Granulocyte Transfusions in Neonates With Presumed Sepsis

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738 PEDIATRICS Vol. 80 No. 5 November 1987

plicants, pediatric educators must be prepared to confront and change attitudes that, in the long run, will serve neither our patients nor our profession.

ALAIN JOFFE, MD, MPH Department of Pediatrics

Johns Hopkins Medical Institutions Baltimore

Granulocyte

Transfusions

in

Neonates

With

Presumed

Sepsis

Neonatal sepsis is a life-threatening disorder

oc-curing in one to ten patients per 1,000 live births and accounts for almost 10% to 20% of all mortality during the first 28 days of life.’ The outcome of neonatal sepsis is dependent on numerous factors including maternal antenatal complications,

ma-tunity and physiologic status of the neonate, and

invasive supportive care, such as vascular catheters. Early diagnosis, initiation of appropriate antibiotic therapy, and management of metabolic and

respi-ratory problems can greatly affect the outcome of neonatal sepsis.

Numerous humoral deficiencies in the term and premature neonate predispose to bacterial

infec-tion. These include decreased maternally derived specific antibodies,2 decreased levels of circulating complement,3 and decreased levels of circulating fibronectin.4 All three of these deficiencies lead to decreased opsonization and phagocytosis of bacte-na.

Cellular deficiency may also play a role in the neonate’s increased susceptibility to sepsis. Quan-titative deficiencies of either bone marrow

poly-morphonuclear leukocyte precursors or circulating

polymorphonuclear leukocytes have been described. The neonate may lack an adequate supply of either bone marrow stem cells or circulating pools of

pol-ymorphonuclear leukocytes.5 During neonatal

sep-sis, even adequate numbers of polymorphonuclear

leukocytes may be insufficient because their ability to function normally may be impaired. Numerous abnormalities have been demonstrated in vitro in neonatal polymorphonuclear leukocytes, especially in times of stress and infection. These include decreased deformability, chemotaxis, phagocytosis,

bacterial cell killing, and depressed oxidative

re-sponses.6

In this issue of Pediatrics, Baley et al7 reported their investigations in a prospective, randomized

study of the role of buffy coat transfusions in

neu-tropenic neonates with presumed sepsis. Their

con-clusion that the efficacy of granulocyte transfusions remains questionable in this setting is difficult to assess because of the heterogeneous group of

neu-tropenic patients that are studied. Their population of 25 patients included patients with and without positive blood culture results and neonates with and without with necrotizing enterocolitis.

Their research protocol included the daily use of

buffy coats from single units of whole blood. This

method would have afforded quick, economical, and widely available treatment throughout this country for neonates in whom presumed sepsis developed.

Unfortunately, from this study, as well as others that have been published to date, it is still difficult

to make a definite conclusion about the efficacy of leukophenesed granulocytes or, as in this study,

buffy coat granulocytes, for the treatment of pre-sumed neonatal sepsis. This study is somewhat difficult to interpret because of the large mix of patients that were admitted to the study. There were 11 patients with necrotizing enterocolitis, a different clinical entity than overwhelming sepsis

that occurs during the first few early days of neo-natal life. There were, additionally, eight patients,

weighing less than 1,500 g, with presumed sepsis, only one of whom cleanly had a bacterial infection. The third distinct and remaining group of patients consisted of five neonates weighing greaten than

1,500 g without evidence of necrotizing enterocolitis but with presumed sepsis.

Baley et al considered 25 of these patients as a single group, when in reality, the reader is faced with three different groups, all of which have

dif-fenent clinical outcomes and all of which should

have required separate randomizations. To mix the group of patients with necnotizing enterocolitis with the group of five patients weighing greater than 1,500 g with positive blood culture results is dan-gerous because of the completely different clinical

outcomes and findings associated with each group.

It would have been more valid to consider two separate groups of patients, one with presumed

sepsis and neutropenia and the other with

necrotiz-ing enterocolitis.

Another important variable in this study was the age of presentation of this patient population. The average age was 20 ± 15 days; this is a much older patient population than is normally considered to be associated with early overwhelming sepsis. Most patients in previous reported studies were those in whom sepsis developed during the first three to

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COMMENTARIES 739

seven days of life, and the morbidity and mortality

in this group is different from that which occurs in

infants in whom sepsis develops at a later age and/

or in whom necrotizing enterocolitis develops.

Buffy coat preparations have not been proven to be efficacious in sepsis with neutropenia in other

settings. However, the authors clearly acknowledge

this limitation in their paper by stating “buffy coat

preparations, although unproven clinically, have been suggested as a source of granulocytes for

tnans-fusions in neonates by other investigators.” Buffy

coat preparations, however, have a significant ad-vantage of immediate availability as compared with

leukopheresed granulocytes and are somewhat

cheaper to obtain. This presents a problem in the interpretation of the data in this study.

The whole question of the role ofleukocyte

trans-fusions for presumed neonatal sepsis is still

confus-ing and controversial. Although Baley et al attempt

to address the use of buffy coat transfusions for

necrotizing enterocolitis, the question remains un-answered. Previous studies, including our own, have shown some benefit of leukopheresed granulocytes

in the early treatment of neonatal sepsis with or

without neutropenia. Several investigators have used granulocyte transfusions to overcome

neutno-phil deficiencies in the hopes of enhancing the neonate’s response to bacterial sepsis. These

stud-ies each included small numbers of cases, used

different methods of obtaining granulocytes, used

different transfusion protocols, and had different outcomes. Laurenti et al8 nonnandomly treated 20 septic infants and found that mortality decreased from 72% to 10%. Christensen et al9 treated seven septic neonates with neutrophil storage pool deple-tion, and all seven transfused patients survived in

contrast to only one of nine nontransfused patients. We recently completed our phase 1 study on the

role of leukophenesed adult polymorphonuclear leu-kocytes in the early treatment of 35 consecutive,

critically ill neonates in a randomized, prospective

trial. This study is an update on our previously reported study in Pediatrics.’0” Twenty-one septic

infants received leukopheresed granulocytes, and

there was only one death among the 21 patients. In

contrast, 14 equally critically ill septic neonates did not receive polymorphonuclean leukocyte transfu-sions and, of these, only nine survived, a survival rate of 64% V 95% for those treated with granulo-cytes

(

P :S #{149}#{216}5)#{149}10.11An additional finding of our study was that low circulating levels of total he-molytic complement were found to be associated with a poor outcome and increased mortality.

