Hemophagocytic syndrome combines febrile hepato-splenomegaly, pancytopenia, hypofibrinemia, and hepatic dysfunction. It is characterized by bone marrow and organ infiltration of activated, nonmalignant macrophages that phagocytize blood cells. It is rare among renal transplant recipients. Here, we present the successful management of late-onset cytomegalovirus-induced hemophagocytic lymphohistiocytosis in a kidney transplant recipient after coronary artery bypass graft surgery. In 2012, our patient had end-stage kidney disease due to diabetic nephropathy and underwent related living-donor renal transplant. He was also hypertensive and hyperuricemic and had heart ischemia for which percutaneous coronary inter-vention for triple vessel disease was performed before transplant. In March 2017, he underwent successful aortic valve replacement and coronary artery bypass graft surgery; however, the patient had persistent thrombocytopenia. Heparin-induced thrombocyto-penia was negative. His bone marrow showed hemophagocytosis possibly due to cytomegalovirus. Moreover, antiglycoprotein IIb/IIIA autoantibodies were positive. A positron emission tomography scan was negative for malignancy. He started treatment for cytomegalovirus with modifi-cation of his immuno-suppressive regimen (pulse steroid). Antiplatelet therapy was held and only resu-med if platelet count exceeded 30 000/L. Moreover, he received intravenous immunoglobulin and romiplostim treatment with partial response. Throughout treatment, he had stable kidney graft function with improving platelet count. A multi-disciplinary approach is needed to treat patients with hemophagocytic syndrome, especially renal trans-plant recipients. Late-onset cytomegalovirus is an important cause for this syndrome.
Key words : Hemophagocyte, Infection, Renal transplant
Hemophagocytic syndrome (HPS) combines febrile hepatosplenomegaly, pancytopenia, hypofibrinemia, and hepatic dysfunction. It is characterized by bone marrow and organ infiltration of activated, nonma-lignant macrophages that phagocytize blood cells. It has rarely been described among renal transplant recipients.1
Hemophagocytic syndrome may be inherited (in pediatric patients) or secondary to infection, malig-nancy, or rheumatologic disease, occurring at any age. It is diagnosed with the use of clinical criteria developed by the hemophagocytic lymphohisti-ocytosis (HLH) study group of the Histiocyte Society.2
Cytomegalovirus (CMV) infection should be suspected in all kidney transplant patients who experience severe septic syndrome. Hemophagocytic syndrome is a potentially fatal hyperinflammatory syndrome characterized by histiocyte proliferation and hemophagocytosis. About 80 cases have been reported in kidney transplant patients3 with an estimated prevalence of 0.4%. Cases are usually triggered by CMV infection4 or other herpesviruses, including Epstein-Barr virus, human herpesvirus 8, and human herpesvirus 6. Other cases have been associated with adenovirus, parvovirus B19, BK polyomavirus, tuberculosis, bartonellosis, toxo-plasmosis, leishmaniasis, babesiosis, and histo-plasmosis.3 Cytomegalovirus replication occurs in most solid-organ transplant recipients during the first 3 to 6 months after transplant, when immuno-suppressive agents are intensely administered.5
Hemophagocytic syndrome can mimic graft-versus-host disease, and a differential diagnosis may be necessary. The prognosis is gloomy, resulting in nearly 50% mortality with a clinical picture of multiorgan failure.3
The presence of hemophagocyte in the bone marrow, spleen, or lymph nodes, elevated serum lactate dehydrogenase levels (> 1000 IU/L), hyperfer-ritinemia (> 500 ng/mL), hypertriglyceridemia (> 3 mmol/L), hypofibrinogenemia (< 1.5 g/L), low or absent natural killer cell cytotoxicity, elevated soluble interleukin 2 receptor (> 2400 U/mL), and cytopenia affecting at least 2 cell lineages (platelets < 100 000/μL or neutrophils < 1000/μL) are suggestive of this entity.6
In the presence of dyspnea and/or tachypnea and/or reduced oxygen saturation, a chest radio-graphy scan should be repeated, if initially negative, and computed tomography may be advisable.7 In the presence of cytopenia (affecting ≥ 2 lineages in the peripheral blood), a diagnosis of HLH should be suspected. Little consensus exists on how to treat posttransplant HLH, and treatment of this is still far from being established. Undoubtedly, infectious agents should be eradicated promptly, which should be accompanied by supportive care.
