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Volume: 19 Issue: 7 July 2021


Hemophagocytic Syndrome in a Pregnant Renal Transplant Recipient Associated With Cytomegalovirus Infection

Hemophagocytic syndrome is a disorder of the mononuclear phagocytic system resulting in uncon­trolled hemophagocytosis and cytokine overpro­duction. We report the first case of hemophagocytic syndrome, which occurred in a pregnant female patient 14 years after kidney transplant who displayed an atypical presentation and who had septic shock following cytomegalovirus infection. The patient, a-39-year-old woman at 27 weeks gestation with end-stage renal disease of unknown etiology, was admitted 14 years after living-donor kidney transplant (donor was her father) with high-grade fever, cough, and pancytopenia. Her immunosuppressant regimen included tacrolimus, azathioprine, and prednisone. Initially, she was hospitalized in the intensive care unit for septic shock without an identifiable focus of infection. She received intravenous broad-spectrum antibiotics before being transferred to our department following optimization of her hemodynamic status. Hemophagocytic syndrome was suspected, and bone marrow aspirate was performed, revealing macrophages with hemophagocytic activity. We confirmed the diagnosis of hemophagocytic syndrome given the presence of more than 5 criteria. We extensively investigated the underlying cause of hemophagocytic syndrome, and we diagnosed cytomegalovirus-induced hemophagocytic syndrome in a pregnant patient receiving immunosuppressive therapy after kidney transplantation. She was treated with corticosteroids and intravenous immunoglobulin. At 31 weeks gestation, she underwent a cesarean section; the baby developed newborn respiratory distress syndrome and died despite adequate resuscitation. We administered ganciclovir for 15 days following an increased cytomegalovirus viral load after delivery, leading to complete recovery. To date, optimal therapeutic and diagnostic guidelines for pregnancy-related hemophagocytic syndrome in female kidney transplant recipients are not well defined, and both patient and allograft survival rates remain low.

Key words : Cytokine storm, Kidney transplant recipient, Pregnancy


Hemophagocytic syndrome is a deadly complication of kidney transplant, with an estimated prevalence of 0.4% and a high mortality rate of 47%, caused by dysregulation in natural killer T-cell function.1 It is a mononuclear phagocytic system disorder, resulting in uncontrolled hemophagocytosis and cytokine overproduction.2 Diagnosis is based on the hemo­phagocytic lymphohistiocytosis (HLH)-2004 criteria, requiring at least 5 of 8 criteria (Table 1).3

Hemophagocytic syndrome is divided into 2 forms: primary (familial) due to genetic mutations (affecting mostly children) and secondary (reactive), commonly associated with malignancies, autoimmunity, or infections (most frequently by viruses).4

We present the first case of cytomegalovirus (CMV)-associated hemophagocytic syndrome in a pregnant patient who received immunosuppressive therapy after kidney transplant.

Case Report

A 39-year-old pregnant woman at 27 weeks gestation who received a living-related renal transplant from her father 14 years previously for end-stage renal disease of unknown etiology was admitted with high-grade fever and cough. Her immunosup­pressant regimen included tacrolimus (levels between 5 and 8 ng/mL), azathioprine (2 mg/kg/day), and pred­nisone (10 mg daily). Both donor and recipient CMV serostatus results were positive. She had a history of primary biliary cirrhosis, discovered 1 year post­transplant, which was treated with ursodeoxycholic acid. She had 2 successful pregnancies, both delivered by cesarean section. Her first and second pregnancies were complicated, respectively, by preterm rupture of membranes at 34 weeks gestation and gestational diabetes.

She presented at the emergency room, at 27 weeks gestation, with pyrexia and cough. Physical examination showed jaundice, mild bilateral basal crackles on auscultation, blood pressure of 60/38 mm Hg, pulse rate of 121 beats/min, respiratory rate of 20 breaths/minute, saturated oxygen of 98% on room air, and temperature of 38 °C.

