Clinics vol.65 número7

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CLINICS 2010;65(7):745-8

Copyright © 2010 CLINICS – This is a n O pe n A c c e ss a rtic l e d istrib u te d u n d e r the te rm s of the Cre a tiv e Com m on s A ttrib u tion Non -Com m e rc ia l Lic e n se (http:/ / c re a tiv e c om m on s. org/ l ic e n se s/ b y-n c / 3 . 0/ ) w hic h pe rm its u n re stric te d n on -c om m e rc ia l u se , d istrib u tion , a n d re prod u ction in a n y m e d iu m , prov id e d the origin a l w ork is prope rl y c ite d .

LETTER TO THE EDITOR

DMIP-LIM-47, Hospital das Clínicas, Faculdade de Medicina, Universidade de São Paulo - São Paulo/ SP, B raz il.

T el. : 5 5 1 1 3 0 8 5 -1 6 0 1 E m ail: evaldostanislau@ uol. com . b r

EXPECTORATION OF LARGE BRONCHIAL CASTS SECONDARY TO THE TREATMENT

OF CHRONIC HEPATITIS C WITH PEGYLATED INTERFERON AND RIBAVIRIN

doi: 1 0 . 1 5 9 0 / S1 8 0 7-5 9 3 2 2 0 1 0 0 0 0 70 0 0 1 6

Evaldo Stanislau Affonso de Araújo, Aleia Faustina Campos, Juliana Yamashiro, Evandro Sobrosa Mello, Teresa Takag aki, Antonio Alc i B arone

IN T R O DUCT IO N

I nfec tions c aused by the hepatitis C virus ( H CV ) are c urrently a serious public health problem. I t is estimated that 3 to 4 million new c ases oc c ur w orldw ide every y ear. O f the

individuals w ith ac ute H CV infec tions, 5 5 % to 8 5 % w ill be c hronic ally infec ted and w ill thus be at risk of liver damag e,

c irrhosis and hepatoc ellular c arc inoma.1 ,2_{I n total, more than}

1 7 0 million people ( i. e. , ≈_{2 % of the w orld’s population) are}

infec ted w ith H CV . The best treatment c urrently available is a c ombination of peg y lated interferon and ribavirin.2 –6

I nterferons are potent c y tokines w ith antiviral, antiproliferative and immunomodulatory ac tivities.7

I nterferons are linked to c ell surfac e rec eptors and c ause a c asc ade of intrac ellular events, inc luding the induc tion of the transc ription of g enes that inhibit c ell g row th and of g enes that alter c ell differentiation, onc og ene ex pression and the ex pression of antig ens on the c ell surfac e. I n turn, these effec ts inc rease mac rophag e phag oc y tosis and the c y totox ic ity of ly mphoc y tes in relation to targ et c ells and hinder mec hanisms of viral replic ation in parasitic c ells.

The treatment of hepatitis C has various limitations: c ost, efic ac y and, princ ipally , adverse effec ts. The numerous side effec ts observed rang e from the trivial, suc h as inluenz a- like sy mptoms, anorex ia, fatig ue, headac he, nausea my algia, diarrhea, loc al reac tions to the applic ation of the medic ation, alopec ia and prurig inous rash, to the severe, suc h as psy c hiatric sy mptoms, c y topenias and respiratory symptoms ( c oug h and dy spnea) . Among the rarest and most potentially deleterious adverse manifestations are panc reatitis, profound

medullary depression and c ardiotox ic ity , w hic h c an lead to c ardiac failure and sudden death.2 ,3 ,8 ,9_{Finally , it has been}

sug g ested that interferon alpha therapy is assoc iated w ith the development and ex ac erbation of autoimmune diseases.3

Severe lung tox ic ity is assoc iated w ith interferon alpha monotherapy as w ell as c ombination therapies involving ribavirin and c onventional or peg y lated interferon alpha. There have also been reported c ases of interstitial pneumonia,2 ,1 0

bronc hiolitis obliterans org aniz ing pneumonia ( B O O P) , sarc oidosis and severe profiles of asthma ex ac erbation.9

For ex ample, K uno et al. desc ribed three c ases involving patients w ith c hronic hepatitis C w ho developed interstitial pneumonitis during treatment w ith interferon alpha and presented c omplete resolution of the sy mptoms after disc ontinuation of the medic ation.1 1_{N evertheless, pulmonary}

c omplic ations assoc iated w ith interferon alpha therapy are rare. I n the literature, the patholog y most c ommonly assoc iated w ith interferon alpha therapy is interstitial pneumonitis, follow ed by sarc oidosis- like c onditions leading to the formation of nonc aseating g ranulomas.3 ,7 ,8

R ibavirin is a purinic nuc leoside analog w ith a modiied base and a D - ribose sug ar. Althoug h the mec hanisms of ribavirin ac tion c ontinue to be the objec t of spec ulation, it is possible that ribavirin ac ts as an immunostimulating antiviral ag ent and has rec ently been proposed to be a stimulator of induc ible interferon g enes.1 2_W _{hen c ombined w ith interferon}

alpha, ribavirin c ontributes g reatly to obtaining a sustained virolog ic al response ( SV R ) and to reduc ing rec urrenc e. R ibavirin side effec ts are hemoly tic anemia, fatig ue, rash and c oug h. H ow ever, there have been no reports of severe c ases or c ases w ith pronounc ed sy mptoms.

