LETTERS TO THE EDITOR

Volume 40, March 2000 TRANSFUSION 381

Transfusion of buffy coat-depleted bloodcomponents and risk of postoperative infectionin orthopedic patientsInnerhofer et al.1 reported an association between the trans-fusion of buffy coat-poor allogeneic RBCs and postopera-tive infection from a carefully conducted, prospective ob-servational study of 385 orthopedic surgery patients. Thisassociation was still significant (p = 0.003) following adjust-ment for the effects of advanced age, female sex, low bodyweight and height, and transfusion of FFP. Twenty-seven ofthe 34 recorded infections were urinary tract infections (UTIs);an association between allogeneic RBC transfusion and postop-erative UTI was thus observed, which had not been notedpreviously in the randomized controlled trials that reportedan increased postoperative infection rate among the recipi-ents of WBC-containing allogeneic blood components.2-4

Nosocomial UTIs are associated, for the most part, withurinary catheters, and urinary catheters are implicated in80 percent of nosocomial UTIs in the United States.5 In theretrospective observational study by Vamvakas et al.6 of al-logeneic transfusion and postoperative infection in patientsundergoing elective colorectal cancer resection, the asso-ciation between allogeneic transfusion and postoperativeUTI disappeared after adjustment for the effects of the num-ber of days with indwelling urinary catheter, the presenceof chronic systemic illness, and female sex. Only these threevariables had a significant effect on postoperative UTI inthat study,6 but Innerhofer et al.1 presented statistical ad-justment for only one of them (i.e., female sex).

It is possible that a policy for universal WBC reductionmay be implemented in the United States in the near future,as it has been implemented in Canada and several westernEuropean countries.7 Should this happen, further investi-gation of the purported, deleterious, immunomodulatoryeffects of allogeneic transfusion will have to rely on obser-vational studies, because random assignment of patients toWBC-reduced transfusion and non-WBC-reduced transfu-sion arms will no longer be possible.7 Attention thus mustbe focused on designing observational studies correctly, asthe credibility of these reports depends on the adequacy ofthe presented adjustment for the effects of confoundingfactors.7 Because the number of days with indwelling uri-nary catheter is by far the predominant risk factor for post-operative UTI,5,6 an observational study can detect an as-sociation between allogeneic transfusion and postoperativeUTI only if it adjusts statistically for the effect of that risk factor.

The purported, deleterious, immunomodulatory ef-fects of allogeneic transfusion are most important for de-veloping rational perioperative transfusion practices, andoptimal use should be made of all the available data sets toprove (or disprove) the existence of these adverse effects ofallogeneic transfusion.8 For this reason, it is essential to

know whether the association reported by Innerhofer et al.1

will persist after adjustment for the effect of the number ofdays with indwelling urinary catheter. Even if this informa-tion was not collected by the authors during the study pe-riod, it is available in the medical records and can be re-trieved retrospectively. Because the authors state, “A Foleyurinary catheter was inserted before surgery and usuallyremoved on the morning of the second postoperative day,”1(p626)

the reporting of these adjusted results will be of great inter-est. It is to be hoped that the authors will consider re-ana-lyzing their data, after including the information on thisimportant confounding factor.

Eleftherios C. Vamvakas, MD, PhD

Department of Pathology

New York University Medical Center

New York, NY 10016

e-mail: stephen.vamvakas@med.nyu.edu

REFERENCES

1. Innerhofer P, Walleczek C, Luz G, et al. Transfusion of buffy

coat-depleted blood components and risk of postoperative

infection in orthopedic patients. Transfusion 1999;39:625-32.

2. Jensen LS, Andersen AJ, Christiansen PM, et al. Postopera-

tive infection and natural killer cell function following

blood transfusion in patients undergoing elective colorectal

surgery. Br J Surg 1992;79:513-6.

3. Heiss MM, Mempel W, Jauch KW, et al. Beneficial effect of

autologous blood transfusion on infectious complications

after colorectal cancer surgery. Lancet 1993;342:1328-33.

4. Jensen LS, Kissmeyer-Nielsen P, Wolff B, et al. Randomized

comparison of leukocyte-depleted versus buffy-coat-poor

blood transfusion and complications after colorectal sur-

gery. Lancet 1996;348:841-5.

5. Meares EM Jr. Current patterns in nosocomial urinary tract

infections. Urology 1991;37(Suppl 3):9-12.

6. Vamvakas EC, Carven JH, Hibberd PL. Blood transfusion

and infection after colorectal cancer surgery. Transfusion

1996;36:1000-8.

7. Blajchman MA. Transfusion-associated immunomodu-

lation and universal white cell reduction: are we putting the

cart before the horse? (editorial). Transfusion 1999;39:665-70.

8. Blajchman MA. Allogeneic blood transfusions,

immunomodulation, and postoperative bacterial infection:

Do we have the answers yet? (editorial). Transfusion

1997;37:121-5.