Blood tests showed severe hemolytic anemia, with hemoglobin level of 5.5 g/dL, with platelet count of 121 000/mm3 and leukocyte count of 3190/mm3 (neutrophils 72%, lymphocytes 10.48%, monocytes 15.6%, eosinophils 0.48%, and basophils 0.42%). Triglyceride level was 3.3 mmol/L, ferritin level was 1000 μg/L, and lactate dehydrogenase level was 427 IU/L. Creatinine level was 205 μmol/L (estimated glomerular filtration rate was 33 mL/min/1.73 m2), which was elevated from 80 μmol/L at the beginning of the pregnancy. Serum alkaline phosphatase level was 446 U/L, gamma-glutamyltranspeptidase level was 338 U/L, and C-reactive protein level was 135 mg/L. Liver enzymes were slightly increased. Chest, abdominal, and pelvic computed tomography scans revealed splenomegaly and ground glass opacities in both inferior lobes. Fetal ultrasonography results were normal.

The patient was initially admitted in the intensive care unit for septic shock without an identifiable focus of infection. She received intravenous broad-spectrum antibiotics before her transfer to our department following hemodynamic optimization. We suspected a hemophagocytic syndrome; therefore, we per­formed bone marrow aspiration that revealed macrophages with hemophagocytic activity (Figure 1). We confirmed a diagnosis of hemophagocytic syndrome, fulfilling more than 5 criteria (fever, splenomegaly, pancytopenia, hyperferritinemia, hypertriglyceridemia, and hemophagocytosis on bone marrow aspirate).

We performed extensive work-up to find the underlying etiology. Autoimmune screening was negative, and serological investigations showed no evidence of active herpes simplex, Epstein-Barr virus, hepatitis B or hepatitis C virus, and human immunodeficiency virus; results of the Venereal Disease Research Laboratory test were also negative. However, tests showed an active CMV disease, with CMV viral load of 3997 copies/mL. We made an official diagnosis of CMV-induced hemophagocytic syndrome in a pregnant kidney transplant recipient.

The patient was treated with intravenous immunoglobulin (IVIg; 2 g/kg) every 3 weeks and prednisone (1 mg/kg/day). She also received a blood transfusion. With regard to her immunosup­pressive therapy, we discontinued azathioprine. She showed clinical and biological improvement, with disappearance of fever, decreased C-reactive protein level, increased platelets to 124 000 mm3, increased hemoglobin level to 8.9 g/dL, and increased leukocyte count to 6800/mm3. However, the CMV viral load increased from 3997 copies/mL to 7000 copies/mL at 31 weeks gestation, and fetal ultrasonography revealed oligohydramnios. Given the circumstances, the patient received a second treatment of IVIg and underwent an emergency cesarean section. After delivery, the male neonate developed newborn respiratory distress syndrome, justifying an endotracheal ventilation; however, the baby unfortunately died. On postpartum day 1, we initiated ganciclovir therapy to the patient for 15 days, after which she completely recovered. Biological abnormalities subsided, and CMV viral load decreased to 79 copies/mL.


Hemophagocytic syndrome control and management in pregnant kidney transplant recipients are challenging because of chronic immunosuppression, comorbidities, and special pregnancy conditions in patients. Herein, we discuss the challenges we faced managing our case.

On admission, the patient presented with pancytopenia and septic shock. Pancytopenia is a common finding after kidney transplant due to multiple causes, namely infections, immune-mediated causes, and drug-induced or inflammatory causes.5 With more than 5 criteria (fever, splenomegaly, pancytopenia, hyperferritinemia, hypertriglyceridemia, and hemophagocytosis in bone marrow), we diagnosed our patient with hemophagocytic syndrome, which met the revised diagnostic criteria guidelines of HLH-2004 of 5 or more of 8 criteria (Table 1).3

Physiopathology of pregnancy-related hemo­phago­cytic syndrome is unknown. It is unclear whether the pregnancy itself predisposes the mother to or is responsible for hemophagocytic syndrome. Teng and associates6 theorized that fetomaternal adhesion was the key factor in pregnancy-related hemophagocytic syndrome and its cytokine storm. Failure of maternal T lymphocytes to perceive fetomaternal human lymphocyte antigens and release of cytotrophoblasts and trophoblast debris into the maternal circulation potentiate a massive systemic inflammatory response, mimicking pregnancy-related hemophagocytic syndrome.6 In our case, the situation was more complicated as it occurred in a pregnant kidney transplant recipient. To our knowledge, this is the first case reported in the literature of CMV-related hemophagocytic syndrome in a pregnant kidney transplant recipient.