CA SE R E PO R T

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CLINICS 2010;65(7):745-8 P e gin te rf e ron -re l a te d b ron c hia l c a sts

A ra új o E SA e t a l .

and smoking ( 8 2 pac k- y ears) soug ht treatment after having rec ently been diag nosed w ith c hronic hepatitis C. A hepatic biopsy , c onduc ted in February of 2 0 0 6 , revealed histolog ic al alterations c onsistent w ith c irrhosis ( METAV I R ibrosis sc ore and ac tivity sc ore, F4 and A3 ) . V irolog ic al tests at baseline show ed infec tion w ith g enoty pe 3 a and a viral load of 7 8 0 ,2 0 3 I U / mL ( CO B AS Amplic or®_{; R oc he}

Molec ular D iag nostic s, B asel, Sw itz erland) . I n July of 2 0 0 6 , treatment w ith a c ombination of peg y lated interferon alpha- 2 a ( P eg asy s®_{; R oc he) and ribavirin ( 1 8 0 µg / w eek}

and 1 0 0 0 mg / day , respec tively ) w as initiated. After 1 2 w eeks of treatment, the patient presented dy spnea on

ex treme ex ertion, w ith episodes of c oug h follow ed by voluminous ex pec toration c onsisting of larg e piec es ( up to 8 . 0 c m in leng th) of muc us- like material mimic king bronc hial c asts ( Fig s. 1 a and 1 b) . Ex pec toration occ urred daily , mainly during the nig ht, and w as ex ac erbated by a c old environment. The patient did not present fever,

nig ht sw eats, orthopnea or parox y smal noc turnal dy spnea. Considering the g ood virolog ic al response to the treatment

( H CV R N A not detec ted at w eek 1 2 of therapy , w hic h is

indic ative of c omplete early virolog ic al response ( c EV R ) ) and the severity of the hepatic impairment, tog ether w ith

the w illing ness of the patient to c ontinue, w e opted for not interrupting the treatment. Empiric ally , w e employ ed anti- inflammatory treatment w ith prednisone ( 4 0 mg / day ) . P artial improvement w as obtained, and the dose w as tapered to the low est possible level that w ould suppress the sy mptoms, being inc reased w hen nec essary . Therefore, there w as no sy mptom prog ression, and the ex ac erbations w ere c ontrolled. D espite the pulmonary proile and the c EV R , but g iven the use of hig h doses of prednisone, the severity of the hepatic histolog ic al lesion and the hig h baseline viral load, w e dec ided to maintain the therapy w ith peg y lated interferon alpha and ribavirin for 4 8 w eeks. I mmediately after the use of peg y lated interferon and ribavirin w as disc ontinued, there w as c omplete remission of the respiratory c omplaints, and the patient remains in remission at this w riting ( 3 y ears) . Six months after the disc ontinuation of the therapy , the patient ac hieved an SV R .

Tests c onduc ted for the purpose of diag nosing and evaluating pulmonary func tion revealed minimum alterations. A hig h- resolution c omputed tomog raphy sc an of the c hest show ed sig ns of diffuse, possibly c hronic , bronc hial disease, w ith ex tensive thic kening of the bronc hial w alls ( Fig . 2 ) . B ronc hosc opy revealed normal morpholog y up to the subseg mental bronc hi. Cy tolog y of bronc hoalveolar lavag e luid revealed abundant

c ellularity : 9 5 % pneumoc y tes/ alveolar mac rophag es and 5 % ly mphoc y tes. D irec t testing , as w ell as c ultures for my c obac teria and fung i, y ielded neg ative results. Double immunodiffusion and c ounterimmunoelec trophoresis for Paracoccidioides brasiliensis and Aspergillus fumigatus w ere neg ative. Transbronc hial biopsy show ed preserved

Fig ure 2 - Tomog raphic slic e: sig ns of diffuse, possibly c hronic , bronc hial disease w ith diffuse thic kening of the bronc hial w alls.