Results of recent animal studies have suggested

that the neonate’s bone marrow neutrophil supply pool contains only two times the number of

poly-morphonuclear leukocytes as the circulating pool.

In contrast, the adult neutrophil supply pool

con-tains ten times that of the circulating pool.

Neo-natal rats also have only 25% as many neutnophil

supply pool precursors as adult rats, and therefore,

polymorphonuclear leukocytes are depleted much

earlier in neonatal rats than in adults. In addition, the proliferative neutnophil pool of the neonatal rat

is already maximally stimulated at 75% to 80% of

capacity compared with the normal adult rat at 6 months of age.5 More recent work by Christensen

et al’2 has demonstrated that the total body

colony-forming unit to granulocyte, erythnoid, monocyte,

megakaryocyte pen gram of body weight was signif-icantly less in fetal animals than in adults and that fetal animals have progressively higher total body myeloid proliferative capacities at the 90% level compared with that of adult rats at approximately 10% to 12%. These additional findings of decreased total body bone marrow stem cell precursors, as well as continued high proliferative rate of bone marrow stem cell precursors, are convincing evi-dence of the increased tendency to neutrophil sup-ply pool depletion in neonatal sepsis. With accu-mulating data suggesting that neutnophil supply pool depletion can be a common occurrence in neonates secondary to decreased pools and already

high proliferative capacities and with the

observa-tion of marked neonatal neutrophil qualitiative de-ficiencies, it becomes imperative for investigators

to determine the exact nature and role of granulo-cyte support in neonates with overwhelming sepsis.

Several questions remain unanswered regarding

the use of adult donor granulocyte transfusion for neonatal sepsis. Important variables that need to

be studied include selection criteria for early

admin-istration, number of granulocytes harvested, and

method of quick and optimal collection, frequency and intervals of polymorphonuclear leukocyte

transfusions, role of plasma factors such as comple-ment in influencing opsonization and phagocytosis

of transfused polymorphonuclear leukocytes, IV administration of immunoglobulin to prevent

neu-trophil supply pool depletion, and improvement in

opsonophagocytic activity of polymorphonuclear leukocytes.

The benefits of polymorphonuclear leukocyte

transfusions must be weighed against reported side effects such as fluid overload from hydroxyethyl

stanch, graft host disease, cytomegalovirus, human immunodeficiency virus, and hepatitis infections, and blood group sensitization.

A large, multicenten study of the role of polymor-phonuclear leukocyte transfusions with or without plasma or IV immunoglobulin is warranted based on these unanswered questions. The work by Baley

et al is important because it develops these ques-tions about the role of granulocyte transfusions in

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740 COMMENTARIES

presumed neonatal sepsis and hopefully will stim-ulate other investigators to cooperate in a multicen-ten study to finally answer this question with den-tainty.

REFERENCES

MITCHELL

S.

CAIRO,

MD

Children’s Hospital of Orange County Orange, CA

1. Siegel J, McCracken G: Sepsis neonatorum. N EngI J Med

1981;304:642

2. McCracken G, Sarff L, Robbins J, et al: Ontogeny of serum and secretory KI antibodies. Pediatr Res 1976;1O:401 3. McCracken G, Eichenwald H: Leukocyte function and

de-velopment of opsonic and complement activity in the neo-nate. Am J Dis Child 1971;121:120

4. Hall HR, Boline J, Augustine N, et al: Decreased plasma fibronectin in neonatal sepsis.

5. Christensen RD, MacFarlane JL, Taylor NL, et al: Blood and marrow neutrophils during experimental group B

strep-tococcal infection: Quantification of the stem cell, prolifer-ative, storage and circulating pools. Pediatr Res 1982;16:549-533

6. Miller ME: Phagocyte function in the neonate: Selected aspects. Pediatrics 1979;64(suppl):709

7. Baley JE, Stork EK, Warkentin P1, et al: Buffy coat trans-fusions in neutropenic neonates with presumed sepsis: A prospective, randomized trial. Pediatrics 1987;80:712-720 8. Laurenti F, Ferro R, Isacchi G, et al: Polymorphonuclear

leukocyte transfusion for the treatment of sepsis in the newborn infant. J Pediatr 1981;98:118

9. Christensen RD, Rothstein G, Anstall HB, et al: Granulo-cyte transfusions in neonates with bacterial infection, neu-tropenia, and depletion of mature marrow neutrophils. Pe-diatrics1982;70:1-6

10. Cairo MS, Rucker R, Bennetts GA, et al: Improved survival of newborns receiving leukocyte transfusions for sepsis.

Pediatrics 1984;74:887-892

11. Cairo MS, Worcester C, Rucker R, et al: The role of circu-lating complement and polymorphonuclear leukocyte trans-fusion in the treatment and outcome ofcritically ill neonates with sepsis. J Pediatr 1987;110:935-941

12. Christensen RD: Developmental changes in pluripotent he-matopoietic progenitors (CFU-GEMM). J Pediatr, in press, 1987

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1987;80;738

Pediatrics

MITCHELL S. CAIRO