A 63-year-old male Kuwaiti patient with diabetes, hypertension, and hyperuricemia and who under-went coronary stenting 30 years previously devel-oped end-stage kidney disease due to diabetic nephropathy. In 2011, he developed acute myocardial infarction, which was managed by angioplasty and stenting. In 2012, the patient underwent renal transplant. Recently, in 2017, he underwent aortic valve replacement (using tissue valve prosthesis) combined with coronary artery bypass grafting. His postoperative course was complicated by persistent thrombocytopenia. He was thoroughly investigated for this issue, and both antiglycoprotein IIb/IIIA and anti-PF4 allo-autoantibodies were positive.
The patient required hospital admission for further care. On admission, his platelet count was 25 000/μL, which gradually decreased to 12 000/μL, for which he received platelet concentrate twice. Treatment of CMV disease was started in view of positive CMV polymerase chain reaction. The patient showed aviremia after 2 weeks of ganciclovir therapy. At that time, he had severe chest pain and shock, and his electrocardiogram showed depressed ST segment in lead 1 and aVL lead, and his serum troponin I level was 4.5 ng/dL, which prompted diagnosis of non-ST segment elevation myocardial infarction. The cardiologist advised a nitrate patch and to resume both clopidogrel 75 mg and aspirin 320 mg whenever platelet counts allowed. His immunosuppressive therapy was modified to ste-roids and cyclosporine, and mycophenolate mofetil was held.
The hematologist had suspected immune-mediated thrombocytopenia; therefore, he planned pulse steroid therapy (1 g/day for 3 days followed by 1 mg/kg/day for 6 weeks), anti-Rh immuno-globulin, intravenous immunoglobulins (IVIG), and romiplostim. This treatment plan was accepted by the cardiologist. Immunologic work-up for auto-immune diseases (antinuclear antibodies, anti-double strand D antibody, anti-CC3 antibody, anti-B2 globulin, antinucleocytoplasma, and Coombs tests) was negative.
A bone marrow biopsy (Figure 1) was conducted during hospitalization, which revealed mild hypo-cellularity, HLH, but no bone marrow infiltration with metastatic or lymphoma cells. Positron emission tomography scan was performed, which showed metabolically active left pleural thickening, mostly inflammatory. In addition, tiny post-coronary artery bypass grafting non-fluorodeoxyglucose avid right lower lobe pulmonary nodules were shown (Figure 2).
Both cholestasis liver enzymes and bilirubin (mainly direct) had concomitantly increased since patient admission, and his abdominal ultrasonog-raphy showed interstitial liver disease and mild spleno-megaly. All hepatotoxic drugs (including ganciclovir and statins) were held; in addition, the patient was screened for both hepatotropic viruses and auto-immune hepatic antibodies. His virology screening (for hepatitis A, B, and C viruses; Epstein-Barr virus; human immunodeficiency virus; and parvovirus) and autoimmune hepatic antibodies were negative. Magnetic resonance cholangiopan-creatography showed shrunken cirrhotic liver with ascites, but no definite hepatic masses with normal spleen. His serum ferritin levels were high (9571 μg/L). On the basis of these data, we surmised that our patient had CMV-induced HLH. His CMV viral load was > 4000 copies/mL, and ganciclovir was resumed. In view of significant improvement of his hepatic function, we resumed small doses of cyclos-porine (10 mg twice daily). Because the patient’s urine and blood samples showed Escherichia coli, he was (successfully) treated with amikacin (guided by drug levels), which was chosen to avoid myelo-suppressive and the hepatotoxic adverse effects of meropenem and piperacillin/tazobactam, respec-tively. The antiplatelet management plan was tailored by both the hemato-logist and cardiologist. Clopidogrel was resumed when the platelet count reached above 30 000/μL, with aspirin added if it exceeded 60 000/μL. His graft kidney function was well functioning throughout the entire period of admission. Unfor-tunately, he developed polymyoneuropathy, which was confirm-ed by electro-myography. This critical illness led to severe axonal sensory and motor neuropathy, for which he has progressed under physiotherapy.