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alveolar w alls w ith no ibrosis or sig niic ant inlammation and few alveolar mac rophag es. There w as no histolog ic al evidenc e of c hronic pulmonary disease, nor w ere there any g ranulomas or sig ns of neoplasms ( Fig . 3 ) . Arterial blood g as analy sis results revealed a P aO₂ of 7 9 mmH g , and the results of pulmonary func tion testing w ere w ithin the limits of

normality ( FEV₁, 8 3 % of predic ted) . W e c onc luded that there w ere no c hronic pulmonary diseases or other assoc iated

pulmonary diag noses that w ould ex plain the profile. Therefore, the established c ause- and- effec t relationship, tog ether w ith the lac k of fac tors other than the use of the peg y lated interferon- ribavirin c ombination, broug ht us to the c onc lusion that the effec ts observed in this c ase w ere induc ed by the therapy ag ainst H CV .

DISCUSSIO N

Case reports that attribute pulmonary sy mptoms and sig ns to the use of interferon alpha and ribavirin have show n that these effec ts appear 2 to 1 2 w eeks after the initiation of treatment. Most of the reported c omplaints are of fever,

prog ressive dy spnea and c oug h. R adiolog ic al imag ing studies detec t diffuse interstitial iniltrates and opac ities

c onsistent w ith a g round- g lass pattern. P ulmonary biopsies reveal interstitial pneumonitis, idiopathic pulmonary ibrosis, B O O P and sarc oidosis. I n all the reported c ases of pulmonary c omplic ations during therapy w ith interferon alpha ( w ith the ex c eption of a c ase of ac ute respiratory distress sy ndrome) , the sy mptoms reg ressed after the disc ontinuation of the treatment.3 –6 ,8 ,1 1

O ur patient also presented sy mptom onset after the tw elfth w eek of treatment. The predominant feature w as c oug h w ith abundant ex pec toration c ontaining bronc hial

c asts. Among the hy potheses c onsidered in the differential diag nosis w ere alveolar proteinosis and allerg ic bronc hial asperg illosis. After c omplementary tests, suc h diagnoses w ere ruled out. Therefore, w e c onsidered the possibility of a late hy persensitivity reac tion to interferon alpha, and that the reac tion w as restric ted to the lung s, more speciic ally to the trac heobronc hial tree, and involved the formation of muc ous plug s. Some authors have stated that the proc ess of interferon- induc ed ex ac erbation of bronc hospasm sy mptoms is similar to that of asthma, w ith the formation of bronc hial c asts and improvement after c ortic osteroid therapy .

Considering that the pathog enesis of the side effects assoc iated w ith peg y lated interferon remains unc lear, tw o possibilities must be c onsidered. O ne is the direc t tox ic ity of the drug to the lung , and the other is the ac tivation of indirec t

tox ic ity mec hanisms that involve immunolog ic al pathw ay s ( e. g . , autoimmune pathw ay s) . I nterferons inhibit suppressor

T c ells, alter c y totox ic T c ells and induc e pro- inlammatory c y tokines. I nterferons also c ause the overproduc tion of

ibrog enic c y tokines, suc h as platelet- derived g row th fac tor and transforming g row th fac tor beta, thereby potentially

induc ing pulmonary ibrosis. I n c ases in w hic h immunog enic mediation is the princ ipal c ause of the ex ac erbation of bronc hospasm sy mptoms, there is an inc rease in the Th1 -ty pe ly mphoc y tic response and a c onseq uent inc rease in the produc tion of interferon g amma and interleukin- 2 . W e also spec ulated that the stimulation of other c ells or c y tokines trig g ered an inlammatory c asc ade. I n c ases of interstitial pneumonia, the mec hanism remains poorly understood. The sug g ested treatment has been the disc ontinuation of

interferon alpha. H ow ever, c ortic osteroid therapy c an also suppress the sy mptoms.

I n the c ase desc ribed, c onsidering the g ood EV R and the severity of the hepatic impairment, tog ether w ith the

c onsent of the patient, w e opted to not interrupt the hepatitis C therapy . Empiric ally , c ortic osteroid therapy w as employ ed at the low est effec tive dose and only until the sy mptoms w ere c ontrolled to avoid any possible immune alterations driven by prednisone. As a result, there w as no prog ression of the sy mptoms, and the ex ac erbations w ere c ontrolled. I mmediately after the use of peg y lated interferon and ribavirin w as disc ontinued, there w as c omplete remission of the respiratory c omplaints, and the patient remains in remission at this w riting . B y six months after the disc ontinuation of the therapy , the patient ac hieved an SV R .

