Influenza A Pneumonitis Following Treatment of Acute Cardiac Allograft Rejection with Murine Monoclonal Anti-CD3 Antibody (OKT3)

2 Connolly JE . Wilson A. T he current stat us of surgery for bullou s e mphyse ma. J T horac Cardiovasc Surg 1989 ; 97:3.51-6 1 3 Nakahara K, Nakaoka K, Ohno K, et ul. Functional indicatio ns fo r bu llec tomy of gian t bu lla. Ann Th orne Surg 1983 ; 3.5:480-87 4 O'B rie n CJ, Hughes CF, Cianoutsos P. Surgical treatm ent of bullous emphyse ma. Aust N Z J Surg 1986; 56 :24 1-45

Influenza A Pneumonitis Following Treatment of Acute Cardiac Allograft Rejection with Murine Monoclonal Anti-CD3 Antibody (OKT3)* Bichanl 1'. Em brei], Ml ); and Lois j. Geist. M D

F II;UIlE :3. Chest radiograph tak en :30 months aft(' r surgery demo nstrating n-expansion of the right middl(' and lowe-r lobes.

he mithorax. It is impo rtant th at the patient has unequivocal preoperative evide nce of compression of relatively normal lun g pa ren ehym a.:2 In patients with underl ying emphysema in th e re maining lung tissue, b ulleetomy JIlay not be help /iii in relieving dyspn ea and other pu lmonary symrtoms and thus, som e authors believe that it is not indicated.' It has also been stated that seve re resp iratory [uilure is a contrai ndication to bullectomy surgery du e to poor outcome." Ot her aut hors believe that pati e nts arc at greater risk of a poor outcome if their FEY, is not greater than 40 % of th e predieted value. 3 T he current case involves a young man with severe bu llous e mphyse ma. Initially, surgical resection of the bullae W,LS not cons idered due to the underlying emphysematous changes in his compressed lung, an FEY, of only 14% of predicted, and respi ratory failure. However, as his hypoxe mia worsened, surgical interventi on was believed to be the on ly viable option . Th is appears to be th e first case of successful su rgical resection of gian t bu llous lesions in a pati ent with severe respiratory failur e rec eiving mechanical ventilatory . assistance. This ease de monstrates that bu llcctomy can be a lifesaving operation in carefully select ed patie nts. The goal of bu lleetomy- resection of nonf unctional spac e-occupying bullo us lesions to allow reexpansion of compressed, but presumably functional lung tissue-s-was clearly achieved in this pa tient. Success ful surgery allowed him to resume an acti ve life. R EFEHEi':CES

Diaz P, Clanton T , Pacht E. Emphysema-like pu lmonary disease associated with hu ma n inununod c ficieucv virus infection. Ann lntr -rn M('d 1992; I16:124-2H .

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A 51 -year-old man developed fever, cough, and dyspnea 5 days after completing murine monoclonal antiCD3 antibody (OKT3) treatment for acute cardiac al lograft rejection. Samples of HAL flui d grew influenza A virus. Progressive pulmonary infiltrates, respiratory comp r omise, and hypoxia developed, and the patient ultimately required 5 days of mechanical ventilation. Treatment with amantadine hydrochloride and ribavirin was prescribed, and the patient was discharged after 19 d ays. Influenza A virus has not been an important pathogen in cardiac transplant recipients. However, this is the first reported case of influenza A pneumonitis complicating anti-T lymphocyte therapy for cardiac allograft r ej ection. In comparison with our patient, two previously reported cases of influenza A infe ction in cardiac transplant patients have been less sever e . The virulence of our patient's, life-threatening infection appears to b e secondary to impairment of T lymphocyte-mediated im m u n ity by OKT3. The role of therapeutic and eve n prophylactic amantadine therapy in this clin ical setting has yet to be determined. (CHEST 1995; 108:1456-59) Key words: cardiac transplan tation ; influenza A; imm unosuppression; O KT3