The recent article on the likely role of allogeneic (buffy coat-depleted) RBCs in postoperative infections following ortho-pedic surgery1 was of special interest, as I have just com-pleted a similar study of 965 patients who underwent totalhip or knee replacement in 8 of the 14 community hospi-

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382 TRANSFUSION Volume 40, March 2000

tals in Vermont in 1998 (Westphal RG, unpublished obser-vations). Infection tallies were limited to wound infections,for reasons given below.

In that study, 374 of 965 patients received transfu-sion(s), and 354 of these received only one type of blood:autologous only, standard allogeneic RBCs, or allogeneicRBCs that were WBC-reduced by filtration before storage.The overall incidence of surgical wound infection was 0.83percent (8/965), with an incidence of 1.3 percent (5/374) inall transfused patients and 0.59 (3/591) in all nontransfusedpatients. The incidence in patients given autologous RBCsonly was 2.4 percent (3/126), that in those given WBC-re-duced RBCs was 1.4 percent (1/71), and that in those givenstandard RBCs was 0.7 percent (1/145).

The OR (risk ratio) for infection in transfused and non-transfused patients was 2.7 (95% CI, 0.48-7.15; p>0.05). OtherORs of risk comparison ranged from 2.0 to 4.67—the latterfor autologous transfusion versus no transfusion—but 95%CIs and p values are not significant for any comparisonsmade, as is likely evident from the small number of infec-tions. In the study by Innerhofer et al.,1 the only nontrans-fused controls were 42 patients whose blood was drawn butwho received no transfusions. This small group does notseem to be a meaningful comparison group. The questionremains: What would the postoperative infection rate be ina comparably sized group of nontransfused patients?

In addition, we excluded patients with UTIs in our study,because, in the data acquisition phase, seven of the firsteight UTIs were present in preadmission studies, whichwere almost always done on an outpatient basis 2 weeksbefore admission. Innerhofer et al. included such patientsif a different organism was found postoperatively, but thisis a confounding factor that begs the question of intercur-rent treatment and of the perioperative antibiotic prophy-laxis. If one excludes patients with UTIs from their study,only 7 of 34 infections remain to be analyzed, 2 of thempneumonias. We excluded patients with pneumonia as well,because aspiration was specifically noted in some cases, andthe smoking status of the patients posed yet another con-founding factor. In addition, clinical signs of fever, leuko-cytosis, and chest film abnormalities are not specific forpneumonia and could be due to transfusion reactions,2 pul-monary embolism, or other circumstances not necessarilyrelated to infection,3 especially as no Gram’s stains or spu-tum cultures were obtained in the study by Innerhofer et al.

If, in responding to these concerns, one finds similarinfection rates in a control, nontransfused group of equalsize and no difference in infections other than UTIs in thetransfused groups evaluated, it is very difficult to make anypoint about the relationship between postoperative infec-tion and blood transfusion. Five of the seven infections (2pneumonia, 2 conjunctivitis, and 1 tracheobronchitis) couldvery easily be more specifically related to other confound-ing or modifying factors.

My view of the data of Innerhofer et al. is that there isno identifiable relationship between transfusion and infec-tion, and I am concerned that we will soon embark on anexpensive strategy of universal WBC reduction on the ba-sis of data such as these.

Robert G. Westphal, MD

Department of Medicine

University of Vermont

Burlington, VT

and

School of Public Health

SUNY at Albany

Albany, NY

e-mail: rgw03@health.state.ny.us

REFERENCES

1. Innerhofer P, Walleczek C, Luz P, et al. Transfusion of buffy

coat-depleted blood components and risk of postoperative

infection in orthopedic patients. Transfusion 1999:39:625-32.

2. Westphal RG, Popovsky MA, O’Neill EM. Adverse reactions

to blood transfusion. In: Rakel RE, ed. Conn’s current

therapy. Philadelphia: W.B. Saunders Company, 1997:442-5.

3. Donowitz GR, Mandell GL. Acute pneumonia. In: Mandell

GL, Bennett JF, Dolin R, eds. Principles and practice of in-

fectious diseases. 4th ed. New York: Churchill Livingstone,

1995:619-37.

The above letters were sent to Innerhofer et al., who offer thefollowing reply.

We appreciate the extensive comments made by Vamvakasand Westphal on our study of increased postoperative in-fection seen after allogeneic transfusion. Both authors ar-gue against relying on an increased incidence of postopera-tive UTIs and the association with allogeneic transfusion.Westphal also criticizes the lack of microbiologic culturesfor a diagnosis of pneumonia and the small population ofpatients receiving no transfusion.