This c ase illustrates an unex pec ted pulmonary - related adverse effec t assoc iated w ith the use of peg y lated interferon and ribavirin for the treatment of hepatitis C. D espite being rare and reversible, the potential severity of this ty pe of adverse effec t sug g ests that the sig ns and sy mptoms of lung disease should be c arefully evaluated in patients

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Espec ially in c ases involving patients w ith a history of c hronic lung disease, asthma or relevant smoking , we rec ommend that the initial evaluation inc lude at least one

c hest X - ray and pulmonary func tion tests. W hen fac ing an adverse and unex pec ted manifestation, one should c onsider

the use of c ortic osteroid therapy to c ontain the ex ac erbated inlammatory response and allow the maintenanc e of the

therapy ag ainst H CV , w hile emphasiz ing that total adhesion to the established dose sc hedule is of ex treme importanc e for ac hieving an SV R . This c ase and the ac c umulation of pulmonary - related adverse events desc ribed during therapy w ith the peg y lated interferon- ribavirin c ombination undersc ore the need for pharmac ovig ilanc e, as w ell as the need to establish minimum therapeutic parameters for the appropriate manag ement of suc h c ases.

R E FE R E N CE S

1 . K amisako T, Adac hi Y, Chihara J, Yamamoto T. I nterstitial pneumonitis and interferon- alfa. B r Med J. 1 9 9 3 ; 3 0 6 : 8 9 6 .

2 . Midturi J, Sierra- H offman M, H urley D , Weissner R , Carpenter inn R , B J. Spec trum of pulmonary tox ic ity assoc iated w ith the use of interferon therapy for hepatitis c : c ase report and review of the literature. Clin I nfec t D is. 2 0 0 4 ; 3 9 : 1 7 2 4 - 9 .

3 . Abi- N assif S, Mark EJ, Fog el R B , H allisey R K . P eg y lated interferon and ribavirin- induc ed interstic ial pneumonitis w ith AR D S. Chest.

2 0 0 3 ; 1 2 4 : 4 0 6 - 1 0 .

4 . K umar K S, R usso MW , B orc z uk AC, B row n M, Esposito SP , L obritto SJ, et al. Sig niic ant pulmonary tox ic ity assoc iated w ith interferon and

ribavirin therapy for hepatitis C. G astroenterolog y . 2 0 0 2 ; 9 7 : 2 4 3 2 - 4 0 .

5 . B runo R , Sac c hi P , Ciappina V , Z oc hetti C, P atruno S, Maioc c hi L , et al. V iral dy namic s and pharmac okinetic s of peg interferon alpha- 2 a and peg interferon alpha- 2 b in naive patients w ith c hronic hepatitis C: A randomiz ed, c ontrolled study . Antivir Ther. 2 0 0 4 ; 9 : 4 9 1 - 7 .

6 . Fuhrmann V , K ramer L , B auer E, L aferl H , Tuc ek G, D ekan G , et al. Severe interstitial pneumonitis sec ondary to peg y lated interferon α_{- 2 b and ribavirin treatment of hepatitis c infec tio}_{n. D ig D is Sc i.} 2 0 0 4 ; 4 9 : 1 9 6 6 - 7 0 .

7 . Manns MP , Mc H utc hison JG , G ordon SC, R ustg i V K , Shiffman M, R eindollar R , et al. I nternational H epatitis I nterventional Therapy G roup:

P eg interferon alfa- 2 b plus ribavirin c ompared w ith interferon alfa- 2 b plus ribavirin for initial treatment of c hronic hepatitis C: A randomised trial. L anc et. 2 0 0 1 ; 3 5 8 : 9 5 8 - 6 5 .

8 . O g ata K , K og a T, Yag aw a K . I nterferon- related bronc hiolitis obliterans org aniz ing pneumonia. Chest. 1 9 9 4 ; 9 9 4 : 6 1 2 - 3 .

9 . Fuhrmann V , K ramer L , B auer E, L aferl H , Tuc ek G, D ekan G , et al. Severe interstitial pneumonitis sec ondary to peg y lated interferon α_{- 2 b and ribavirin treatment of hepatitis C infec tio}_{n. D ig D is Sc i.} 2 0 0 4 ; 4 9 : 1 9 6 6 - 7 0 .

1 0 . L auer G M, W alker B D . H epatitis C virus infec tion. N Eng l J Med. 2 0 0 1 ; 3 4 5 : 4 1 - 5 2 .

1 1 . Chin K , Tabata C, Sataka N , N ag ai S, Moriy asu F, K uno K . P neumonitis assoc iated w ith natural and rec ombinant interferon alfa therapy for c hronic hepatitis C. Chest. 1 9 9 4 ; 1 0 5 : 9 3 9 - 4 1 .

1 2 . Feld JJ, N anda S, H uang Y, Chen W , Cam M, P usek SN , et al. H epatic g ene ex pression during treatment w ith P eg interferon and ribavirin: