Hemophagocytic lymphohistiocytosis in early pregnancy: A rare and fatal diagnostic challenge

Introduction

Hemophagocytic lymphohistiocytosis (HLH) is a rare but life-threatening immunopathological condition that is often underrecognized because of its varied and nonspecific presentation. ¹ Characterized by hyperinflammation, fulminant hypercytokinemia, and potential multiorgan failure, the complexity of HLH is compounded by pregnancy-related immunological changes, often leading to delayed diagnosis and management. ²

Our case and literature review aim to highlight the importance of considering HLH early in the differential diagnosis for pregnant patients presenting with fever, cytopenias, and organomegaly. Through this report, we also provide additional information on diagnosis amidst the physiological adaptations of pregnancy and treatment options.

Patient information

A 20-year-old woman presented 8 weeks into her second pregnancy with abdominal pain, fever, and lower gastrointestinal bleeding. She had a medical history of a caesarean section due to fetal death 2 years prior and an episode of hematemesis with abdominal pain 3 months earlier. The patient was febrile (temperature of 39 °C) and had several anomalies, including leukopenia (white blood cells at 0.5 × 10³/mm³), thrombocytopenia (platelet count 25.0 × 10³/mm³), and anemia (hemoglobin at 6.5 g/dL). After a gynecological assessment, she was referred to a tertiary care center and intensive care unit (ICU) for admission.

In the ICU, the patient's condition deteriorated, with a sequential organ failure assessment (SOFA) obstetric score of 7, requiring vasopressor support and antibiotic therapy. The patient was suspected of having septic shock from an unidentified source. Trends in laboratory tests revealed worsened leukopenia with a sudden elevation in the white cell count and an abrupt drop in the platelet count and hemoglobin level. The patient received a massive transfusion, defined as the administration of more than four units of packed red blood cells. We also detected elevated bilirubin levels, liver enzyme derangements, coagulation disorders, and electrolyte imbalances (Figure 1). Due to clinical evolution, a peripheral blood smear showed only microcytosis and haptoglobin processing was impossible.

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Figure 1.

Hematological trends over time in a pregnant patient with HLH. (A) Hemoglobin levels (g/dL), (B) leukocyte count (×mm³), (C) platelet count (×mm³), (D) coagulation time (seconds), (E) transaminases (u/L), (F) temperature timeline (°C). HLH: hemophagocytic lymphohistiocytosis; PT: prothrombin time; PTT: partial thromboplastin time; AST: aspartate aminotransferase; ALT: alanine aminotransferase.

A venous Doppler ultrasound was negative for thrombosis. Abdominal ultrasound revealed hepatomegaly and a viable uterine pregnancy. After a hematologist consultation, the patient underwent further bone marrow sampling for flow cytometry, karyotyping, and myelogram. Despite intensive care management, the patient's condition deteriorated, and infection-related tests, including blood cultures, failed to identify the infectious source of the fever. Tests for human immunodeficiency virus, dengue, Leptospira, Leishmania, malaria, Cytomegalovirus, Epstein-Barr virus, Varicella-zoster, SARS-CoV-2 antigen, and viral hepatitis A, B, and C serology were negative. The patient developed sudden neurological deficits suggestive of a cerebrovascular accident and suffered cardiorespiratory arrest, making it impossible to perform brain imaging studies. Despite resuscitative efforts, the patient's hemodynamic instability persisted, leading to another instance of cardiac arrest and subsequent death. With negative autoimmune laboratory results, fever, hepatomegaly, and cytopenia affecting three lineages in the peripheral blood, along with decreased fibrinogen (90 mg/dl), elevated ferritin (2985 ng/ml), and triglyceride (350 mg/dl) levels, hemophagocytic syndrome was strongly suspected. Postmortem results of the bone marrow biopsy confirmed atypical hematopoiesis, with a histiocyte appearance suggesting lymphohistiocyte syndrome (Figure 2). We finally considered the diagnosis of HLH based on the HLH-2004 criteria and the H-score. The patient met 8 out of 9 H-score criteria, yielding a score of 273, which translates to a >99% probability of HLH.

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Figure 2.

Clinical and microscopic findings. (A) Purpuric macules on the right lower limb. (B, C) Sample of bone marrow slices stained with May–Grünwald Giemsa. (B) Low magnification highlights the hematopoietic activity across three cell lines. (C) High magnification (40×) of a bone marrow biopsy image showing cells with eosinophilic, clear cytoplasm and uniformly structured nuclei.

