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A previously healthy 25-year-old male presented to the Emergency Department after being found unconscious, shortly following ingestion of a 454 mL bottle of 84.3% malathion with suicidal intent. Urgent toxicology consult was made, with definitive antidote treatment for organophosphate poisoning started in the emergency department with IV atropine infusion and IV pralidoxime. He was managed in the intensive care unit due to complications of organophosphate poisoning resulting in hypoxic ischemic encephalopathy, multiorgan dysfunction, and hypocalcemia. Adjusted calcium levels were normal on admission at 2.37 mmol/L; however, this decreased on Day 2 of admission to 1.90 mmol/L and only normalized on Day 5 of admission despite aggressive intravenous (IV) calcium replacement. Blood cultures performed on admission were negative. Qualitative blood and urine toxicology testing confirmed the presence of malathion, associated with markedly low serum acetylcholinesterase levels of <1000 U/L (reference range 5900–12 220). Full blood count performed on admission showed a leucocytosis of 16.5 109/L, hemoglobin of 12.7 g/dL, and platelet count of 265 109/L, with the peripheral blood film showing reactive leucocytosis with neutrophilia and lymphocytosis (Image 1A) (Wright stain, 80 objective, Motic EasyScan Infinity 60). NETosis was subsequently observed in the blood film on Day 2 of admission, with a significant number of neutrophils undergoing NETosis on Day 4 of admission (Image 1B, C), together with an increased number of echinocytes, and marked thrombocytopenia. Dysplasia was observed in the neutrophils with pseudo-Pelger-Huët anomalies and abnormal nuclear folding on Day 7 of admission (Image 1D). These dysplastic changes were resolved on Day 10 of admission. Organophosphates are agricultural
Organophosphates are agricultural pesticides that inhibit acetylcholinesterase, an enzyme that breaks down acetylcholine in postsynaptic neuromuscular junctions. This inhibition of acetylcholinesterase leads to a surge in acetylcholine activity, thereby resulting in a host of physiological sequelae, including the impairment of calcium homeostasis. 1 Organophosphate toxicity impacts calcium homeostasis detrimentally by causing markedly raised levels of intracellular calcium concentration above physiological levels.2 An increase in intracellular calcium concentration has the potential to initiate NETosis, a process in which calcium flux is guided through intricate molecular pathways. The pivotal events in NETosis, such as the production of reactive oxygen species (ROS), and chromatin decondensation via histone citrullination by peptidylarginine deiminase 4, are profoundly shaped by calcium-dependent mechanisms.3 While NETosis is commonly seen and described as a defense mechanism against microbial infections, inflammatory signals, and immune responses, it may also be triggered by non-infectious stimuli, with excessive or dysregulated NETosis being implicated in various autoimmune and inflammatory diseases.4,5 Although studies have identified common triggers of NETosis, there are no studies to date on toxins such as organophosphates as a trigger of NETosis. Given our patient had impaired calcium homeostasis early during his admission which coincided with the presence of NETosis, we postulate that calcium dysregulation secondary to organophos-phate toxicity could account for the presence of NETosis seen on the peripheral blood film of our patient. Further studies are recommended to reveal the pathophysiology between NETosis and organophos-phate poisoning and to identify strategies to effectively modulate dysregulated NETosis.
