COVID-19 Induced Hemophagocytic Lymphohistiocytosis in a Patient with Novel Homozygous UNC13D Gene Variant

Introduction

Symptomatic infection caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) induces a great variety of clinical symptoms, ranging from mild to critical illness and mortality. COVID-19 is generally mild in children with a small proportion of patients developing severe disease. However, some children may develop a hyperinflammatory response like that observed in adults with COVID-19. The systemic inflammatory syndromes associated with COVID-19 have heterogeneous clinical phenotypes and appear generally age-related. Although these hyperinflammatory conditions present with the multisystem inflammatory syndrome in children, they share essential features with cytokine-release syndrome, acute respiratory distress syndrome, or hemophagocytic lymphohistiocytosis (HLH) in adults. Here, we present a patient with HLH with a homozygous UNC13D gene variant triggered by COVID-19 infection.

Case Presentation

A 2-month-old girl was admitted to the emergency department of our hospital with a fever continuing for the last 24 h. Past medical history was unremarkable. She was born at term after an uneventful pregnancy. Her parents were consanguineous, and she had a healthy sister ([Fig. 1a]). There were no inborn errors of immunity (IEI) and other genetic diseases in the family history. On physical examination, the weight assessment was 5,300 gr (50–75th percentile), height was 57 cm (50th percentile), and head circumference was 39 cm (50th percentile). Although the other physical examination findings were normal, it seemed like a restless patient with a body temperature of 39°C. She was hospitalized, and broad-spectrum empiric antibiotic therapy was already been initiated. Pancytopenia was detected in her initial laboratory tests, and a lumbar puncture could not be performed due of thrombocytopenia. The nasopharyngeal PCR swab test was positive for SARS-CoV-2. There was no bacterial growth in blood and urine cultures. Epstein-Barr virus (EBV), cytomegalovirus (CMV), and parvovirus B19 PCR were negative in the blood samples. Human immunodeficiency virus (HIV) serology was negative. Laboratory investigations of the patient showed pancytopenia, slightly elevated C-reactive protein (CRP), markedly elevated ferritin and triglyceride, and decreased fibrinogen ([Table 1]). The immunological evaluation revealed slightly decreased serum IgG, normal IgA, and IgM levels. Peripheral lymphocyte subsets showed markedly decreased CD3+CD4+T, CD19+B, and CD3-CD16+56+natural killer (NK) lymphocytes ([Table 1]). Echocardiography revealed a small secundum atrial septal defect (ASD), small patent ductus arteriosus (PDA), and normal coronary arteries. The chest radiograph was normal. In the case of SARS-CoV-2 infection confirmed with biochemical markers of hyperinflammation, the possibilities of COVID-19-associated cytokine-release syndrome, a multisystem inflammatory syndrome in children (MIS-C), or HLH secondary to SARS-CoV-2 were evaluated. Bone marrow smears demonstrated hemophagocytosis, more histiocytes, and no evidence of malignancy. This raised the concern that the patient had developed HLH secondary to SARS-CoV2. The patient fulfilled five of eight HLH-2004 diagnostic criteria, and her H-score was calculated at 231, predicting the probability of HLH at 98%-99% (Fardet L et al., Arthritis Rheumatol 2014;66:2613–2620) (Debaugnies F et al., Am J Clin Pathol 2016;145:862–870). An HLH-2004 protocol including dexamethasone and etoposide was started. Familial HLH or other IEIs were considered due to consanguinity and laboratory findings, and whole-exome sequencing (WES) was performed. A novel homozygous frameshift variant [NM_199242.3: c.1082del; p.(Tyr361SerfsTer43)] was identified in the UNC13D gene ([Fig 1b]), which is classified as pathogenic based on the American College of Medical Genetics (ACMG) classification. Mother, father, and sister were heterozygous carriers of the variant ([Fig 1a]). The diagnosis was confirmed as an autosomal recessive FHLH type 3. The patient was included in the bone marrow transplantation program.

Fig 1 a: Family pedigree of the case. b: Schematic of UNC13D protein to indicate location p.Tyr361SerfsTer43 variant.

Table 1 Laboratory investigations of the patient.

	Case	Reference
Hb (g/dL)	7.1	10.5–14
WBC (mm3)	2,750	6,000–14,000
ANC (mm3)	420	1,000–8,500
ALC (mm3)	2,120	4,000–13,500
PLT (mm3)	19,000	150,000–450,000
IgG (mg/dL)	187	280–666
IgA (mg/dL)	<6,67	5–39
IgM (mg/dL)	27	19–94
IgE (IU/ml)	4	<100
ESR (mm/h)	4	0–10
CRP (mg/L)	16.4	1–4
Ferritin (ng/mL)	5,389	6–340
Fibrinogen (mg/dL)	38	130–330
Triglyceride (mg/dL)	552	35–110
PT (sec)	15	10–15
APTT (sec)	20	23–36
INR	1.27	0.53–1.26
CD3+CD16–56- % (mm3)	65 (1,378)	51–79 (2,400–8,100)
CD3+CD4+% (mm3)	22 (466)	31–54 (1,400–5,200)
CD3+CD8+% (mm3)	22 (466)	10–31 (600–3,000)
CD3-CD16+56+% (mm3)	4 (84)	5–23 (200–1,800)
CD19+% (mm3)	4 (84)	14–44 (500–3,600)
HLA-DR+% (mm3)	60 (1,272)	15–48 (700–3,900)

Hb hemoglobin, WBC white blood cell, ANC absolute neutrophil, ALC absolute lymphocyte count, PLT platelet, CRP C-reactive protein, ESR erythrocyte sedimentation rate, PT prothrombin time, aPTT activated partial thromboplastin time, INR international normalized ratio.

Publication History

Article published online:
07 July 2023