21 March 2023: Articles
Perioperative Management of Recurrent Hemophagocytic Syndrome in a Pregnant Woman: A Case Report
Challenging differential diagnosis, Management of emergency care, Patient complains / malpractice, Rare disease, Educational Purpose (only if useful for a systematic review or synthesis)Ayako Sumii1ABEF, Hirotsugu Miyoshi 1ADEF*, Takahiro Kato 1BE, Sachiko Otsuki1ABE, Yousuke T. Horikawa12AE, Shiho Satomi1ABD, Noboru Saeki1BF, Yasuo M. Tsutsumi 1AE
Am J Case Rep 2023; 24:e939369
BACKGROUND: Hemophagocytic syndrome (HPS) is a rare syndrome characterized by abnormal activation of histiocytes and hemophagocytosis. We report the clinical management of recurrent HPS following 2 cesarean sections in the same patient.
CASE REPORT: A 33-year-old primiparous mother presented during her second trimester of pregnancy, and HPS was diagnosed based on pancytopenia, hyperferritinemia (13 170 ng/ml), and hemophagocytosis in bone marrow examination. Despite steroid therapy, her HPS did not improve. Following the delivery of a healthy premature infant, there was no improvement in HPS, and immunochemotherapy was started 4 days postoperatively. Thrombocytopenia and hyperferritinemia persisted but normalized over the next 2 months, and immunochemotherapy was discontinued after 6 months. About 1 year after chemotherapy, the patient became pregnant with her second child. At 35 weeks of gestation, recurrence of HPS was suspected, and a C-section was performed at 36 weeks of gestation. The surgery was complicated by placenta previa, and general anesthesia was initiated after successful delivery of the infant. Epidural anesthesia was not performed due to concerns for postoperative thrombocytopenia.
CONCLUSIONS: Interestingly, HPS was likely triggered twice by pregnancy in this patient. Although reports of HPS during pregnancy are rare, there have been reports of rapid deterioration and death. Early diagnosis and therapeutic intervention are essential.
Keywords: Cesarean Section, Lymphohistiocytosis, Hemophagocytic, Perioperative Medicine, Pregnancy
Hemophagocytic syndrome (HPS) is characterized by phagocytosis of autologous blood cells by activated macrophages in the reticuloendothelial system. It is a syndrome with a poor prognosis with clinical symptoms such as hyperthermia, pancytopenia, and coagulopathy . The triggers for the onset of HPS are diverse, and it is often difficult to identify the cause. HPS sometimes has a fatal course. Identification of the reason is important because the prognosis depends on the underlying disease, and the primary treatment is treatment of the underlying condition. It has been reported that pregnancy can trigger HPS, but there are few reported cases, and the relationship between HPS and pregnancy is unclear [2–4].
There are few reports on the perioperative management of HPS triggered by C-sections. In this case, a patient was diagnosed with HPS following 2 pregnancies. The first cesarean section was performed emergently immediately after the onset of HPS, and the second cesarean section was elective. HPS was thought to be triggered by pregnancy both times. Early diagnosis and initiation of treatment and careful observation are essential for HPS.
A 33-year-old primiparous woman presented at 23 weeks of gestation with persistent fever and common cold symptoms and was treated with antibiotics. At 27 weeks of gestation, blood tests revealed pancytopenia, elevated liver enzymes, and elevated ferritin. The patient was referred to our obstetrics and gynecology clinic because of suspicion of HPS. Blood tests at the time of transfer showed AST 2134 U/L, ALT 841 U/L, and ferritin 13 170.0 ng/ml. Bone marrow examination revealed hemophagocytosis, and a diagnosis of HPS was made. We also made a differential diagnosis of secondary hemophagocytic lymphohistiocytosis (HLH) . Viral infections, adult-onset Still’s disease (AOSD), systemic lupus erythematosus (SLE), and malignant lymphoma were the likely causes of HPS in this patient. However, she had negative blood cultures and serological tests for Ebstein-Barr virus, cytomegalovirus, hepatitis A virus, hepatitis B virus, and hepatitis E virus. She did not show skin or joint manifestations commonly observed in adult-onset Still’s disease or systemic lupus erythematosus. She was positive for speckled pattern of anti-nuclear antibody with a titer of 1: 320, but was negative for specific autoantibodies of SLE against double-stranded DNA, Sm, ribonucleoprotein, and phospholipid. A random skin biopsy and bone marrow biopsy did not reveal the suggestive findings of malignant lymphoma. Based on the above results, she was diagnosed with idiopathic HLH. Steroids were started after the diagnosis of HPS, with 1 mg/kg prednisolone, followed by 2 days of intramuscular 12 mg betamethasone for the child’s pulmonary maturation with consideration of premature delivery, and 3 days of methylprednisolone 500 mg/day steroid pulse therapy.
