A Case of Hemophagocytic Lymphohistiocytosis Coexisting with Pulmonary Hypertension

Hemophagocytic lymphohistiocytosis (HLH) is a fatal disease associated with multiple organ dysfunctions and overwhelming inflammation. To date, pulmonary hypertension (PH) coexisting in patients with HLH is rare, and the treatment is unknown. Here we present an interesting case involving a 27-year-old male with dyspnea and irregular fever that eventually certified as PH coexisting with HLH. The patient finally died for severe infection 21-days post hematopoietic stem cell transplantation (HSCT). The necessity and timing of HSCT in this kind of patient need to be more careful.

A 27-year-old unmarried male with no prior history admitted to our hospital on 16/08/2017 with complaints of coughing and shortness of breath for 6 months, irregular fever for 1 month. Six months ago, he suffered from a worsening coughing without sputum and shortness of breath, more noticeable on climbing steep stair (no more than 20 steps). One month ago, he began to have a recurrent fever with maximum temperature of 39℃ , withoutchest pain, rash, nausea, vomiting, diarrhea, swollen lymph nodes, myalgias, decreased appetite and weight loss. He had no infectious disease, no allergies, no family history of heritable disease, and never used tobacco, alcohol or recreational drugs. He was a local food factory worker and denied occupational dust and radiation exposure. Physical Exam: His liver was palpated 5cm below the right costal margin and the spleen was 3cm below the left costal margin. No enlarged lymph nodes were palpated. He was first admitted to respiratory department of the Henan Provincial People's Hospital (22/06/2017-09/07/2017).
During his first hospitalization, echocardiography analysis suggested enlarged right heart (right ventricle (RV) 42.6 mm (normal range: 7-23 mm) and right atrium (RA) 55 mm (normal range: 33-41 mm)) and severe pulmonary hypertension (PH)with a pulmonary arterial systolic pressure (PASP) of 88mmHg (normal range: 15-30mmHg). The serum B-type natriuretic peptide (BNP) was 2773 pg/ml (normal range: ＜450 pg/ml). He was then diagnosed with idiopathic pulmonary arterial hypertension (IPAH) and initiated the therapy with sildenafil (25mg, tid) at 01/07/2017. His shortness of breath slightly improved after receiving the treatment and he was discharged on 09/07/2017. However, he still got a recurrent fever a few days after his discharge.
Then, he was re-admitted to our hospital on 16/08/2017. The computerized tomography pulmonary angiography (CTPA) demonstrated enlarged RV and RA due to PAH and no significant lesions in the lungs. Right heart catheterization (RHC) evidenced critical PH with a pulmonary arterial pressure of 37/14mmHg (mean 22mmHg), pulmonary capillary wedge pressure (PCWP) of 3 mmHg and pulmonary vascular resistance (PVR) of 3.8 Wood units (Table 1). Moreover, echocardiography revealed an enlarged right heart (RV 42 mm and RA 46 mm) and moderately PH with a PASP of 60 mmHg. Consistent with RHC and echocardiography, BNP was mildly decreased in this patient (1382 pg/ml). V/Q scan, pulmonary function test, autoantibody (such as ANA, ANCA, ferritin, etc.), HIV antibody and portal venous pressure were at normal range. In conclusion, the diagnosis of IPAH was confirmed and the treatment of sildenafil was effective.

Hemodynamics and Oxygen Saturation
However, he still had a fever from time to time, even after broad-spectrum antibiotic (moxifloxacin, 400mg, qd). Besides, several things remain hard to explain based on the diagnosis of IPAH: the reduction of WBC, RBC and PLT in peripheral blood (Table 2), an ultrasound indicated hepatomegaly and splenomegaly ( Figure 1) and elevated Epstein-Barr virus (EBV)-DNA (3.62*10 4 copies/ml in plasma).   In line with the finding of bone marrow biopsy, we detected a p.G863D (SNP rs140184929) and a p.K867E (SNP rs1135688) mutation in UNC13D gene, p.R49Q (SNP rs17073498) mutation in STX11 gene and p.I526V(SNP rs6791) mutation in STXBP2 gene (   Figure 3). Given the fact that ultimate treatment for FHLH is hematopoietic stem cell transplantation (HSCT)(1), he received allogeneic HSCT (allo-HSCT) on 10/10/2017, using HLA-half matched related donor (his mother). Unfortunately, he died for severe aspergillomycosis 21 days post-allo HSCT.
As the EBV-DNA was upregulated in this case, we also believed EBV infection may play a role in the disease process. And further studies focus on this issue need to be performed.
PH is a progressive, life-threatening disease, characterized by increased pulmonary arterial pressure [8]. In this case, not only repeated echocardiography confirmed increased PASP, but also CTPA and BNP evidenced the diagnosis of PH. However, RHC identified critical PH in this patient. The use of sildenafil (almost one month) before RHC examination may lead to this result. What is more, laboratory tests, such as negative autoantibody etc., also indicated the diagnosis of IPAH. Unfortunately, we did not perform a genetic test of IPAH in this patient.
Notably, all the evidences suggested that both PH and familial HLH coexisted in this patient.  [12]. Moreover, PH was not a rare complication of HSCT for primary HLH [13,14]. Reviewing this case, whether patient with both PH and HLH benefited from HSCT was thought-provoking. And the timing of HSCT was also a challenge. To date, studies focus on this issue are rare. We recommend consultation of multi-disciplinary team (MDT) and close monitor of right heart function and PVSP before and after HSCT. Further studies should be performed to solve this problem. Besides, disseminated histoplasmosis and multiorgan failure were identified as etiological factors of secondary HLH [15,16,17]. The patient died for severe aspergillomycosis 21 days post-allo HSCT in our case, which reminds the awareness of fungal infection monitor should be strengthened.
Although the topic of PH involved in HLH has been illustrated, the underlying mechanism is still unknown. EBV was a well-known causative factor of both PH and HLH [18,19,20,21,22]. A retrospective analysis identified both HLH and PH were common complications for EBV infection [23]. PH was also observed in patient with chronic active EBV infection [18,21,23,24]. Furthermore, macrophage activation in HLH was also a potential mechanism for the development of PH [9].
There are limitations in this report: (1) the study of genetic defects of IPAH were absent here; (2) the lung pathology was lacked; (3) RHC should be performed before using sildenafil. HLH is a devastating disease, we should pay more attention if a PAH patient presents persistent fever together with the reduction of WBC, RBC and PLT in peripheral blood, hepatomegaly, splenomegaly and EBV infection.