% 0 .69

Spirometry and bronchodilator use % fall in FEV 1

Fall of ;>15% FEV 1

Regular bronchodilator before aerosol pentamidine

Baseline pulmonary function tests

-10.8±10.1

25%

58%

- 6.5±10.4

18%

23%

0.21

0.9

0.052

Total lung capacity(% predicted)

Forced vital capacity (% predicted)

FEV1 (% predicted)

DLCO (% predicted)

89±16

88,:13

87±13

64±15

85±15

881: 13

88±13

71 ±20

0.34

0.83

0.87

0.11

DLCO Single breath diffusion capacity for carbon monoxide: FEV1 Forced expiratory voume in 1 s; PCP Pneumoncystis carinii pneumonia

means and standa rd deviations. An unpaired two-tai led Stu­dent' s t test was used to compare L·ontinuous variables, and a

) . . . . . . . x- iest w1Lh corrcct1on tor cont1nutty was used !or categorical variables. P<0.05 was rnnsidcn:d significant.

RESULTS A total of l 344 individuals were enrolled during this

period. Seventy-eight per cent ( l 048) were receiving aerosol pent:imidine as primary PCP prophylax is (CD4 count less than JOO cells/mm\ Twenty-two percent (296) WCI'L'. receiv­ing .ic.rosol pcntamidine as secondary PCP prophylaxis (one or more previous episodes of PCP) . Ninety-se ven per cent of patient s were receiving concurrent antirelroviral therapy with zidovudine (AZT ) or didanosine (dell) during the time of this study. Due to the flexible clinic hours and schedule, compliance was excel lent in all gro ups with more than 90% of ind iv idual.~ attending more than lJOCfo of scheduled visits. Primary prophylaxis Fifty-three cases ofbrcakthrnugh PCP occurred in the group receiving primary prophylax is (53 of 1048, 5%). They were matchL'd with 98 contro ls. Mean age was 40 years in the cases compared with 42 years in controls (P=0. 14). Mean CD4 count was 116±74 cells/mm' in the cases compared with I 75±85 in the controls (P=0.00 l ). T ime from initiation o f aerosol prntamidine to breakthrough PCP in the cases was 16.7±9. 1 months. To e nsure that cont rol subjects were at the sa111e risk of breakthrough PCP, the cuntrols were fo llowed !'or a significanlly longer period of' time. compared with the time to breakthrough PCP for the cases, a mean of20.5±8.6 mo nths (P=O.O 16) (Table l ). Forty­three per cent of the cases were smokers, compared with 54c;1,

of the controls (P=0.28). Spirometry before and a fter aerosol pentamidine therapy shuwcd a mean reduction in FEY I or - 9.4±11.0 in the cases compared with - 9.5±9.5 in the con-

52

trols (P=0.96). Twenty-six per c,·n t of cases and :?Nil or controls had a documented fall in FEY I of I 5% or more (P=0.84). In both the case (68rk) and control (54%) groups ( P=0.28 ), approxi111atl'ly twice as many individuals look regular bronchodilators 20 mins before administration of aerosol pentamidine compared with those who had a docu­men ted fall in FEY I of I 5% or more . Base line pulmonary function tests showed no statist ical difference in lung vo l­umes, l1ow rates or DLCO corrected for hemoglobin between cases and controls (Table I) . Secondary prophylaxis: Forty-three cases o f breakthrough PCP in the group receiv ing secondary prophylaxis (43 of296, 14.5% ) were matched with 77 controls. Mean age was 40 years in both groups (P=0.45). The time from the latest episode of PCP to initiation of aerosol pentamidinc therapy was 6.1 8±6.6 months in the cases compared with 3. I _t2. l months in the controls (P=0.02). The cases occ urred at a mt:an of l 0 .8±6 months on aerosol pcntamidine, and control subjects were followed for a signifi cantly longer period by design , for 15 .3±7 months (P=0.002 ) (Table 2). Subsc4uent case. of breakthrough PCP occurred at 14.8±6.5 months following the previous episode: control .q1bjects were lol­Iowed for I 7 .9±8.2 mo nths following the previous episode (P=0.04), a signi fica ntly longer period, during whic h time they remained PCP free. Forty-two pn CL'nt or the cases were smokers compared with 36% of controls (P=0.69). Spi­romctry before and arter aerosol pentamidine therapy showed a mean reduction in FEV1 or - 10.8±10.4% in the cases compared with -6.5±6.4% in the controls (P=0.21 ). Twenty-five per cent of the cases and l Wk of controls had a documented fa ll in FEY t of I Y/c, or more (P=0.9). Approxi­mately twice as many cases re4uired regular bronchodilation before aerosol pentamidine, compart:d with 23'/c or rnnlrnis (P=0.052) . Baseline pulmonary function tests showed no

Can Respir J Vol 2 No 1 Spring 1995

slalislically significant <lifference in lu ng volumes. flow ralL's or DLCO corrected for hcmoglohin. hetwccn cases ;:ind con­trols (Table 2).

DISCUSSION One of the major thrusts in HIV management in the scct1nd

half of the first dcca<lc of the HIV q,i<lemic ha., hecn the allcmpl ln prevent or delay PCP (4).