I nfluenza A is a common viral pathogen that typically

causes a low-grade febril e illness and mild respiratory symptoms. This rather innocuous pathogen may be life-threatening in elderly, debilitated or imrnunocomprom ised patients, however. Solid-organ trans plant recipients are particularly susceptible to viral infections, and this risk is increased by anti-T lymphocyte therapy for graft reject ion. This report documents a case of severe influen za A pneu monitis, which occurred in a heart tran splant patient following treatm ent 'From the Divisions of Cardiothoracic Surgery (D r. Em brey ) and Pulmonary Medicine (D r. Geist ), the Unive rsity of Iowa College of Medi cine , Iowa City. Reprint requests: Dr. ElIlhrey , Division o!Cardio thoradc SurgenJ, Departmen t of Su rgen/ , The Medica l College of Virgi nia, PO Box 980068, Bich inorul, VA 232 .98. SelectedReports

FIGUIl E 1. Chest radiograph take n at time of ad mission. The elevated left hemidiaph ragm and left lower lobe atelectasis are chron ic changes present since transplantation.

FIGUIlE 2. Chest radiograph taken on 7th hospital day showing bilate ral pul monary infiltrates .

with murine monoclonal anti-C D3 antibody (OKT3) (Ortho Pharmaceutical, Raritan, NJ).

and cyto megalovinrs inclusions . Over the next several days, th e patient became progressively more dyspn eic, req uiring increasing amount s of suppl em ental oxygen . On the 2nd hospital day, rap id scree ning techniques of th e cultures obtained at BAL confirmed the presen ce of Influenza A vinrs, and therapy with amantadine hyd rochloride (l OO mg twice daily, orally) was initiated . By th e 4th hospital day, the mdiograph of the chest began to show bilate ral patchy infiltrat es (Fig 2). Th e patient' s respiratory status continued to deteri orat e despite this therapy, and on the 7th hospital day he required intubation . Bronchoscopy done a second time showed no abnonnalities, and BAL fluid samples from this examination subseq uently had no viral growth. At this point , treatm ent with ae rosolized ribaviran was start ed (6 gld for a pe riod of 18 h) and was cont inued for 6 days. Th e patient slowly improved with decreasing hypoxemi a, and mechani cal ventilation was discontinu ed on the 13th hospital day, 5 days afte r intubation. During his hosp ital cours e, the patient underwent three e ndo myocardial biopsies which were all negative for rejec tion . The pat ient was discharged on the 19th hospital day and was alive and well 24 months late r. Pulmonary funct ion, art erial blood gas values, and clinical cours e are summarized in Table 1.

CASE R EPORT

In December 1992, a 51-year- old man und erwent orthotopic heart tran splantation for ischemi c cardiomyopathy. Both donor and recipient were eytom egalovinrs antigen-positive, and a standa rd tripl e-dru g immunosuppression prot ocol W,L~ e mployed. Th e immedi ate postope rative course was uneventful unt il grade II rejection was disco vered on the 5th weekly posttransplant biopsy. Treatment was begun with intravenously ad ministe red methylprednisolone, 500 mg onee daily for 3 days. M aintenan ce therapy con sisted of 20 mg of prednisone and 150 mg azathioprine pe r day as well as eyclosporin 275 mg given twice daily with levels of 217 to 321 nglmL (liq uid ehromatographie method on whole blood ). Subsequ ent e ndomyocardial biopsies in the 7th and 9th postoperative weeks were interpreted as grade Ib rejection , A routine surveillance cat het eriza tion in the 12th postoperati ve week found normal he modynamics in the right side of the heart, but hiopsy showed grade Ii -lIla rejection. Th e patient W,L~ hospitalized and received a lO-day course of O KT3 , 5 mg/day. Five days after completing treatmen t, the patien t W,L~ readmi tted to the hospital. I Ie had a feve r (te mpe rature of 38.3°C, oral), a cough, mild dyspnea , nasal congestion , and myalgia. Physical examination disclosed apthous ulcers on the soft palate and lowe r lip, clear eye grounds, and fine crackles on auscultation of the lung bases, Th e WBC count W,L~ 28,600/mm 3 (institutional normal values, 3,700 to 10,400) with an increased neutrophil count (26,3 I2Imm3 , normal , 1,750 to 6,359/mm 3 ) but no increase in immature form s; monocytosis (2,OO2lmm3 ; normal, 0 to 709 mm''), and relative lymph openia (286/mm3; norm al, 590 to 3,199 mm''), Lactate dehydro genase was mildly elevated (360 IUlL; normal , 100 to 2 to lUlL). Arteri al blood g,L~ levels with the patient breath ing room air revealed a pH of7.53 (normal, 7.35 to 7.45); PC02 of 27 mm I lg (normal, 35 to 45 mm IIg); and a 1'0 2 of 57 mm Hg (normal, 80 to 90 mm Hg ). A radiograph of the chest (Fig 1) showed no changes when compared with one taken postoperativ ely, showing left lowe r lobe atelectasis secondary to an elevated left hemidiaphragm . No infiltrates were noted. Empirically, treatment with ganciclovir and high-dose trim ethoprim-sulfamethoxazo le was begun . Bronchos copy with BAL was performed , however , stains we re negative for PlleIlllwcystis carinii

