Acute respiratory distress syndrome associated with tumour lysis syndrome in leukemia

T treat ment of acute leu ke mia and lym phoma may lead to acute tu mour ly sis syn drome (ATLS). ATLS oc curs sec on dary to the pro duc tion of tu mour cell break down prod ucts that over whelm the body’s nor mal ho meo static mecha nism (1). ATLS is most com monly as so ci ated with Burkitt’s lym phoma (2,3) but also oc curs not in fre quently with other high grade nonHodgkin’s lym pho mas and acute leu ke mias. Ab nor mali ties as so ci ated with this en tity in clude hy perka lemia, hy peru ri ce mia, hy pocal ce mia, hy per phos phatemia and azo temia. These may lead to lifethreatening meta bolic and elec tro lyte ab nor mali ties and even death. Oc ca sion ally it has been re ported that ATLS may lead to res pi ra tory fail ure (4,5). Pul mo nary com pli ca tions of acute leu ke mia are nu mer ous (6). They may be at trib ut able to in fec tion, pri mary leu ke mic in fil tra tion, pul mo nary hem or rhage or em bo lism and even to com pli ca tions as so ci ated with ther apy, oc ca sion ally in clud ing acute res pi ra tory dis tress syn drome (ARDS) (6). ARDS is a com mon cause of res pi ra tory fail ure in criti cally ill pa tients, and has a gen er ally ac cepted mor tal ity of 50% to 70% (7). It is as so ci ated with non car dio genic pul mo nary edema, re duced lung com pli ance, pro found hy poxe mia and the need for me chani cal ven ti la tion (8). Al though ARDS is not a com mon pul mo nary com pli ca tion of acute leu ke mia, it has been re ported in the ab sence of in fec tion (4,6,9,10). Two cases of pa tients with acute leu ke mia who de vel oped ARDS as so ci ated with ATLS are de scribed.


CASE PRESENTATIONS -CASE 1
A 74-year-old pre vi ously healthy woman pre sented with a one-month his tory of fe ver, chills and mal aise.On physi cal ex ami na tion, there were sub con junc ti val and mu co sal pe techiae and he pa tosple nomegaly.A com plete blood count dem on strated he mo glo bin of 74 g/L, white blood cell count (WBC) of 151×10 9 /L (Ta ble 1) with 110×10 9 /L blasts and 109×10 9 /L plate lets.Her bone mar row bi opsy was con sis tent with acute mye lo gen ous leu ke mia (AML M 4 ).Chest x-ray was nor mal.
The pa tient was treated with leu ko pho re sis, ag gres sive hy dra tion, al ka lini za tion of her urine, al lopuri nol and hydroxyu rea.In duc tion che mo ther apy was be gun with cy to sine ara bi no side 320 mg/day.Within hours she be came profoundly hy poxe mic, re quir ing 100% oxy gen to ob tain an arte rial oxy gen satu ra tion of 92%.She also be came feb rile, olig uric and hy poten sive re quir ing ino tropes.Chest x-ray showed dif fuse bi lat eral patchy in fil trates with air space consoli da tion (Fig ure 1).WBC had de creased from 155×10 9 /L to 55×10 9 /L, and po tas sium and phos phate had in creased to 7.5 mmol/L (nor mal 3.5 to 5.0) and 3.46 mmol/L (nor mal 0.85 to 1.85), re spec tively.Cal cium was 2.12 mmol/L (normal 2.2 to 2.6), and lac tate de hy dro ge nase was 1259 U/mL (nor mal less than 200).
The pa tient was trans ferred to the in ten sive care unit (ICU) with a di ag no sis of tu mour ly sis syn drome and res pi ratory dis tress.She was in tu bated, and me chani cal ven ti la tion was in sti tuted.A pul mo nary ar tery cathe ter was placed and con firmed non car dio genic pul mo nary edema (pul mo nary artery oc clu sion pres sure 8 mmHg).
The pa tient de vel oped acute re nal fail ure sec on dary to tumour ly sis syn drome, and he mo dialy sis was ini ti ated.Broncho scopy was per formed to rule out in fec tions and pul mo nary hem or rhage.Her blood, urine, spu tum, cytomega lovi rus and acid-fast bac cil lus cul tures were nega tive and re mained nega tive through out her ICU stay.
De spite ag gres sive care, the pa tient died.Autopsy confirmed ARDS with no evi dence of bron cho pneu monia.There was 200 mL of blood-tinged pleu ral fluid in each lung.Lung sec tions showed pul mo nary con ges tion, edema and re cent hem or rhage with dif fuse hya line mem branes.The al veo lar cap il lar ies, lym phat ics and per ilym phatic soft tis sues were in fil trated with blasts (Fig ure 2).Fig ure 1) Case 1 chest x-ray show ing dif fuse bi lat eral patchy in filtrates with air space con soli da tion which, along with other clini cal and he mo dy namic pa rame ters, is con sis tent with acute res pi ra tory dis tress syn drome

