Progressive lymphocytosis in familial hemophagocytic lymphohistiocytosis with lymphocytic interstitial pneumonia: a case report

Familial hemophagocytic lymphohistiocytosis (FHL) is a genetically heterogeneous disorder with autosomal recessive inheritance, characterized as a hyper-inflammatory syndrome with fever, hepatosplenomegaly, and pancytopenia. Several genes have been identified to be involved in FHL, including Perforin (PRF1), MUNC-13–4 (UNC13D), MUNC19-2 (STXBP2), and Syntaxin11 (STX11), which play a key role in lymphocyte cytotoxicity [1]. Lymphocytic interstitial pneumonia (LIP) is a rare disease and usually associated with a variety of clinical conditions, such as Sjőgren syndrome and lupus erythematosus for autoimmune diseases and human immunodeficiency virus and EBV for infections. We reported an adult-onset FHL identified by whole genome sequencing, presenting with progressive lymphocytosis and LIP.

A 20-year-old female was admitted to our institution with a 6-day history of cough and fever on March 18, 2020. Seventeen months prior to admission, she was hospitalized with a 1-week history of fever. Laboratory and medical imagining findings on October 2018 revealed the following: white blood cell (WBC) 1.6 \(\times\) 10⁹/L (3.5–9.5 \(\times\) 10⁹/L); neutrophils 0.32 \(\times\) 10⁹/L (1.8–6.3 \(\times\) 10⁹/L); lymphocytes 1.22 \(\times\) 10⁹/L (1.1–3.2 \(\times\) 10⁹/L); hemoglobin (HB) 7.7 g/dL (11.5–15.0 g/dL); red blood cell (RBC) 3.14 \(\times\) 10¹²/L (3.8–5.1 \(\times\) 10¹²/L); and platelets (PLT) 90 \(\times\) 10⁹/L (125–350 \(\times\) 10⁹/L). Abdominal ultrasonography showed enlargement of the hilar lymph nodes with splenomegaly (179 × 57 mm) and no hepatomegaly. Bone marrow cytology and biopsy showed proliferative anemia with granulocytopenia. Chest CT showed a few exudative lesions in the left lower lung. Positron emission tomography-CT (PET-CT) showed multiple enlarged lymph nodes, including submandibular, cervical axillary, and mediastinal lymph nodes, many of which revealed increased 18F-deoxyglucose uptake (maximum SUV: 3.14), and increased uptake of spleen (maximum SUV: 3.31). To attenuate pancytopenia, splenectomy was performed to treat hypersplenism, and the histopathological examination showed no hemophagocytic cells or clonal T-cell receptor gene rearrangements.