Steroid administration improved liver dysfunction, but the thrombocytopenia, hyperferritinemia, and fever did not improve. A C-section was scheduled at 29 weeks of gestation under general anesthesia to prevent maternal complications. Preoperative risks were pancytopenia, steroids, and liver dysfunction with ASA-PS class 3. For thrombocytopenia of 57 000/µl, 10 units of irradiated concentrated platelets were transfused on the day of surgery. General anesthesia was rapidly induced with sodium thiamylal, and after administration of suxamethonium, the patient was intubated with a 7.0-mm tube using a McGRATH® video laryngoscope.
She was hemodynamically stable and a healthy newborn (1096 g) was delivered. Blood loss including amniotic fluid was 550 ml and 2 units of irradiated concentrated red blood cells were transfused. She was returned to the ward after removal of the tracheal tube in the operating room. Because of persistent increase of ferritin and decreased platelet count, immunochemotherapy with dexamethasone, etoposide, and cyclosporine was started on postoperative day 4 according to the HLH 2004 guideline . Her platelet count was normalized 1 month after starting chemotherapy and she was discharged from the hospital. Ferritin normalized 2 months later and treatment was completed at 6 months. The perioperative course during the first C-section is shown in Figure 1.
Approximately 1 year after the completion of chemotherapy, the patient became pregnant again and was admitted to our hospital for perinatal management at 31 weeks of gestation. On admission, there were no findings of HPS relapse, but at 35 weeks of gestation, she had a fever and elevated ferritin (3483.2 ng/ml), likely HPS. A total placenta previa was present, and a C-section was planned at 36 weeks. Anesthesia was performed under spinal anesthesia until fetal delivery and general anesthesia after delivery of the child. Preoperative risks were total placenta previa, after HPS treatment, anemia, and ASA-PS class 3. Spinal anesthesia was performed by puncturing the L3/4 vertebral space and administering 2 ml of 0.5% bupivacaine isobaric, 0.1 mg morphine, and 5 µg fentanyl. The baby was delivered without problems, and the mother was intubated with rapid induction before delivery of the placenta. Briefly, to avoid exposing the fetus to general anesthetics, we performed spinal anesthesia until the fetus was delivered and general anesthesia after the fetus was delivered. Hemorrhage was 2149 ml together with amniotic fluid, and 2 units of irradiated concentrated red blood cells, 2150 ml of extracellular fluid, and 1000 ml of colloid fluid were trans-fused intraoperatively. The patient was extubated successfully. Postoperatively, anemia with Hb 7.3 g/dl and platelet counts as low as 126 000/µl were observed but improved on postoperative day 5 with follow-up, and no coagulopathy or liver dysfunction was observed. Ferritin showed a decreasing trend after cesarean section and was high but stable at 508 ng/ml at 2 months postoperatively. The perioperative course during the second C-section is shown in Figure 2.
HPS is a syndrome in which immune cells such as macrophages and neutrophils, which usually protect the body, phagocytose their blood cells (especially platelets) due to overproduction of cytokines. Primary HPS commonly develops in childhood; our patient likely developed HPS secondary to some other cause. About half of adult HPS is associated with lymphoma, 30% with a viral infection, and 10% with a bacterial infection . In our patient, these causes were not found, and the sudden onset of HPS during the second trimester of pregnancy suggests pregnancy as the cause of her HPS. Furthermore, pregnancy was also associated with the pathogenesis of HPS since the patient’s HPS condition worsened in the second trimester during her second pregnancy. Marked thrombocytopenia and elevated transaminase in the second trimester of pregnancy suggest severe infection, HELLP syndrome, and gestational fatty liver. Still, pregnancy-related HPS should also be listed in the differential.