Fig ure 2) Case 1 autopsy lung find ings. Film dem on strates dif fuse al veo lar dam age with hya line mem brane for ma tion (black ar rows) con sis tent with acute res pi ra tory dis tress syn drome. A mono nuclear and neu tro philic in flam ma tory cell in fil trate is seen in the alveo lar space and within the in ter stitium (he ma tox ylin and eo sin stain, mag ni fi ca tion 400×)
CASE 2 A 53-year-old man pre sented with head aches, fe ver, chills, pe te chiae on his legs and bloody di ar rhea.Physi cal exami na tion re vealed a tem pera ture of 39.1°C, bi lat eral cer vical lym pha de no pa thy and oral mu co sal hem or rhage.His he mo glo bin was 87 g/L, WBC 198×10 9 /L (Ta ble 2) with 147×10 9 /L blasts and plate let count of 29×10 9 /L.He was leu ko pho re sed, ag gres sively hy drated and given hy droxyurea and al lopuri nol.Bone mar row bi opsy showed acute leuke mia (AML M 4 ).
Treat ment with cy to sine ara bi no side and dauno ru bi cin was started.He then de vel oped short ness of breath and dimin ished urine out put.Bio chem is try tests showed po tas sium of 7.3 mmol/L (nor mal 3.5 to 5.0), cre ati nine of 252 µmol/L (nor mal 60 to 100), lac tate de hy dro ge nase 14530 U/mL (normal less than 200), cal cium 1.73 mmol/L (nor mal 2.2 to 2.6), uric acid 5111 µmol/L (nor mal 120 to 420) and phos phate 2.10 mmol/L (nor mal 0.85 to 1.85).Chest x-ray showed atelec ta sis at the right lung base, an ele vated right hemid iaphragm and peri hi lar air space con soli da tion.Blood cul tures grew a Gram-positive ba cil lus (shown later to be Lis teria mono cy to genes), and he was started on ampicil lin and gen tami cin.Thus, there was a pre limi nary di ag no sis of sep sis and acute re nal fail ure sec on dary to ATLS.His oxy gena tion dete rio rated, and he re quired in tu ba tion, ven ti la tion and transfer to the ICU.A pul mo nary ar tery cathe ter was placed and con firmed non car dio genic pul mo nary edema (pul mo nary artery oc clu sion pres sure 13 mmHg).
Bron cho scopy dem on strated no ac tive bleed ing or in fection (in clud ing cy tomega lovi rus, Pneu mo cys tis car inii, herpes sim plex vi rus and vari cella zos ter vi rus).He mo dialy sis was ini ti ated.De spite ag gres sive care, two weeks af ter admis sion to the ICU he died.Autopsy find ings were con sis tent with ARDS, and no signs of in fec tion were de tected.

DISCUSSION
We have pre sented two cases of ARDS in as so cia tion with ATLS in pa tients com menc ing che mo ther apy for acute leuke mia (AML M 4 ).ARDS was con firmed in both pa tients by non car dio genic pul mo nary edema, pro found hy poxe mia and need for me chani cal ven ti la tion.Both pa tients suc cumbed to their dis ease, and autopsy con firmed the di ag no sis of ARDS.
Pul mo nary com pli ca tions, es pe cially in fil trates, in a leuke mic popu la tion are com mon and pose a di ag nos tic challenge.In one se ries of 139 leu ke mic pa tients, 82% of lo calized pul mo nary in fil trates were re lated to an in fec tious eti ol ogy while none were re lated to the leu ke mic pro cess (11).In con trast, dif fuse lung in fil trates had an in fec tious cause 35% of the time while 20% of the time they were at tribut able to the leu ke mic pro cess (11).ARDS is fre quently reported in im mu no com pro mised pa tients but in fre quently reported as a com pli ca tion of acute leu ke mia (4,6,9,10,12,13).
Ob struc tion of the pul mo nary microves sels, in clud ing cap il lar ies, by tu mour growth lead ing to en do the lial and alveo lar cell in jury has been im pli cated as a po ten tial mechanism of ARDS in leu ke mic pa tients (4,12).This is sup ported by the find ing of pul mo nary leu kosta sis at autopsy in more than 10% of pa tients dy ing of acute leu ke mia (es pe cially when WBC counts are over 100×10 9 /L) (14).As well, the release of va soac tive cell break down prod ucts and in flam matory me dia tors by the dy ing tu mour cells and dur ing reper fu sion has been im pli cated as a cause of en do the lial and al veo lar dam age lead ing to res pi ra tory fail ure (4).
Cy to sine ara bi no side has even been im pli cated in pre cipitat ing epi sodes of ARDS, per haps through in trapul mon ary cell ly sis (15) or di rect in jury to en do the lial sur faces (13).One se ries showed that 13 of 103 pa tients with acute or chronic leu ke mia in blast phase who were treated with cy tosine ara bi no side de vel oped ARDS (10).The find ing of acute tu mour ly sis syn drome may be an in di ca tor of ele vated WBC count, ie, in creased tu mour bur den.High tu mour bur den would be es pe cially dele te ri ous in the pul mo nary vas cu lature, thus pre dis pos ing to pneu mo pa thy.There fore, the chemo thera peu tic agent may play an im por tant role in ini ti at ing the pro cess, as this en tity has also been de scribed with another an ti me tabo lite, fluda ra bine (5).
Our pa tients pre sented with res pi ra tory dis tress and tumour ly sis syn drome shortly af ter ini ti at ing che mo ther apy to treat the acute leu ke mia, even with pre ven ta tive meas ures towards ATLS.The clini cal data, labo ra tory re sults and autopsy find ings con firm the pres ence of ARDS.The damage caus ing the ARDS may have oc curred through a va ri ety of mecha nisms, but al most cer tainly the chain of events was ini ti ated by the com mence ment of che mo ther apy.Cli ni cians treat ing pa tients with leu ke mia should be aware of this poten tial life-threatening com pli ca tion.

TABLE 1 Selected laboratory values (case 1) Time (h) White blood cell count (×10 9 ) Potassium (mmol/L)
*Time when che mo ther apy ini ti ated.N/a Data un avail able

TABLE 2 Selected laboratory values (case 2) Time (h) White blood cell count (×10 9 /L)
*Time when che mo ther apy ini ti ated.N/a Data un avail able