LAUSR

Natural killer (NK) cell abnormalities, such as familial hemophagocytic lymphohistiocytosis (FHL) and isolated NK cell deficiency, can cause life-threatening hyperinflammation triggered by infection because the NK cells are incapable of eradicating infectious pathogens, leading to excessive activation of macrophages and T cells. Usually, such diseases are caused by genetic disorders that cause a permanent decrease in NK cell activity. We describe the first case of a hemophagocytic lymphohistiocytosis (HLH)-like episode in which the NK cell activity was persistently low from early infancy but returned to normal at the age of 3 years. The present patient, a 4-month-old boy without a family history of primary immunodeficiency (PID), presented with cough and rhinorrhea. Starting on day 12 of his illness, the patient had a sustained fever, eruption and diarrhea. On day 21, he developed thrombocytopenia (platelets, 47 9 10/lL) and mild liver dysfunction (aspartate aminotransferase, 218 IU/L; alanine aminotransferase, 90 IU/L). Although the thrombocytopenia and liver dysfunction improved spontaneously, the fever, eruption, and diarrhea persisted, and generalized edema and ascites developed. On day 28, laboratory data indicated disseminated intravascular coagulation, elevated lactate dehydrogenase, hypoalbuminemia, electrolyte abnormalities, marked elevation of soluble interleukin-2 receptor and serum inflammatory cytokines with low NK cell activity (Fig. 1). Flow cytometry indicated T-cell activation and a low number of NK cells (Fig. S1). Bone marrow aspiration showed no findings of hemophagocytosis. Based on the symptoms and laboratory data, an HLH-like state with systemic hyperinflammation was strongly suspected. Despite dexamethasone treatment, hepatosplenomegaly (liver and spleen were palpable at 8 and 3 cm, respectively, below the costal margins), pleural effusion, ascites, hypercytokinemia, anemia (minimum, hemoglobin 6.5 g/dL) and thrombocytopenia (minimum, platelets 65 9 10/lL) worsened, but these symptoms resolved quickly after cyclosporine treatment. Infectious pathogens, including Epstein–Barr virus, cytomegalovirus, Herpes simplex virus, parvovirus, human herpesvirus 6, hepatitis B virus, hepatitis C virus, measles, and rubella, were not identified on serology. No causative virus (e.g. enterovirus or parechovirus) was detected in samples from the pharynx, in the urine or in the stool, according to the viral isolation and identification method. PID, including FHL types 2, 3, and 5, Wiskott–Aldrich syndrome and X-linked lymphoproliferative disease, all of which are related to low NK activity, were excluded on previously reported methods. After recovering from HLH, NK cell activity remained relatively low, even though the number of NK cells was within the normal range and lacked subset abnormalities (Fig. 1). When the patient developed a viral respiratory infection at 9 months, mild pancytopenia and hypercytokinemia were observed, but when he developed a bacterial infection at 11 months, unlike during the two previous episodes, there were no findings indicative of HLH. Prophylactic i.v. immunoglobulin (IVIG) was given to prevent infections from triggering HLH until the age of 3 years, when the NK cell activity recovered to normal levels. Informed consent to publish this case was obtained from the patient’s parents. Generally, NK cell activity rapidly increases after birth and reaches the adult level (18–40%) by 1 month of age. Although low NK cell activity persists for a while after secondary HLH episodes, a relatively low NK cell activity, which seemed to be actively involved in the clinical course and pathophysiology, lasted several years in the present case. Similar to childhood immune disorders or parameters that improve with age, such as transient hypogammaglobulinemia of infancy, and total number of immunoglobulin and neutrophils, the delayed recovery of NK cell activity in the present case might be such an entity. This may also be the case for infant HLH, especially with regard to those patients who improve easily by supportive therapy alone. In which case, in the situation of long-lasting low NK cell activity, the prevention of infection by IVIG until spontaneous recovery of NK cell activity might be effective at preventing HLH-like episodes. Correspondence: Ryosei Nishimura, MD PhD, Department of Pediatrics, School of Medicine, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, 13-1 Takaramachi, Kanazawa, Ishikawa 920-8641, Japan. Email: [email protected] Received 21 April 2018; revised 19 December 2018; accepted 31 January 2019. doi: 10.1111/ped.13803