Once a diagnosis of hemophagocytic syndrome is established, it is necessary to rapidly search for an underlying etiology. It can be classified as either a primary or secondary form. Primary hemophagocytic syndrome is associated with genetic disarrangements, and secondary forms are commonly associated with infections, malignancies, or autoimmune diseases (Table 2). Viral infection is the most frequent cause of hemophagocytic syndrome in transplant recipients, occurring mainly when immunosuppression is high, especially during the initial period after transplant.1 Our patient presented with symptoms 14 years after transplant, suggesting an important immunosup­pression aggravated by pregnancy. Cytomegalovirus infections are the primary cause of virus-associated hemophagocytic syndrome, representing 10.5% of the infectious causes in immunocompromised recipients.7 To date, there are few reported cases of pregnancy-associated hemophagocytic syndrome.

Regarding the septic shock initially presented by the patient, we suggest that hemophagocytic syndrome was the cause. In the report from Danwen and associates8 of a kidney transplant patient who presented with septic shock caused by hemophago­cytic syndrome, the authors concluded that this syndrome has variable presentations due to chronic immunosuppression and it should be suspected in any kidney transplant recipient presenting with sepsis-like symptoms without a clear infectious cause.

Early therapeutic intervention is crucial because the disease is associated with high morbidity and mortality.9 The aim of treatment in secondary hemophagocytic syndrome is to suppress the inflammation with corticosteroids, polyvalent IVIg, cyclosporin A, and/or anticytokine agents. Activated immune cells can also be the target of therapeutics, such as rituximab, etoposide, and/or antithymocyte globulin. Identified etiologies of hemophagocytic syndrome, such as malignancies and infections, must be treated.8 On the other hand, in order to improve the resistance to infection, the immunosuppressive drugs must be reduced in dose or withdrawn in most transplant patients with hemophagocytic syndrome.2

The optimal treatment and guidelines for pregnancy-related hemophagocytic syndrome are so far not well defined. However, high-dose steroids alone, IVIg alone, IVIg and steroids, steroids and acyclovir, and IVIg and acyclovir are always the choices of treatment in pregnancy-related hemo­phago­cytic syndrome.10

In our case, the high-dose steroids associated with IVIg that we administered helped to control our patient’s condition temporarily. Ganciclovir was not initially prescribed because it is counter-indicated during pregnancy due to its potential toxicity.11 Studies have shown that polyvalent IVIg improves outcomes of virus-associated hemophagocytic syndrome. The therapeutic mechanism of action of IVIg in this disease is its anti-inflammatory potential, its probable function via pathogen-specific antibodies (which may be potent in controlling B and T-cell activities), and its role in altering cytokine release.12 The mechanism of CMV reactivation in our patient was likely multifactorial: pregnancy, kidney transplantation with previous CMV infection, and severe lymphopenia.

Pregnancy-related hemophagocytic syndrome has been reported to cause significant obstetric complications to both the fetus and mother. The development HELLP syndrome (hemolysis, elevated liver enzymes, low platelet count) and severe preeclampsia in mothers can possibly lead to death due to coagulopathy and multiorgan failure.13 Neonatally, newborns risk congenital CMV and preterm birth.14


Hemophagocytic syndrome appears to be rare in pregnant female kidney transplant recipients; however, it is possible that this disease has not been identified in an undefined number of recipients. The clinical manifestations can be unspecified and can overlap with a variety of other diseases, such as septic shock. Hemophagocytic syndrome secondary to CMV has been described in patients in the early period after kidney transplant. Here, we have reported the first case of hemophagocytic syndrome in a pregnant woman 14 years after kidney transplant with an atypical presentation that included septic shock during CMV infection. Rapid diagnosis and therapeutic intervention are extremely essential; however, optimal treatment and guidelines for pregnancy-related hemophagocytic syndrome in kidney transplant recipients are not well defined to date.


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Volume : 19
Issue : 7
Pages : 739 - 743
DOI : 10.6002/ect.2021.0041

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From the 1Department of Nephrology, Dialysis and Kidney Transplantation, Fattouma Bourguiba University Hospital of Monastir, Tunisia; and the 2Hematology Laboratory and Blood Bank, Fattouma Bourguiba University Hospital of Monastir, Tunisia
Acknowledgements: The authors have not received any funding or grants in support of the presented research or for the preparation of this work and have no declarations of potential conflicts of interest.
Corresponding author: Ben Salem Meriem, Department of Nephrology, Dialysis and Kidney Transplantation, Fattouma Bourguiba University Hospital of Monastir, Tunisia
Phone: +216 94365531