Eur J Clin Microbiol Infect Dis (2004) 23:212–214DOI 10.1007/s10096-003-1091-3

C O N C I S E A R T I C L E

M. Elias · N. Bisharat · L. H. Goldstein · R. Raz ·W. Saliba

Pneumococcal Sepsis due to Functional Hyposplenismin a Bone Marrow Transplant Patient

Published online: 19 February 2004� Springer-Verlag 2004

Abstract Encapsulated bacteria can cause severe infec-tions following bone marrow transplantation, usually inpatients with chronic graft-versus-host disease (GVHD).Presented here is the case of an allogenic bone marrowtransplantation recipient with chronic GVHD who devel-oped overwhelming pneumococcal sepsis 3 years follow-ing transplantation. One year earlier the male patient haddeveloped non-meningococcal, non-gonococcal neisseriainfection. The infection recurred repeatedly despitemonthly replacement immunoglobulin prophylaxis. Theseinfections were attributed to functional hyposplenismafter a prominent number of Howell-Jolly bodies wasnoticed in a peripheral blood smear during the patient’smost recent admission. The case report is followed by adiscussion of the policy of administering antibioticprophylaxis to patients with chronic GVHD.

Introduction

Recurrent infections are a major cause of morbidity andmortality following bone marrow transplantation (BMT),

and recipients remain prone to infections for a variableperiod of time, even after adequate hematologic recon-stitution has been achieved. Three periods of immuno-logical deficiency occur predictably in these patients.They are (i) the pre-engraftment period, (ii) the early post-engraftment period (defined as day 1–100 post-transplan-tation), and (iii) the late period, which ends when thepatient regains normal immunity, usually within 18–36months following BMT. In most cases, immune recoveryis substantial by the end of the first year followingtransplantation; thus, most infections occur during thefirst 12 months.

Chronic graft-versus-host disease (GVHD) can extendthe period of immunosuppression during the late periodindefinitely. One of the main pathogens affecting BMTpatients during the late post-transplantation period isencapsulated bacteria [1]. Presented here is the case of anallogenic BMT recipient with chronic GVHD who devel-oped recurrent encapsulated bacterial infections duringthe late post-transplantation period. We discuss the mainfactors that contributed to his recurrent infections and thepolicy of administering antibiotic prophylaxis to patientswith chronic GVHD.

Case Report

A 35-year-old male was admitted with septic shock and bilateralpneumonia. Five years prior to admission he had been diagnosedwith chronic myelocytic leukemia. One year following the diag-nosis he underwent allogenic BMT after failure of interferontherapy. Following transplantation, severe chronic GVHD devel-oped, with marked dermal involvement. Since then, the patient hadbeen treated with azathioprine, prednisone (10–20 mg daily) andmonthly intravenous immunoglobulin. His post-transplantationcourse was further complicated by recurrent pneumonia andlower-extremity erysipelas. One of the episodes of pneumoniaoccurred secondary to a Neisseria lactamica infection diagnosed byrepeated positive blood cultures.

At the time of admission, 4 years following transplantation, thepatient’s vital signs included a temperature of 40�C, a heart rate of145 beats/min, and a respiratory rate of 20 breaths/min. Bloodpressure was 70/40 mmHg. Physical examination was remarkablefor bilateral inspiratory crackles, decreased breath sounds and

M. Elias ()) · W. SalibaDepartment of Internal Medicine C,Central Emek Hospital,Afula, 18101, Israele-mail: elias_m@clalit.org.ilTel.: +972-4-6495139Fax: +972-4-6495134

N. BisharatNuffield Department of Clinical Laboratory Sciences,University of Oxford,Headington, Oxford, OX3 9DU, UK

R. RazInfectious Diseases Unit,Central Emek Hospital,Afula, 18101, Israel

M. Elias · L. H. Goldstein · R. Raz · W. SalibaFaculty of Medicine,Technion—Israel Institute of Technology,Afula, Israel

severe scleroderma-like skin, with multiple digital ulcers. Labora-tory results showed a hematocrit level of 34%, a leukocyte count of29,800/mm3, and a platelet count of 100,000/mm3. Urea nitrogenmeasured 45 mg/dl and creatinine 3.5 mg/dl. Glucose and electro-lyte levels were normal, as were prothrombin and partial-throm-boplastin times. Chest radiographs showed bilateral basal infil-trates.

The patient was admitted to the intensive care unit and treatedwith piperacillin-tazobactam, high-dose hydrocortisone and vaso-pressors. Azathioprine therapy was withheld. Blood cultures werepositive for Streptococcus pneumonia with intermediate sensitivityto penicillin (MIC, 0.5 mcg/ml), and the antibiotic treatment waschanged to ceftriaxone. Under this regimen the patient graduallyimproved.

A peripheral blood smear performed during this period ofhospitalization was remarkable for Howell-Jolly bodies, which ischaracteristic of functional hyposplenism. At discharge, the patientwas advised to receive pneumococcal, Neisseria meningitides, andHaemophilus influenzae vaccines and to take maintenance penicil-lin V prophylaxis.