Hemophagocytic lymphohistiocytosis is an ag-gressive and life-threatening immune dysre-gulation syndrome. It was first described in 1939 by Scott and colleges8 and is characterized by persistent activation of the mononuclear phagocytic system, which can lead to an uncontrolled systemic hyper-inflammatory response. It is a clinical syndrome characterized by infiltration into bone marrow and the reticuloendothelial system of macrophages and activated histiocytes, which can lead to uncontrolled phagocytosis of blood. Patients present with high fever, hepatosplenomegaly, lymphadenopathy, and cytopenia. Central nervous system involvement, cutaneous manifestations, severe coagulation distur-bances, and multiple organ dysfunctions can also occur, although less frequently. Laboratory findings of high levels of ferritin, hypertriglyceridemia, and hypofibrinogenemia can also be present.9
The proliferation and activation of histiocytes and lymphocytes can lead to a cytokine storm.10 Fever, cachexia, elevated serum triglycerides, high serum ferritin levels, acute kidney injury, and tubular necrosis, which present in this situation, all can attribute to the high cytokine levels.11
According to the Histiocyte Society protocol, our patient had fulfilled 5 of 8 diagnostic criteria for HLH.6 Primary CMV infection in immunocompetent hosts is usually asymptomatic or associated with nonspecific symptoms similar to acute viral infec-tions. However, in immunosuppressed patients, this infection can cause retinitis, gastroenteritis, colitis, pneumonitis, and encephalitis and may be responsible for significant morbidity and mortality.The causes of HLH can be familial or acquired later, which is more frequent. The familial form is related to genetic immune defects, whereas the acquired form is associated with viral (Epstein-Barr virus, CMV, and human immunodeficiency virus), bacterial, fungal, and protozoa infections as well as malignancies (lymphomas) and other conditions, such as rheumatic disease.9 In our renal transplant patient, we excluded the different possible causes of this syndrome except CMV infection with significant viral load.
Kidney transplant recipients are at increased risk of HLH due to immunosuppression, and most such cases of the disease are triggered by infection with over 50% mortality. Immunosuppression and deregulated immune systems are risk factors for both opportunistic infections and malignancies. Despite this situation, HPS is a rare condition. Posttransplant HPS usually occurs during the early period, when patients are in their highest immunosuppressed condition.12
In a retrospective analysis, Karras and associates1 reported 17 renal transplant recipients with HPS who presented with fever, with hepatosplenomegaly shown in more than 52% of these patients. The group reported elevated liver enzymes in nearly 60% of patients. Our patient showed the same findings. Most cases of the disease are due to viral infections, whereas some are due to bacterial and fungal infections and malignancy. In our case, we had excluded other infective causes in addition to malignancy. In the study from Karras and associates,1 graft nephrectomy had been performed in 4 of 9 surviving patients.
In our case, we had excluded other infective causes in addition to malignancy. Graft nephrectomy was performed in 4 of the 9 surviving patients.1 Our reported patient had a functioning graft, possibly because of early diagnosis, optimization of his immunosuppression, and aggressive management.
Allograft rejection by itself could be a trigger for HPS evolution8; however, in our case, the graft function was normal throughout the course of illness and there was no indication to proceed for graft biopsy to rule out this possibility. Acute kidney injury was the most common renal disorder in HPS followed by nephrotic syndrome13; however, our patient did not show renal dysfunction that necessitated further work-up.
Management of HPS in renal transplant recipients requires immunosuppressive dose reduction and introduction of specific antiviral treatment. High-dose polyvalent immunoglobulin is a beneficial treatment. Elimination of triggers (mainly infections) is critical for treatment of adult patients with HPS. High-dose polyvalent IVIG is beneficial in infection-, autoimmune-, and transplant-related HPS.
In accordance with our treatment policy, our patient received IVIG and pulse steroid therapy and resumed cyclosporine. Interestingly, steroids and cyclosporine have been proposed as treatments for HPS. The use of cyclosporine in patients with HPS who did not respond to IVIG and alemtuzumab was reported in 3 adult patients with HPS with reliable results.14
This is the first report of HPS in an older renal transplant recipient with late-onset CMV infection. A multidisciplinary approach is needed for care and treatment of patients with HPS, especially for those who are immunocompromised such as renal transplant recipients. This report serves to remind transplant physicians to consider HLH when cytopenias and hyperinflammation are shown, which can be atypical for the usual posttransplant course, even during later periods posttransplant.
The possibility of HPS should be considered in any renal transplant recipient with pancytopenia and allograft dysfunction, and a multidisciplinary ap-proach will be the best way for successful manage-ment of such cases.
Volume : 17
Issue : 1
Pages : 207 - 211
DOI : 10.6002/ect.MESOT2018.P67
From the 1Nephrology Department, Hamd Al-Essa Organ Transplant Center of Kuwait,
Kuwait; the 2Hematology Department, Ibn Sina hospital of Kuwait, Kuwait; and the
3Urology and Nephrology Center, Mansoura University, Mansoura, Egypt
Acknowledgements: The authors have no sources of funding for this study and have no conflicts of interest to declare.
Corresponding author: Osama Ashry Gheith, Hamd Al-Essa Organ Transplant Center of Kuwait, Kuwait
Phone: +96 566641967
Figure 1. Bone Marrow Showing Hemophagocytosis
Figure 2. Positron Emission Tomography Axial Scan Showing Metabolically Active Left Pleural Thickening