[Show abstract][Hide abstract] ABSTRACT: A 14-year-old male presented to the hospital after syn-cope during football practice on a hot summer day. On examination, temperature was 40.41C (104.71F) and heart rate was 180 beats per minute. He was unresponsive, intu-bated, and cooled in the pediatric intensive care unit. Laboratory values revealed acute kidney injury and ische-mic hepatitis. Complete blood count showed a white blood cell count of 17 Â 10 9 /L, hemoglobin of 14.8 g/L, platelet count of 395Â10 9 /L, and mean corpuscular volume of 83.8 fL (normal, 81.4 to 91.9 fL). Peripheral blood smear showed hypersegmented neutrophils with " botryoid " nuclei (Supplemental Fig. 1 Supplemental Digital Content 1, http://links.lww.com/JPHO/A98). Hypersegmented neutrophils are classically seen with folate (vitamin B 9) orcobalamin (vitamin B 12) deficiency. These morphologic changes of the neutrophil nucleus occur due to impaired DNA synthesis from inadequate substrate or impaired replication from a toxin or medication effect. Arrest of nuclear maturation, impaired cell division, and unbalanced cell growth results in characteristic large cells with immature nuclei with relative cytoplasmic maturity. Red blood cell macrocytosis often accompanies hyper-segmented neutrophils and can be seen in hypothyroidism, alcohol abuse, uremia, and myelodysplastic syndromes. Hypersegmented neutrophils without red blood cell macrocytosis, as in our patient, has been described in patients with hyperthermia, uremia, and concurrent mega-loblastic and microcytic anemia from combined folate and/ or cobalamin deficiency along with iron deficiency or tha-lassemia. As the finding of hypersegmented neutrophils preceeds macrocytosis, neutrophil hypersegmentation without macrocytosismay represent early cobalamin and folate deficiency. 1 The term " botryoid " refers to nuclei that appear like a cluster of grapes around a stem. 2 Botryoid nuclei have been described in patients with hyperthermia due to cocaine and methamphetamine use, 3 malignant hyperthermia, neuro-leptic malignant syndrome, 4 and autoimmune disorders such as rheumatoid arthritis, psoriatic arthritis, and sys-temic sclerosis. 5 In comparison, the multilobed nuclei in cobalamin and folate deficiency appear disorganized. The pathogenesis of botryoid nuclei in hyperthermia has not been clearly elucidated. Hyperthermia may activate the intrinsic signaling pathway that initiates apoptosis since pyknosis, nuclear condensation in the setting of irreversible cell death, is seen in neutrophils in response to hyper-thermia. 6 In addition, microtubular decomposition may play a role. 7 In vitro experiments have shown that radially segmented neutrophils are induced by applying heat. 8 Botryoid changes in >50% of neutrophils on a peripheral blood smear may be sufficient to diagnose heatstroke. 2 Fewer than 50% botryoid neutrophils is suggestive of heatstroke. Clinicians should be aware that hyperthermia can cause hypersegmented neutrophils so as to avoid unnecessary evaluations for other etiologies. Our patient's mental status and renal function improved with cooling and intravenous fluids. He was extubated on the first day of hospitalization. Subsequent peripheral blood smears showed resolution of hyper-segmented neutrophils by the second hospital day. He was discharged home after 3 days without any complications.
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