Discussion

This case illustrates the complexity of diagnosing HLH, a rare but life-threatening immunopathological condition that presents variably and can be especially masked by pregnancy. A literature review through PubMed via the keywords “hemophagocytic lymphohistiocytosis” AND “pregnancy” OR “postpartum” revealed 35 cases of HLH during pregnancy from 2014 to 2024 (Supplementary Figure 1). The case reports provide a summary of the conditions, including the publication date, author(s), maternal age, gestational age, medical history, initial signs, differential diagnoses, final diagnosis method, H-score usage, treatment approaches, pregnancy evolution, and maternal outcome (Supplementary Table 1).

Our patient, a 20-year-old woman with a history of hematemesis and leukopenia, developed HLH at 8 weeks’ gestation, making her one of the youngest reported cases. The rare occurrence in the first trimester (all cases described were beyond 12 weeks’ gestation) and the subtle onset represent significant diagnostic challenges.^3,4

A consensus on therapy for HLH in children and adults suggests the use of the SOFA score to stratify organ dysfunction severity. Rapid progression to multiorgan failure and high SOFA scores, as in our case, determines the most severe disease spectrum. ⁵

Although hemophagocytosis was noted in the bone marrow, it was not the sole criterion. Cytopenias, elevated ferritin, and hypofibrinogenemia reinforced and guided the diagnosis of HLH. Predisposing factors for HLH include infections (e.g., Epstein–Barr virus), neoplasia (commonly non-Hodgkin lymphoma), and rheumatologic disorders (e.g., systemic lupus erythematosus, vasculitis, immunodeficiency). ⁴ Despite extensive investigations, no specific trigger for HLH was found in our patient. The H-score, a diagnostic tool used to evaluate nine variables—three clinical (underlying immunosuppression, fever, and organomegaly), five biological (triglycerides, ferritin, serum transaminase, fibrinogen levels, and cytopenia), and one cytologic (hemophagocytosis in the bone marrow)—is helpful for risk assessment. Specific criteria in other reported pregnancy cases suggest the utility of this approach in diagnosing HLH in pregnant individuals.^1,3–6

The cutoff value may be adjusted on the basis of population, emphasizing the need to consider pregnancy-specific variations in inflammatory and coagulation markers for early treatment decisions. Pregnant patients' coagulation profiles can rapidly deteriorate, making a tailored score for critical bleeding crucial for timely intervention. In HLH, a modified disseminated intravascular coagulation (DIC) score for pregnant individuals, reflecting International Society on Thrombosis and Haemostasis score adjustments, is decisive in identifying potential severe bleeding. ⁷

The patient's leukocytosis during hospitalization is likely related to catecholamine-induced neutrophilia, a response to clinical stress and interventions that involve activation of alpha-adrenergic receptors, rather than the physiological leukocytosis commonly associated with pregnancy. This understanding is crucial for accurate clinical decision-making and interpreting trends in HLH markers. ⁸

The diagnostic challenge in our case was complicated by its tropical location, which necessitated considering diseases such as leptospirosis and dengue fever. This step is crucial in tropical regions where tropical diseases can mimic HLH presentation. The differential diagnosis expanded to include potential malignancies and blood disorders, but ultimately, a conclusive bone marrow biopsy confirmed the diagnosis.^4,9

Cutaneous eruptions, such as maculopapular or petechial purpuric rashes, are present in 65% of HLH patients. Although cutaneous symptoms are not typically observed in pregnant individuals, their unique appearance on imaging can serve as a crucial visual clue. ¹⁰

Pregnant patients with HLH must receive the same life-saving treatments as nonpregnant individuals, with careful consideration of both maternal and fetal outcomes. First-line therapies such as steroids, immunoglobulin, and etoposide were not feasible in our case due to the patient's unstable condition in the ICU, the initial diagnosis of septic shock, the lack of suspicion for HLH, and the short time between disease suspicion and patient death.^4,7,9,11

Unexpected neurologic complications, including seizures, stroke, and possibly intracranial bleeding due to DIC, are notable, as they can be late manifestations of HLH and indicate a severe catastrophic disease course. Despite advancements in diagnosis and treatment, the mortality rate of HLH remains substantial, potentially reaching 40%, emphasizing the need for increased clinical suspicion and rapid therapeutic intervention.^7,12 This report emphasizes the importance of a prompt, coordinated, and multidisciplinary approach in diagnosing and managing HLH, emphasizing the need for early detection and intervention to improve outcomes in similar situations, given the severe nature of HLH.

In conclusion, to accurately diagnose HLH in pregnant individuals, both pregnancy-adapted DIC and validated H-scores are crucial, as these scores are sensitive to clinical changes during pregnancy, ensuring a comprehensive strategy to mitigate risks associated with nonspecific symptoms.

Supplemental Material