A case of pulmonary arterial hypertension associated with adult hemophagocytic lymphohistiocytosis

Abstract Abstract

Hemophagocytic lymphohistiocytosis (HLH) is an aggressive, life-threatening syndrome of excessive immune activation. Presentation is most common among the pediatric population, and cases in adults are rare. The number of nonhematologic presentations described in relation to HLH has been growing. We present a case involving a woman who developed HLH after autologous stem cell transplantation for mantle cell lymphoma. Months later, she received a diagnosis of pulmonary arterial hypertension (PAH) while undergoing treatment for her HLH. To our knowledge, PAH associated with adult HLH has only been described in the literature once before. PAH may now be a potential differential diagnosis for patients with HLH who present with respiratory symptoms.

Case Description

A 64-year-old female patient presented to her family physician with abdominal pain. An ultrasound revealed splenomegaly, and subsequent blood tests showed a hematologic abnormality with a white blood cell count of 70.5 × 10⁹ cells/L. Computerized tomography (CT) of the chest, abdomen, and pelvis demonstrated enlarged axillary, mediastinal, and portacaval lymph nodes as well as splenomegaly. A bone marrow biopsy demonstrated a B cell lymphoma with coexpression of CD5 and an interstitial infiltrate. Test results were negative for cyclin D1 but positive for chromosomal translocation (11;14). Mantle cell lymphoma was diagnosed on the basis of morphology, CD20 positivity, and CD23 partial positive expression as well as t(11;14) chromosomal translocation. The patient was treated with 4 cycles of cyclophosphamide, hydroxydaunorubicin, oncovin, prednisone, and rituximab alternating with dexamethasone, cytarabine, and cisplatin. This was followed by autologous stem cell transplantation. Before receiving chemotherapy, the patient underwent a multigated acquisition scan that revealed normal left and right ventricular function.

Six months after the transplantation, the patient developed a transfusion-dependant anemia with fever and thrombocytopenia (platelet count of 15 × 10⁹ platelets/L). Bloodwork was significant for elevated liver enzymes (aspartate aminotransferase level of 166 U/L and alanine aminotransferase level of 181 U/L) and elevated ferritin level (4,570 ng/mL). A bone marrow biopsy was performed and showed an increase in macrophages with hemophagocytosis, consistent with hemophagocytic lymphohistiocytosis (HLH). Notably, there was no evidence of lymphoma in the bone marrow. The patient was treated with prednisone and intermittent transfusions followed by two courses of etoposide, after which the patient achieved hematological remission.

Unfortunately, the patient presented with dyspnea 3 months after receiving a diagnosis of HLH and began to require home oxygen. The patient also complained of ankle edema, and an echocardiogram revealed moderate right ventricular dilatation and hypokinesis with normal left ventricular function. Right ventricular systolic pressure was 75 mmHg with moderate tricuspid regurgitation. There was no evidence of atrial septal defect or patent foramen ovale. A right heart cathetarization revealed pulmonary arterial pressures of 75/35 mmHg with a mean of 49 mmHg. The patient’s left ventricular end-diastolic pressure was 13 mmHg, and her pulmonary capillary wedge pressure was 14 mmHg. Cardiac output was calculated at 3.9 L/min, and pulmonary vascular resistance (PVR) was 9 Wood units. The catheterization results were consistent with precapillary pulmonary hypertension (PH).¹ The findings of a V/Q scan were negative for pulmonary embolism. Pulmonary function test results revealed a ratio of forced expiratory volume in 1 second to forced volume vital capacity of 89%, a total lung capacity of 95%, and diffusion capacity of the lungs for carbon monoxide (DLCO) of 82%. A CT showed trace bilateral pleural effusions and resolving focal right lower lobe opacities (related to earlier pneumonia). There were no reticular opacities, lymphadenopathy, or ground-glass nodular changes. The patient was also seen by a rheumatologist who excluded an underlying connective tissue disease (laboratory investigations had results that were negative for antinuclear antibodies, rheumatoid factor, and antineutrophil cytoplasmic antibodies; there was no active joint disease, and there were no features of connective tissue disease).

The patient initiated oral therapy with tadalafil and macitentan. Over the next 6 months, she was weaned from her supplemental oxygen, and her 6-minute walk test distance improved from 178 m with minimal saturation of 87% on room air to 303 m with a minimal saturation of 91% on room air. A repeat right heart catheterization showed pulmonary artery pressures of 36/13 mmHg with a mean of 23 mmHg, cardiac output of 4.26 L/min, wedge pressure of 16 mmHg, and PVR of 1.6 Wood units.

Discussion

This is, to our knowledge, the second report of adult PH in the context of HLH.^2,3 HLH is an immune-mediated disease that was first described in 1939.⁴ It is caused by impaired natural killer cell and cytotoxic T cell function and excessively activated macrophages in hematopoietic organs.⁵ HLH can be triggered by a variety of events that disrupt immune homeostasis. Although rare, it has been well described as a complication of stem cell transplantation. A recent review has found that 29 of 2,197 identified cases of HLH were triggered by a stem cell transplantation procedure.⁶

Clinically, the syndrome is characterized by fever, peripheral blood cytopenia, splenomegally, and the finding of hemophagocytosis in bone marrow, spleen, lymph node, or liver.^5,7 However, nonhematopoietic manifestations of HLH have been well documented.⁸ Pulmonary involvement can occur, with cough and dyspnea resulting from hemophagocytotic lung infiltration or secondary to pneumonia.⁶

The rapid onset of PH, a lack of clear precipitant, and its temporal association with HLH suggest that the PH was a nonhematopoeitic manifestation of HLH in this case. Other potential causes of PH were ruled out, including left heart disease, interstitial lung disease, and connective tissue disease. Pulmonary venoocclusive disease (PVOD) was considered as a possible diagnosis, because there have been reports of PVOD associated with hematological malignancies and chemotherapeutic agents.^9-11 Our patient did not have hemoptysis and had a normal DLCO on pulmonary function testing. Radiographically, the CT thorax did not show centrilobular ground-glass opacities, septal lines, or mediastinal lymph node enlargement.¹² In addition, the patient experienced a dramatic improvement after receiving pulmonary vasodilator treatment, which is not typical for PVOD.¹³

A few potential mechanisms for the development of PH in the context of HLH have been reported in the literature.^2,3,14 Macrophages have been found to be highly activated in studies involving patients with familial PAH.¹³ Furthermore, high levels of proinflammatory cytokines and macrophage infiltrates have been isolated from lung samples obtained from patients with PAH, suggesting a possible role of inflammation and autoimmunity in PAH that could potentially be triggered or exacerbated by active HLH.^15-17 Autopsies performed on two pediatric cases of PH in the context of HLH found no evidence of infectious cause or diffuse alveolar damage, which suggests a direct connection between the two diseases.³

HLH is a rare disease entity, especially in the adult population. As such, its connection to nonhematologic complications is poorly understood. Our case report demonstrates only the second adult association between PH and HLH ever reported, although the physiology connecting the two diseases remains unclear. However, PH should be a potential differential diagnosis for patients with HLH who present with respiratory distress.

Source of Support: Nil.

Conflict of Interest: None declared.