Discussion

Chronic graft versus host disease (GVHD) has beenshown in a number of studies to be a major risk factor forthe development of late infections following bone marrowtransplantation. Some of the main pathogens affectingpatients during the late post-transplantation period areencapsulated bacteria, such as Streptococcal pneumoniae,Neisseria spp. and Haemophilus influenzae [1]. Patientsdeveloping GVHD remain prone to infections for longperiods of time, sometimes for several years, as long astherapy for chronic GVHD continues [2]. This suscepti-bility to infection with encapsulated bacteria is due to theabsence of specific antibody production. All BMT recip-ients may have abnormal T-cell function with defectiveT-helper stimulation of B-cells and inhibition of IgGproduction by non-specific T-suppressor cells [2]. Win-ston et al. [3] found decreased serum opsonic activity forStreptococcus pneumoniae [3]. In another study, totalimmunoglobulin levels in allogenic BMT patients werefound to be low at 12 months post-transplantation and theIgG subclass pattern did not normalize until 24 monthspost-transplantation [4].

Our patient had normal immunoglobulin levels andwas on monthly intravenous immunoglobulin replace-ment therapy. Despite this, he still had recurrent encap-sulated bacterial infections. His peripheral blood smeardemonstrated a prominent number of Howell-Jolly bodiessuggesting that his splenic function was severely impaired[5]. In a previous study conducted by Knecht et al. [6],splenic function was evaluated in 15 BMT recipients. Thefindings showed that splenic hypofunction occurredmainly in patients with intensive primary inductionchemotherapy, and the authors attributed the functionalhyposplenism to the combination chemotherapy andconditioning regimen, including total body irradiation,that the patients received.

Kalhs et al. [7] showed that functional hyposplenismdeveloped in as many as 40% of allogenic BMT recip-ients. Since all patients with functional hyposplenism had

extensive chronic GVHD, they concluded that this com-plication was related to chronic GVHD. Similar conclu-sions were recently proposed by other groups [8, 9].

The patient reported on here was an allogenic BMTrecipient with severe chronic GVHD who had beentreated with immunosuppressive therapy. We believe oneof the main factors contributing to his recurrent encap-sulated bacterial infections was the severe impairment ofsplenic function indicated by the presence of Howell-Jollybodies in his peripheral blood smear. We cannot excludethat prolonged immunoglobulin replacement therapy mayalso have contributed to his susceptibility to infections. Apreviously reported controlled trial of long-term immu-noglobulin therapy in patients with chronic GVHDshowed that the recovery of humoral immunity was im-paired and infections were more common [2].

The case reported here emphasizes that functionalimpairment of the spleen should be considered in allallogenic BMT recipients, especially those who developchronic GVHD. Due to their increased susceptibility toencapsulated bacterial infections, the question of whetherantibiotic prophylaxis is required for allogeneic-BMTrecipients with chronic GVHD and a hypofunctioningspleen should be considered. Unfortunately, no prospec-tive or randomized studies examining the efficacy ofprophylactic antibiotics against late post-transplant infec-tions with encapsulated bacteria are available. However,according to the guidelines of the Centers for DiseaseControl and Prevention (Atlanta, GA, USA) antibioticprophylaxis is recommended for preventing infection withencapsulated organisms in allogenic transplant recipientswith chronic GVHD for as long as active chronic GVHDtreatment is administered [10].

References

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2. Roy V, Ochs L, Weisdorf D (1997) Late infections followingbone marrow transplantation: suggested strategies for prophy-laxis. Leuk Lymphoma 26:1–15

3. Winston DJ, Schiffman G, Wang DC, Feig SA, Lin CH, MarsoEL, Ho WG, Young LS, Gale RP (1979) Pneumococcalinfections after human bone-marrow transplantation. AnnIntern Med 91:835–841

4. Hammarstrom V, Pauksen K, Svensson H, Longvist B, Simon-sson B, Ringden O, Ljungman P (2000) Serum immunoglobulinlevels in relation to levels of specific antibodies in allogenicand autologous bone marrow transplant recipients. Transplan-tation 69:1582–1586

5. Robertson DAF, Bullen AW, Hall R, Losowsky MS (1983)Blood film appearance in hyposplenism of celiac disease. Br JClin Pract 37:19–22

6. Knecht H, Jost R, Gmur J, Burger J, Fehr J (1988) Functionalhyposplenia after allogenic bone marrow transplantation isdetected by epinephrine stimulation test and splenic ultraso-nography. Eur J Haematol 41:382–387

7. Kalhs P, Panzer S, Kletter K, Minar E, Stain-Kos M, Waltter K,Lechner K, Hinterberger W (1988) Functional asplenia afterbone marrow transplantation. A late complication related to

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9. Cuthbert RJG, Iqbal A, Gates A, Toghill PG, Russell NH(1995) Functional hyposplenism following allogenic bonemarrow transplantation. J Clin Pathol 48:257–259

10. Centers for Disease Control and Prevention (2000) Guidelinesfor preventing opportunistic infections among hematopoieticstem cell transplant recipients. MMWR 49(RR10):1–128

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