We had a unique opportunity lo monitor a large cnhnrl nf in<lividuals on aerosol pentamidinc in Toronto. In this study. we wanted lo ascertain whether there were any prognostic

indicators, particularly with respect to underlyi ng lung fu nc­tion. identifiable at enrolment that may pre<lict subsequent breakthrough PCP in patients receiving aerosol pentamid ine for PCP prophylax is . The Mu lt icenter A ids Cohort Study (8) suggested that the C D4 count was an important predictor of subsequent development of PCP in individuals not receiving PCP prophylaxi s. However. with secon<lary prophylaxis no

strong predictor for breakthrough PCP has been identified: breakthrough PCP was felt not In be related to the C D4 count in this group. anu C D4 counts were not obtaineu in the secondary prophylaxis g roup.

ln the present study, the nnly ilkntifiable risk factor for

development of breakthrough PCP in primary prophylaxis was a lower CD4 count at inception. Baseline pulmonary function IL' .,l profile., were similar; in particular there was no

cviuL'ncc of worse airllow ob.struction or reduced DLCO in the cases comparc<l with contrnls.

In the scclm<lary prophylaxis group. a delay in the time from the last episo<lc of PC P to initiation or aerosol pentami<l­inc therapy was highly predictive for subsequent break­through PC P. ThL' mean time to the loading doses of aerosol pentamidinc in the cases wa., six months. almost double the delay in the controls. The main reason for this Jc lay was that aerosol penlami<line therapy was nol widely avai!Jble until May 1989 in Toronto. :ind patients intolerant lo T MP-SMX

before this had not heen receiving ade4uale prophylaxis. because dapsonc with or without TMP was not wide ly used in J lJWJ or J lJl)(I al our L'entre. V1/e now encourage commence­

ment oJ' aerosol pcntamidinc therapy as soon as possible following completion or a l"ull course of anti-PCP therapy. Controls receiving secon<lary prnphylaxis were followeu and remained J'rec from breakthrough PC P for longer - 17.9 months cnmpareu with 14.8 months for cases (P=0.04 ). Also in the secondary prophylaxis group, there were no differences between cases anu nmtrols wit h respect to enrolment lung

volumes. flow rates or DLCO. We particularly fon1sed on haselinc pulmonary fu11etion

lL'.sls and spiromclry pre- and postanosol pcntamid ine as risk !'actors. since acro.,ol pentamiuine is an inhaled medication and i., known to cause bronchnspasm (5-6 ). Our data do not

suggest that airflow nhstruction was a major factor for break­through PC P on aerosol pentamidinc. However, there was a trend towarus increased bronchodilator use in cases receiving aerosol pentami<linc for secondary prophylaxis. although this did not reach statistical significance. Approximately twice as many individuals took regular bronchodilator before aerosol

Can Respir J Vol 2 No 1 Spring 1995

Breakthrough PCP on aerosol pentamidine prophylaxis

pentami<linc a., those who hau a documented fall in FEY I or

15'k- or more . This may in part rellecl the aggressive moni­toring of the aerosol penlamidine program for cough anu hrnnchnspasm. with the use of an inhaled beta-agnnist as prcmcdicalion for aerosol penlamidinc .

Pulmonary function abnormalities arc felt to be important in identifying subclinical PC P. A reduction in lung volume or a red uced DLCO may suggest .q1hclinical pneumonilis. Dr

perhaps for those on secondary prophylaxis. unresolved or persistent PCP. There was no signiJ'icanl difference between the pu lmonary function tests or cases and controls enrolled

for primary or sl'cnndary prophylaxis in this study. It should. however. be noted that the DLCO in both ca."es anJ controls enrolled for seL·omlary prophylaxis is rcduce<l compared with those rece ivi ng primary prophylaxis. Whether the lindings suggest adequate suppression of P rnrinii before initiation of aerosol pentamidi ne in our population or merely ind icate the lack of sensi tivity or pulmonary funl'lion testing in dc!L'L'ting subclinical PCP is open tn debate.

Our study strongly suggests that in patients receiving primary prophylaxis as much t'i'forl as possihlc shoul<l be <lirected towards obtaining and maintaining a high CD4 count, because even on auequate aerosol pentamiuine pro­phylaxis a hi gh C D4 count is an important prognostic factor in the Jelay of subsequent PCP. In patients with one or more episodes or PCP. prophylactic therapy should be commenced as soon as possible after treatment for PC P.

Ri sk !'actors for breakthrough PCP i<lcnlifiecl in this study may not he gcncrali1ablc to other systemic PCP prnphylaxi., protocols. However. the ri .,k factors identifi ed in this study appear lo reflect underlying immune dysfunction or a Jclay in the initiation or PC P prophylaxis rather than be ing directly linked to aerosol pcnlamidinc treatment. Thus, until similar analysis is conducteu on patil'nls on systemic prophylaxis rnr

PC P. one should apply the same principles of early initiation of PC P prophylaxis when the C D4 starts falling or as soon as possible afte r recovery from an episode or PC P.

ACKNOWLEDGEMENTS: This program w,1s funded hy the Ministry of I lealth or Ontario.

REFERENCES I. Onlario AIDS Bulletin 19ll.1. Toronto: ivlinistry nf f-kal1h.

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KoC1ka C. ACTG Protocol 021. !\ L"Ontrolled trial of trimcthoprim-sulfamethoxa7.olc or annsoli.i:cd pcntamidinc for secondary prophylaxis of P11n1111,,cn1i., rnri11ii pnculllonia (PCPJ in patients with the acquired imnrnnndclicicncy syndrome. N Engl J Med 1992:327: 1842-8.

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Can Respir J Vol 2 No 1 Spring 1995