Luis A. Sánchez‑Ato is a 26-yearold Peruvian Medical Doctor at
the Peruvian University of
Applied Sciences (UPC), who
was a junior researcher at the
UPC Research Center part of a
research on a biophysical platform with fuorescent ribosomal
proteins for the study of new
antibiotics. As part of the investigation, he made a rotation in
the Laboratory of Camerino University in Italy. He is currently
working as a Medical Doctor in
Vista Alegre Clinic. He is a proactive doctor, with high investigative capacity and collaborator. He has proper interpersonal development to create and maintain a professional relationship, as well as an
excellent doctor–patient relationship. He is interested in taking on tasks
that involve new challenges for the improvement of health.
The Hemophagocytic Lymphohistiocytosis (HLH) is a very rare and challenging disease. (1) The presentation, diagnosis, treatment, and recovery of this condition are highly variable among different population groups. (2,3) It is categorized in Primary HLH, which affects more children and has a strong genetic component, and Secondary HLH is usually associated with infections, autoimmunity, and malignancies. (4,5) The clinical presentation involves multiple organs, being the most common symptoms hepatosplenomegaly, fever, cytopenias, liver dysfunction, increased ferritin, and neurological affection. (6–8) The information on this disease is even more scarce for pregnant women due to the few cases reported. We report the case of a 23-year-old woman with pregnancy-induced Hemophagocytic Lymphohistiocytosis that had a mild recuperation after the delivery of the baby but unfortunately died.
We present a 23-year-old pregnant woman gravida 3, para 1 27 weeks of gestation complaining of intermittent fever, hyporexia, and vomiting since one week. She had history of malar rash that increased with sun exposure since adolescence. Physical examination revealed fever, pulse of 99 beats per min, blood pressure of 80/50 mmHg, and breathing frequency of 19/min. She was pale, a maculopapular skin rash over both cheeks was observed. There was no lymphadenopathy or joint pain. The liver was palpable 2 cm below the right costal margin and tender; the spleen was not palpable. The uterus was gravid, normal tone, fetal heart rate was 158 beats per min, fetal movement was present, and uterine height was 23 cm. She was awake, oriented, and responsive. Laboratory results showed a hemoglobin of 11.1 g/dL, leukocytes of 6220/mm3 , a platelet count of 240,000/mm3 , and C protein reactive of 13.3 mg/L, urinary sediment showed leukocyturia without nitrites.
There was a suspicion of urinary tract infection; therefore, urinary and blood culture (both negative) were performed, and empiric antibiotic treatment was started using ceftriaxone. TORCH, HTLV I-II, and EBV serology tests were negative. An autoimmune disease was ruled out with negative ANA, anticardiolipin, ANCA MPO, and ANCA PR3. Tumor screening was negative according to abdominal CT, AFP, CEA, CA19-9, and CA-125. The patient presented with acute respiratory distress and was transferred to intensive care unit, with the chest skiagram showing difuse infltrates in both lung felds (Fig. 1). New laboratory test was performed 16 days after the admission, which was suggestive of hemoglobin 5.3 mg/dL, total leukocyte count 2240/ mm3 , and platelets 38,000/mm3 . Renal function revealed an increase in creatinine to 1.74 and urea of 110 mmol/L. Liver biochemistry showed a raised serum TGO – 1345 U/L, TGP – 142 U/L, and hyperbilirubinemia (total 11.97 mg/ dL, direct fraction 8.95 mg/dL). Serum LDH was raised to 9540 U/L. Ferritin measure showed a level of 1278 ng/mL. The echocardiogram was suggestive of moderate pericarditis with competent cardiac valves and no vegetations. Abdominal sonography was suggestive of hepatomegaly and splenomegaly, associated with difuse hepatopathy. Liver biopsy showed chronic hepatopathy with steatohepatitis. HELLP syndrome was likely; nevertheless, the blood pressure was always normal.