DISCUSSION

Infectious comp lications continu e to be the leading cause of death following cardiac transplantation, and pneum onia occurs in up to 24% of all patients within the first 18 months after trans plantation.! Typical pathogens are cytomegalovirus, P carinii and Gram -negative bacteria , with mixed infections being commonplace. Influenza A pneumonitis has not been problematic in this patien t popu lation. However , two cases have been reported previously; one case was document ed retrospectively by serum antibody titers, and the second infection was diagnosed concurrently by viral cultur es obtain ed from BAL fluid specimens.v' All three patient s present ed with fever and with varying degrees of pulmonary distress, ranging from cough and chest discomfort to dyspnea and hypoxemia . On e patient had a very limited febril e illness requiring 4 days of hospitalization, and only the patient describ ed in this report required mechan ical venti lator support and specific antiviral therapy. No episodes of graft rejection occurred in association with the inCHEST / 108 / 5 / NOVEMBER, 1995

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Table I- Arterial Blood Gas Levels, Oxygen Requirements, Tempe rature, WBC Count, and Th era peutic Interventions in a Heart Tr anspla nt Reci pient With Influenza A Pneu monitis Hospital Day

pH I' c 0 2 P0 2

Flo 2 M aximu m tempe ratu re. °C

WIlC

l1111n t ,

1,(KlO ce lls/mnr!

7..5.'3 27 .57 0.21 37 .3 2S.0

.5

7

9

11

14

17

7.49

7.40 20 01 0..50 .'38.2 10.9

7.40 2S 64 0.90 30 .8 12.4

7.48 2S 93 0..50 37.2 8.0

7.4.'5 30 101 0.40 30

7.47 30 74 2L 30..'3 0.0

23

.'54 1L 3S 8.2

5.7

20 7.49

34 fi4 0.21 37

8.9

Mech an ical ventilation ITri' m et Ilopnnt-SII . 1/'mne t IlOXltJ'1>Ie I

Therapy

C unciclovir

Amantadine

Hihavirin

fluenza A infe ctions, and no patient died of the illness. Frequentl y used to treat severe lower respiratory tract infection s due to respiratory syncytial virus in hospitalized childre n, aerosolized ribavirin has activity against a wide variety of viruses, including influenza A and B. In rando mized trials, both oral and aeros olized ribavirin significantly improved signs and symptoms of influenza A infection in healthy patients vs controls; however , duration of viral shedding W
controls subj ect s, and becaus e vaccination has not been shown to cause graft rejection or dysfunction, yearly inllucnza vaccination of tran splant patien ts is undertaken as a matt er of policy in many tran splant programs.!" Other institutions forego such routine immunizations bec ause the safety of vaccinations has not been firmly establishe d in this popul ation. Because vaccination may not be effec tive and influenza A pu eu monitis is potentially life-threatening in cardiac trans plant patients receiving antibody ther apy for acute rejection, ama ntadine may be particularly useful in this setting. Amant adine is up to 90% effective in the prophylaxis of in/luenza A in a nonnal tie, nonimmunosuppressed) population . IS Furthermore, the drug may reduce the duration and seve rity of symptoms if administered ea rly during the cours e of influenza A illness.!" Th e side effects of amantadine are mild, and no adverse interaction with cyclosporin or azathioprine Il
FI ( ;lJIl E .'3. Chest radiograph taken 1 week after discharge from hospital. Pulm ona ry infiltrates have resolved .