Our study was designed in 1996, and we used similarcriteria for diagnosis of postoperative infection as in previ-ously reported studies on this topic.1-3 Furthermore, noneof our patients were on prolonged mechanical ventilation,which explains why no sputum cultures were obtained andwhy classic clinical signs (fever, leukocytosis, and chest infil-trate) were used for the diagnosis of pneumonia. We statedthat, in patients with a history of preoperative UTI, a post-operative infection was identified only when a differentorganism was found. There were four patients in our studypopulation with a preoperative positive urine culture, butnone of them developed a postoperative infection acccordingto our criteria; this meant that, of the 27 patients with post-operative UTI, none had had a preoperative UTI. It is inter-esting that the number of patients with preoperative UTI

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Volume 40, March 2000 TRANSFUSION 383

was much higher in the study of Westphal (unpublishedobservations) than in ours. This high number led Westphalto exclude patients with UTIs from their analysis. A possiblereason for our small number of preoperative UTIs is that ourstudy included only otherwise healthy patients scheduled forelective orthopedic surgery and able to undergo preopera-tive autologous blood donation.

This was also the reason why the confounding variable,chronic systemic illnes, was not forced into our multivari-ate analysis. Further, we included only patients who werethought to need perioperative transfusion. Otherwise, auto-logous blood donation would not have been justified. Thisexplains the small study group of patients who needed notransfusion support (mainly, allogeneic blood donors). Theincidence of infection in this group (42 patients) was 4.7percent in our study, which is in accordance with the 6.4percent reported in a retrospective analysis, including 216orthopedic patients without perioperative transfusion supply.1

We agree with Vamvakas that UTIs are associated withthe use of Foley catheters. Despite this fact, we includedUTIs in our analysis, because all our patients were treatedwith Foley catheters and UTIs are the most frequent noso-comial infection seen in hospitalized patients. Furthermore,despite the inclusion of UTIs in our analysis, we found, as hadanother study,4 that patients exposed to allogeneic trans-fusion and with postoperative infection had longer hospi-tal stays and received more antibiotics. On the other hand,wound infections are very rare in elective orthopedic sur-gery (0.5% in our study and 0.83% in that of Westphal),which means that several thousand patients would have tobe studied to determine presumed differences between pa-tient groups. This would imply the need for a multicentertrial or a study period of several years, both of which wouldinfluence results. On the other hand, wound infections aremore frequent after colorectal surgery, and pulmonary sideeffects have to be expected after cardiac surgery. These factsmake a comparison of our results with data obtained inother patient populations even more difficult. We also in-cluded only infections diagnosed in the immediate postop-erative course, to minimize environmental influences, al-though different observation periods were used in other studies.

Unfortunately, in our prospective study, we did not col-lect data on the number of days with indwelling urinarycatheter. To reply to Vamvakas’s letter within a reasonabletime, we retrospectively obtained these data from medicalrecords, including those for all patients with diagnosed UTI,and compared the data with those for a group of matchedpatients (similar age, sex, operative procedure) in whom noUTI was diagnosed. In the infected group, 37 percent ofpatients had a urinary catheter >5 days, while this was trueof 35 percent of patients in the matched, uninfected group.These findings support our view that differences in post-operative infection are due to differences in transfusionregimens, rather than differences in perioperative treat-

ment. Up to now, it has not been entirely clear whether WBCfiltration will ensure the prevention of immunomodulationafter allogeneic transfusion. In a smaller, similar populationof orthopedic surgery patients, we found a smaller T-cellproliferative response, even after WBC-filtered allogeneictransfusion, than in recipients of autologous buffy coat-de-pleted RBCs.5 This unexpected finding might be related tothe higher percentage of transfusions of units stored formore than 21 days in the group of patients receiving prestorageWBC-filtered RBCs. This suggestion is supported by the re-cently published data on the increased risk of pneumoniain patients undergoing coronary bypass graft surgery andthe association with storage time of transfused non-WBC-reduced allogeneic RBCs/and or platelets.6

Petra Innerhofer, MD

e-mail: petra.innerhofer@ubik.ac.at

Christian Walleczeck, MD

Wolfgang Schobersberger, MD

Department of Anesthesia and

Intensive Care Medicine

The Leopold-Franzens

University of Innsbruck

Innsbruck, Austria

REFERENCES

1. Vamvakas EC, Moore SB, Cabanela M. Blood transfusion

and septic complications after hip replacement surgery.

Transfusion 1995;35:150-6.

2. Triulzi DJ, Vanek K, Ryan DH, Blumberg N. A clinical and

immunologic study of blood transfusion and postoperative

bacterial infection in spinal surgery. Transfusion 1992;32:517-24.

3. Fernandez MC, Gottlieb M, Menitove JE. Blood transfusion

and postoperative infection in orthopedic patients. Trans-

fusion 1992;32:318-22.

4. Vamvakas EC, Carven JH. Allogeneic blood transfusion,

hospital charges, and length of hospitalization. Arch Pathol

Lab Med 1998;122:145-51.

5. Innerhofer P, Luz G, Spötl L, et al. Immunologic changes after

transfusion of autologous or allogeneic buffy coat-poor versus

white cell-reduced blood to patients undergoing arthroplasty. I.

Proliferative T-cell responses and the balance of helper and sup-

pressor T cells. Transfusion 1999;39:1089-96.

6. Vamvakas EC, Carven JH. Transfusion and postoperative

pneumonia in coronary artery bypass graft surgery: effect

of the length of storage of transfused red cells. Transfusion1999;39:701-10.