The patient had persistent fever despite antibiotics; infectology suggested adding meropenem plus vancomycin due to probable sepsis of respiratory origin. Hematologist performed a bone marrow biopsy where hemophagocytosis was observed, which was suggestive of HLH. The result of a lipid profile demonstrated an increase in triglycerides of 369 mg/ dl. At 29 weeks of gestation, intra uterine fetal demise was diagnosed, and the gynecology team elected accentuation and vaginal delivery of the stillborn, after which the patient showed clinical and laboratory improvement adding to the scheme of treatment with dexamethasone, etoposide, cyclosporine, and blood transfusions. Nonetheless, she acquired a nosocomial infection leading to fatality 3 months after delivery
The diagnosis of HLH in this pregnant patient was made using the 2004 diagnostic and therapeutic guidelines for HLH, since fve of the eight criteria were fulflled [1–4]. The patient had fever, hepatosplenomegaly, cytopenias afecting two cellular lineages (hemoglobin <9.0 mg/L, platelets <100,000/mm3 ), hypertriglyceridemia, and hemophagocytosis in the bone marrow. It is essential to consider HLH as a possible diagnosis in the context of a patient with persistent fever and general discomfort without apparent cause. In the laboratory analysis, the appearance of increased transaminases and triglycerides, anemia, thrombocytopenia, leukopenia, decreased fbrinogen, and an altered coagulation profle should also indicate HLH as a diferential diagnosis [5–12]. Other pathologies that should be considered as diferentials include HELLP syndrome in which arterial hypertension, anemia, thrombocytopenia, fever, and increased liver enzymes may be found [13]. Fatty liver of pregnancy is characterized by fever, jaundice, pain in the right upper quadrant, and central nervous system involvement [14]. Drug reaction with eosinophilia (DRESS) also has similarities to HLH such as dermatitis, fever, visceral organ involvement, and lymphadenopathy [15]. Sepsis should also be taken into consideration.
According to the study “Pregnancy-associated hemophagocytic lymphohistiocytosis secondary to NK/T cells lymphoma,” there were 19 cases of HLH in pregnancy from 1991 to 2017, of these ten were associated with viral infections (Epstein–Barr infection the most common), two cases were induced by an autoimmune disease, six patients did not have a known cause and may have been induced by pregnancy, and one case was related to malignancies [16]. Our patient was diagnosed with a secondary HLH induced by pregnancy after negative TORCH and Epstein–Barr results, negative antibodies, and negative screening for malignancy (negative tumor markers and images). According to the literature, HLH related to pregnancy may be a common cause for this disease [16–18].
The pathophysiology is not well described during pregnancy. It seems to be similar to what occurs in preeclampsia, a rejection of fetal material which is taken as an antigen, caused by an exaggerated natural killer and T lymphocyte reaction [19]. The trafcking of feto-maternal antigens (fetal genetic material, cytotrophoblast, and syncytiotrophoblast cells) may then induce a severe systemic inflammatory response causing multiorgan failure. All these hypotheses are based on the already known fact that the placental barrier cannot completely evade the immune system. In the study of “Foreign fetal cells persist in the maternal circulation,” the authors concluded that fetal cells persisted in maternal circulation years after delivery and they avoid destruction by host immune system with an unknown mechanism [20].
Treatment of HLH during pregnancy is not established;
usually, there is an improvement in the maternal condition
after the delivery. The management varies depending on several factors like the gestational trimester, clinical severity,
state of the fetus, added complications, among others. When
it occurs during the frst trimester, it is more severe, and the
mothers health is given priority since the fetus is less likely
to survive. Then, the option to end the pregnancy should be
considered as the choice of treatment. During the second trimester it is more difcult to decide whether or not to end the
pregnancy, and the other factors previously mentioned should
be taken into consideration. In the third trimester, the fetus
and the mother have a better prognosis, and premature delivery is preferred. Drugs that will reduce infammation and
immune responses (corticosteroids, cyclosporine A, intravenous immunoglobulin, etoposide, etc.) should be utilized.
Conflict of interest The authors declare that they have no confict of interest.
Ethical Approval This study is exempted from ethical approval by ethics committee of Hospital Nacional Edgardo Rebagliati Martins.
Research Involving Human Participants and/or Animals This article
does not contain any studies with animals performed by any of the
authors.