SelectedReports

Although the u sefulness of a mantadi n e in the t re atment of tra nsplant patients with e stab lished influenza A infections is clear, the p rophylacti c use o f aman tadi ne in hi gh-risk t ransplant p atients h as not be e n e val uated , d espite b eing the ore ti cally ap p ealing. In cardiac tran splant p atients w h o re q u ire OKT3 o r a n ti -thymocyte g lo b ulin for t re atm ent o f rejection duri n g in fluenza A e pid emics, a nd in p atients who a re not vaccinated or d o not e xh ib it adequate an tibody titers foll owing vaccination , the p rophylactic administration of amantadine may reduc e the incid e nce a nd seve rity o f in flu enza A infe ctio n s. A re gim en of aman tadine , 100 m g orally twice d aily, d u ring an tilymp hocyte the rapy and for tw o we e ks the re after until the patie n t' s T lympho cyt e fu n ction re c overs, wou ld seem logical. Such p rophylacti c tre atment cannot be firmly e n dorsed , howe ver, until a n ap p ro p riate ra ndomize d , prospe ctive study h as b e e n comp le ted . R EFERENCES

1 Gorensek MJ, Stewart RW, Keys TF , et aI. A mu ltivariate analysis of risk factors for pn eu monia following cardiac tran splant ation . Transplantation 1988; 46:860-65 2 Beyer WEP, Diepersloot HJA, Masurel N, et al. Doubl e failure of influenza vaccination in a heart transplant patient [letter). Tra nsplantation 1987; 43:319 3 Albat B, C hanez P, Wintrebert P, et aI. Grippe chez Ie greffe cardiaq ue, cause inhabitu elle de pne umon ie virale. Presse Medi 1993; 22:174 4 Stein DS, C reticos C M, Jackson GG , e t aI. Oral ribavirin treatmen t of influenza A and B. Antimicrob Age nts C hemother 1987; 31:1285-87 5 Wilson SZ, Gilbert BE , Quarles JM, et aI. Treatment of influenza A (H IN 1) virus infection wi th ribavirin aero sol. Antim icrob l Agents Chemother 1984; 26:200-03 6 Knight V, Gilbert BE. Ribavirin aerosol treatmen t of influenza. Infect Dis Clin North Am 1987; 1:441-57 7 Englund JA, Sullivan CJ, Jordan C, et aI. Hespiratory syncytial virus infection in imm unoco mp rimised adults. Ann Intern Med 1988; 109:203-08 8 Bell M, Hunter JM , Mostafa SM. Nebu lized ribavirin for influenza B viral pneumonia in a ventilated immu nocom pro mised adult. Lancet 1988; 2:1085 9 G reen berg SB, C riswell BS, Six H H, et aI. Lymp hocytic cytotoxicity to influenza virus-infected cells: response to vaccination and viral infec tion. Infect Immunol 1978; 20:640-45 10 Ennis FA, Wells MA, Butchko G M, et al. Evide nce that cytotoxic T cells are part of the host' s response to influen za pneumonia. J Exp Med 1978; 148:1241-50 11 Stive r H G, Graves P, Meiklejoh n G, et aI. Impaired seru m antibody response to inactivated influenza A and B vaccine in renal transplant recipients. Infect Imrnunol 1977; 16:738-41 12 Hu ang KL, Armstro ng JA, Ho M. Antibody response after influenza imm unization in ren al transplant patien ts rece iving cyclosporine A or azathioprine. In fect Immunol 1983; 40:421-24 13 Englehard D, Nagler A, Hardan 1. Antibody respons e to a twodose regimen of influe nza vaccine in allogeneic T cell-depleted and autologous BMT recipients . Bone Marrow Transplant 1993; 11:1-5 14 Hibberd PL, Rub in RH . Approach to immunization in the immunosuppressed host. Infect D is Clin North Am 1990; 4:123-42 15 He rmans PE, Cocke rill FR III. Antiviral age nts. Mayo Clin Proc 1987; 62:1108-15 16 Delker LL, Moser RH , Nelson JD , et aI. Amantadine: does it have a role in the p reven tion and treat ment of influenza ? A National Institu tes of Health Consensus Developm e nt Con ference. Ann Int ern Med 1980; 92:256-58