Physical examination on admission included body temperature 37.1 °C, blood pressure 120/70 mmHg, respiratory frequency 23 times per minute, and heart rate 121 times per minute. No rashes or superficial lymph nodes were observed. Auscultation of her lung revealed a few moist rales over both lung bases. Significant laboratory values were as follows: WBC 8.6 \(\times\) 10⁹/L; neutrophils 1.8 \(\times\) 10⁹/L; lymphocytes 6.2 \(\times\) 10⁹/L; HB 15.2 g/dL; RBC 4.89 \(\times\) 10¹²/L; PLT 335 \(\times\) 10⁹/L; CD4 + T lymphocytes 1.570 \(\times\) 10⁹/L; CD8 + T lymphocytes 1.532 \(\times\) 10⁹/L; B lymphocytes 0.949 \(\times\) 10⁹/L; NK lymphocytes 1.859 \(\times\) 10⁹/L; fibrinogen 1.7 g/L (2.0–4.0 g/L); fasting triglyceride 1.89 mmol/L (0.56–1.7 mmol/L); ferritin 77.2 ng/mL (10.0–291.0 ng/mL); aspartate aminotransferase (AST) 7.9 U/L (5.0–40.0 U/L); total bilirubin (TBil) 9.3 umol/L (5.1–28.0 umol/L); total protein (TP) 53.9 g/L (65.0–85.0 g/L); albumin (ALB) 34.5 g/L (40.0–55.0 g/L); globulin (GLB) 19.4 g/L (20.0–40.0 g/L); positive results for blood influenza A and B virus IgM antibodies; other laboratory tests including blood CMV-DNA, EBV-DNA, autoimmune markers, immunoglobulin, complement, C reactive protein (CRP), procalcitonin, GM test, G test, and cryptococcal capsule antigen were unremarkable. Abdominal ultrasonography showed the absence of spleen without hepatomegaly or abdominal lymph node enlargement. Arterial blood gas analysis revealed marked hypoxemia despite giving 5 L/min nasal catheter oxygen therapy: pH 7.425 (7.35–7.45), PaO2 62 mmHg (80.0–100.0 mmHg), and PaCO2 33.0 mmHg (35.0–45.0 mmHg). Chest HRCT revealed diffuse GGO in bilateral lung field (Fig. 1A and B). Bone marrow smear revealed 30% abnormally shaped lymphocytes, and flow cytometric analysis was normal. Cell classification of bronchoalveolar lavage fluid (BALF) from right middle lung indicated 75% lymphocytes, 10% neutrophils, and 15% histiocytes. Next generation sequencing (NGS) method was used to determine the pathogenicity of BALF, and EBV was found. The NGS reported detecting thirty EBV nucleotide sequences in the BALF sample. Transbronchial lung biopsy (TBLB) in the right middle lung showed lymphocytic infiltration in alveolar wall and aggregation in some area with CD3 + , CD4 + , CD8 + , and CD20- immunophenotyping (Fig. 2). No hemophagocytic cells were observed in TBLB and BALF samples. The diagnosis of lymphoproliferative disorder was considered basing on the imaging manifestation and lung tissue biopsy. She underwent intravenous methylprednisolone (160 mg/day for 5 days, 80 mg/day for 2 days, and then 40 mg/day for 7 days). A chest HRCT on the seventh day after treatment revealed significant reduction in the original lesions (Fig. 1C and D). After discharge, the patient was prescribed prednisone (0.75 mg/kg/day) and mycophenolate mofetil (1.5–2 g/day) treatment, and the prednisone was gradually reduced to 10 mg once a day for maintenance. After 9 months of treatment, follow-up chest CT showed that the lesions had disappeared completely, but the increase in peripheral blood lymphocytes still existed. The definitive diagnosis of FHL3 was based on whole genome sequencing by which heterozygous UNC13D mutation test was positive with exon14 (c. 1275delA p. A426Pfs*16) and exon31 (c. 3151G > A p. G1051R). Chest CT showed no abnormality and blood routine examination showed WBC 8.7 \(\times\) 10⁹/L (neutrophils 1.0 \(\times\) 10⁹/L, lymphocytes 6.8 \(\times\) 10⁹/L), HB 13.1 g/dL, and PLT 328 \(\times\) 10⁹/L at the 1-year follow-up.

Hemophagocytic lymphohistiocytosis (HLH) is a heterogeneous and life-threatening disorder characterized by prolonged fever, hepatosplenomegaly, and pancytopenia. This fatal disorder can be categorized into two distinct forms: familial HLH (FHL) and secondary HLH. The diagnosis of FHL can be established with the presence of typical FHL gene mutations detected by molecular genetics modalities [2]. This case developed FHL in adulthood and was diagnosed 2 years after the onset of symptoms with the absence of hemophagocytosis in the bone marrow.

LIP is an uncommon entity characterized as a benign lymphoproliferative disorder limited to the lungs. Based on the lung biopsy with diffuse infiltration of mixed population of CD4 + and CD8 + T lymphocytes, this patient was diagnosed with LIP. EBV infection plays an essential role in some case of LIP and HLH [3, 4], previously report of one child-onset HLH with blood lymphocytosis (92%) and EBV infection suggested an association between lymphocytosis, EBV infection, and HLH [5].

Corticosteroids have been the primary therapy of LIP, and other immunosuppressive agents are also used. This patient received a combination therapy of corticosteroids and MMF, one therapeutic regimen for LIP, instead of chemotherapy or an allogenic stem cell transplantation (ASCT) which was the generally recommended treatment options for HLH. Initial clinical remission was achieved while markedly increased lymphocytes persisted. Long-term efficacy needs further follow-up, and it remains to be observed whether ASCT is required for the future treatment options.

The clinical features of adult-onset FHL may be heterogeneous and confusing, leading to delays in definitive diagnosis. Lymphocytosis is a remarkable feature of some patients with FHL. When the definitive diagnosis remains unknown, performing gene sequencing is helpful to achieve timely detection of FHL. The relationship between FHL and lymphocytosis needs further study.