Liu et al reported that in 13 singleton pregnancies diagnosed with HPS during the perinatal period, 4 (30.8%) women died, and 8 (61.5%) fetal or neonatal deaths occurred by 1 week after delivery . Liu et al reported that among the 4 deaths, 3 of the patients may have delayed therapeutic intervention, which directly resulted in their death . Yamaguchi et al reported that steroid therapy was started early during pregnancy. Still, since the patient was corticosteroid-resistant, cyclosporine needed to be administered, and the patient delivered a healthy baby after remission . These data suggest that early therapeutic intervention is essential for effective treatment; according to a case report by Chien et al, a pregnant woman diagnosed with HPS was treated with therapeutic intervention, including steroid therapy, early during her pregnancy at 23 weeks of gestation . However, she was discharged from the hospital after improvement. She later returned at 28 weeks of gestation with worsened fetal heart rate bradycardia, and the patient underwent an emergency C-section under general anesthesia. The patient remained hemodynamically unstable postoperatively and was extubated after admission to the intensive care unit and treated in the intensive care ward for 4 postoperative days . Unlike that patient, our patient had minimal complications due to the early diagnosis of HPS and initiation of steroid therapy. This was followed by the delivery of the fetus via cesarean section. Chemotherapy for the mother was started within 2 weeks of the diagnosis of HPS, and both mother and fetus are doing well. This suggests that not only is early treatment necessary, but continuous monitoring for rebound symptoms may be essential to the outcomes of HPS resulting from pregnancy. It is crucial to initiate steroids and immunochemotherapy as early as possible because HPS can rapidly deteriorate during the disease and have poor outcomes.
Early treatment of the cause of HPS and therapeutic interventions such as immunosuppressive therapy is essential to improve prognosis. There is no established theory regarding the anesthetic management of cesarean sections in patients with HPS. Spinal, subarachnoid, or epidural anesthesia is contraindicated in patients with thrombocytopenia or coagulopathy. Therefore, in this syndrome, which is prone to thrombocytopenia and disseminated intravascular coagulopathy complications, the anesthetic method should be selected with attention to platelet counts and coagulation abnormalities. Tumian et al reported that pregnant women with HPS continue to have transfusion-resistant anemia and thrombocytopenia after delivery . In our patient, despite transfusion of 10 units of irradiated concentrated platelets immediately before surgery for a low platelet count of 57 000/µl during the first C-section, the platelet count was 56 000/µl the next day and continued to decrease, reaching a nadir of 24 000/µl on the fifth day after the C-section. In addition, although hemolysis, elevated liver, and low platelet (HELLP) syndrome showed improvement in disease status about 48 hours after delivery , thrombocytopenia and coagulopathy in HPS may not improve immediately after delivery. In our patient, thrombocytopenia at the time of the initial C-section persisted after the C-section. It began to improve only after chemotherapy, but platelet levels did not improve until 1 month later.
Treatment of HPS involves treatment of the disease causing HPS and administration of steroids and immunosuppressants. In addition, some patients may require chemotherapy with anticancer drugs such as etoposide. There are restrictions on the use of drugs during pregnancy due to the need to consider effects on the fetus. Therefore, we need to determine the appropriate time to terminate the pregnancy to save the life of the mother while considering fetal development.
We report the case of a patient with HPS who underwent 2 C-sections during her 2 pregnancies. The patient’s HPS was thought to be pregnancy-induced, as her HPS worsened with each of her 2 pregnancies. It is essential to note that HPS requires early intervention and does not improve immediately after delivery, in contrast to HELLP syndrome.
FiguresFigure 1.. Patient presentation and treatment course during the first pregnancy. At 28 weeks of gestation, HPS was diagnosed, and steroid therapy was initiated. Hepatic dysfunction improved, but serum ferritin did not decrease, platelet count dropped, and fever persisted. To prevent maternal complications, premature delivery of the fetus and a cesarean section were performed at 29 weeks. However, after delivery, HPS did not improve, and immunochemotherapy with dexamethasone, etoposide, and cyclosporine was started on the fourth postoperative day. After the start of chemotherapy, the patient’s fever gradually resolved, and her platelet count increased. The patient was discharged from the hospital after her platelet count normalized 1 month following delivery. Ferritin was normalized 2 months after surgery, and chemotherapy was completed 6 months after delivery. Figure 2.. Patient presentation and treatment course during the second pregnancy. The patient presented with fever and elevated ferritin (3483.2 ng/ml) at 35 weeks of gestation and was diagnosed with recurrent HPS and scheduled for cesarean section at 36 weeks of gestation. Postoperatively, anemia with Hb 7.3 g/dl and decreased platelets (126 000/µl) were observed, but with follow-up, they improved on the 5th postoperative day, and no coagulopathy or liver dysfunction was observed. Ferritin showed a decreasing trend after delivery, and at 2 months postoperatively it was elevated but stable at 508 ng/ml.
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