Myocardial Stunning Following Respiratory Arrest* Riyaz Bashir, MD; Farooq A. Padder, JI"f D; and Faroque A. Khan, MBB S, FCCP

Myocardial stunning is defined as a prolonged myocardial dysfunction with gradual return of contractile activity after a brief episode of severe ischemia. Usually it is seen in patients with myocardial infarction foDowing treatment with thrombolytic agents, in patients with angina, and in patients recovering from cardiopulmonary bypass surgery. We report an interesting case of myocardial stunning foDowing respiratory arrest. (CHEST 1995; 108:1459-60) Key words: m yocardium; respiratory a rrest; re suscitation; stu n n ing

H

e re in is the report of a case o f myoc ardial stunning after respiratory arre st. C ASE R EPORT

Sudden respirato ry arrest following intravenous injection of d iazepam and methohexatal developed in a 24-year-old previously healthy white woma n during a dental procedure. She became cyano tic and was successfully intubate d within 3 to 4 min. Th e cardiac moni toring at that time revealed a normal sinus rhyth m, and she was transfe rred to Nassau County Medical Cente r. At the time of arriva l in the e me rge ncy departmen t, find ings of th e physical examination wer e as follows: pulse, 90 beats per minute; BP , 80150 m m Hg, temperature, 35 .5°C ;and spo ntan eous respiratory rate, 20 breath s per min ute. The re mainde r of the physical exam ina tion disclosed no ab norma lities . At the time of ad mission, laboratory values, includi ng com plete and differential WB C counts and re nal and hepatic profiles, were normal. Th e arte rial blood gas level with an FI o2 of 1.0 revealed a pH value of 7.52, a P0 2 value of 554 mm Hg, and a PC02 level of 32 mm Hg. A 12-lead ECG was normal except for sinus tachycardi a. For hypoten sion , she required tempo rary inot ropic suppo rt . She was extubate d 4 h afte r admission to the hospital , and the postextubation arteri al blood gas values were normal. Ten hours late r, she developed precord ial chest pain and shortness of breath . Th e pain was localized an d rep roducible in nature . Results of physical examination d isclosed a pulse of 110 beats per minu te, BP of 100no mm Hg, and a respiratory rate of 30 br eaths per minut e . She had bib asilar crackles and an S3 gallop . An ECG reve aled T-wave inve rsions in leads 1, aVL , V3-6. A tran sth oracic two-dimensio nal echocardiogram reve aled diffuse hypokinesis of the le ft ve ntricle with an approxi mate ejection fraction of25%. Le ft ven tricu lar size was norm al, an d ther e was no evide nce of pe ricar dial e ffusion. A chest roentgen ogram showed pul monary ede ma. Serial tests for creatine kinase-MB isoen zyme wer e negative. The patient was treated with bed rest, analgesic agents, and diuretics, and he r symp toms improved . Subs equen t ECGs showe d diffuse and deep T-wave inversions and QT interva l p rolongation. Th ese cha nges were most p ronounced on day 3 of hospit alization , after which they started reced ing gradually (F ig 1). A repe at 'From Depart ment of Medi cine, Nassau County Medical Ce nte r, East Meadow, NY, and the State University of New York, Sto ny Brook. Reprint requests: Dr. Khan, Naussau County Medical Cente r, 2201 Hem pstead Tu rnpike, East Meadow , NY 11554 CHEST / 108 / 5 / NOVEMBER , 1995

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