Life-Threatening Primary Varicella Zoster Virus Infection With Hemophagocytic Lymphohistiocytosis-Like Disease in GATA2 Haploinsufficiency Accompanied by Expansion of Double Negative T-Lymphocytes

Abstract

Two unrelated patients with GATA2-haploinsufficiency developed a hemophagocytic lymphohistiocytosis (HLH)-like disease during a varicella zoster virus (VZV) infection. High copy numbers of VZV were detected in the blood, and the patients were successfully treated with acyclovir and intravenous immunoglobulins. After treatment with corticosteroids for the HLH, both patients made a full recovery. Although the mechanisms leading to this disease constellation have yet to be characterized, we hypothesize that impairment of the immunoregulatory role of NK cells in GATA2-haploinsufficiency may have accentuated the patients' susceptibility to HLH. Expansion of a double negative T-lymphocytic population identified with CyTOF could be a further factor contributing to HLH in these patients. This is the first report of VZV-triggered HLH-like disease in a primary immunodeficiency and the third report of HLH in GATA2-haploinsufficiency. Since HLH was part of the presentation in one of our patients, GATA2-haploinsufficiency represents a potential differential diagnosis in patients presenting with the clinical features of HLH-especially in cases of persisting cytopenia after recovery from HLH.

Keywords: GATA2 deficiency; NK cell abnormalities; TCRγδ T cells; hemophagocytic lymphohistiocytosis; primary immumunodeficiencies; varicella-zoster virus.

Figures

Figure 1

Clinical presentation of VZV disease in GATA2-haploinsufficient patient (A) An erytematous, vesicular skin rash on the back of patient 1 with GATA2-haploinsufficiency, 4 days after the onset of VZV disease. (B) Targetoid lesions on the left arm of the same patient, 7 days after the onset of illness. (C) A chest X-ray 8 days after the onset of illness, showing diffuse alveolar involvement with a miliary pattern of pulmonary opacities. (D) Histograms showing perforin expression in CD56+CD16+ lymphocytes from patient 1 (gray), patient 2 (black), an individual with heterozygous A91V PRF1 mutation (green), a healthy control (blue) and isotype control (red dotted line) as assessed by intracellular flow cytometry.

Figure 2

High-dimensional mass cytometry for the analysis of immune populations in GATA2-haploinsufficient patients PBMCs of 3 patients (patients 2–4) and 3 healthy controls were stained with 27 heavy-metal labeled antibodies (Supplementary Table 2) and acquired on a CYTOF2 mass cytometer. (A) Cells identified as CD45+ were exported, downsampled to 900 events and the combined dataset (5,400 cells) subjected to dimensionality reduction using the t-SNE algorithm. Density plot of total (left panel), control (middle panel) and patient (right panel) cells based on tSNE analysis. The manually gated XYZ population consist of closely grouped cells present mainly in the patients and not belonging to any immune subpopulation defined by manual annotation. (B) Color-coded manual gates are plotted by density for the combined dataset. (C) Density plots of the different subpopulations in patients and controls with the fraction out of all CD45+ cells indicated. (D) Histograms of markers with the largest expression discrepancies between patients and controls in the XYZ population and among monocytes based on visual analysis. (E) Percentages of XYZ cells from the CyTOF data, out of all CD45+ plotted for patient 2 (HLH), the 2 additional patients with germline GATA2-mutations (patient 3 and 4) and the 3 healthy controls. (F) Timecourse of TCRγδ+ cells (percentage of lymphocytes) measured by conventional flow cytometry in GATA2-haploinsufficient patients 1 to 4.