Case number PHHY2011US100194 is an initial literature report received on 14 Nov 2011: The authors reported the first case of central diabetes insipidus associated with hemophagocytic lympho-histocytosis following vaccination with H1N1 vaccine. This report refers to a 75-year-old female patient. Her past medical history was significant for osteoporosis treated with risedronate for one year, then alendronate for one year, after which she received two infusions of zoledronic acid, her last one in Oct 2009. She had a history of gastric ulcer at age 60, a possible transient ischemic attack in Jul 2009, and hypertension. Computed tomography of the brain without contrast in Jul 2009 revealed small vessel ischemia. Her only medications were vitamin D, 50,000 IU once a month, and lorazepam, 0.5 mg, for anxiety. She was vaccinated with H1N1 vaccine (batch number and manufacturer: unknown) on an undetermined date in 2010. One month after vaccination she presented with flu-like illness in Mar 2010 and was treated with oseltamivir phosphate. However, within several days of developing this flu-like illness, she began to have polyuria associated with polydipsia and loss of appetite. A urine culture was negative. She was asked to record her urinary volume over a 24-hour period. On two successive days, her 24-hour urinary volumes were 3, 990 mL and 2, 550 mL respectively. An overnight dehydration test was performed, and her morning urine sodium concentration was 22 mEq/L, urine osmolarity was 145 mOsm/kg, serum sodium concentration was 147 mEq/L, and serum osmolarity was 314 mOsm/kg. She continued to complain of generalized weakness, loss of appetite, loss of taste for salt, excessive thirst, and frequent urination. She was found to have iron-deficiency anemia with an elevated erythrocyte sedimentation rate of 42 mm/hour (normal, less than 20 mm/hour). Her fasting serum gastric level was 44 pg/mL (normal, less than 200 pg/mL), serum prolactin level was 16.7 ng/mL (reference range, 1.9 to 25 ng/mL), and serum protein electrophoresis revealed a polyclonal gamma increase. Her follicle-stimulating hormone level was 24.2 mlU/mL (normal postmenopausal, more than 25) and luteinizing hormone level was 11.2 mlU/mL (normal postmenopausal , more than 20 mlU/mL). Thyroid and liver function tests were normal. Magnetic resonance imaging  (MRI) of the pituitary revealed a 4-mm nodular lesion within the left lobe of the pituitary gland, consistent with a possible pituitary micro adenoma. In May 2010, she was started on intranasal 1-deamino-8-D-arginine vasopressin (DDAP) supplementation, one puff at bedtime, with marked improvement of her polyuria. A few days later she developed gastrointestinal bleeding and was hospitalized. She was found to have three non bleeding polyps on colonoscopy and had a negative capsule endoscopy. Her polyuria remained improved on DDAVP. In Aug 2010, she was readmitted with intermittent daily fevers that reached 39.5 degree Celsius, a white blood cell (WBC) count of 20, 000/L (reference range, 3, 500 to 9,000/L) with 65% neutrophils, 15% lymphocytes, 17% monocytes, and 3% band forms indicating leukocytosis, and a urinary tract infection (indicated by the presence of 3+ leukocyte esterase, no nitrites, and 31 WBCs on urinalysis). She had progressive fatigue and anorexia and had lost 3.6 kg in the past few months (from 49.5 to 45.9 kg). She appeared cachectic on examination. She was not orthostatic, acromegalic, or Cushingoid and demonstrated full visual fields. Her thyroid was not enlarged. There was a diffuse, maculopapular rash confluent on her torso and abdomen and palpable hepatosplenomegaly. Aside from leukocytosis, admission laboratory results were also notable for normocytic anemia (hemoglobin, 9.1 g/dL (reference range, 12 to 15.8 g/dL); mean corpuscular volume, 79.5 fl (reference range, 79 to 93 fL); red blood cell distribution width, 15.1% (normal, less than 14.5%), with absence of reticulocyte response (1.5%), mild thrombocytopenia (platelet count was 134 x 103/uL, reference rang 165 to 415 x103/uL), an elevated international normalized ratio of 1.39 (reference range, 0.86 to 1.16), and a partial thromboplastin time of 43.4 seconds (reference range, 24.4 to 37.9 seconds). Electrolytes and hepatic function tests were essentially normal with the exception of mildly reduced total protein 6.5 g/dL (reference range, 6.7 to 8.6 g/dL). Results of a fasting lipid panel were as follows: high-density lipoprotein, 3 mg/dL; low-density lipoprotein, 46 mg/dL; and triglycerides, 118 mg/dL. Assessment of the hypothalamic-pituitary-adrenal axis demonstrated a robust 8 am serum cortisol of 22.3 ug/dL (reference range, 5 to 21 ug/dL), normal thyroid function tests thyrotropin, as 2.43 mlU/L (reference range, 0.32 to 4.05 mlU/L) and free thyroxine as 1.09 ng/dL (reference range, 0.7 to 1.24 ng/dL), mildly suppressed gonadotropins for a postmenopausal woman (follicle-stimulating hormone, 10.4 mlU/mL and luteinizing hormone, 6.9 m;U/mL), and a normal prolactin level (22.5 ng/mL). Two MRIs of the brain with focused imaging of the sella region were performed at 1.5 Tesia before and after administration of contrast material. The overall appearance of the brain was unremarkable for a 75-year-old woman with history of mild hypertension. Specifically, no parenchymal brain mass and no abnormal parenchymal or meningeal enhance, enhancement affected the cerebrum, brainstem, or cerebellum. The ventricular size was normal. There was focal thickening of the pituitary infundibulum extending to its insertion into the hypothalamus. This finding was most obvious as plaque like contrast enhancement surrounding the infundibulum. The pituitary gland was of normal size. The posterior pituitary signal intensity was a bit lower and more heterogeneous than normal. The pituitary gland enhanced somewhat heterogeneously post contrast administration, but there was no clear evidence of microadenoma. The sella and the remainder of the hypothalamus were entirely unremarkable. These findings were similar on both MRI exams performed. The patient remained febrile despite the escalation of her antibiotics to treatment with piperacillin and tazobactam. Polydipsia and polyuria remained well-controlled on DDAVP. Dermatology was consulted and performed a skin biopsy; the pathologic findings showed histiocyte collections within the epidermis and papillary dermis that stained positive for CD43. Computed tomography of the abdomen and pelvis showed hepatosplenomegaly with heterogeneous enhancement suggestive of an infiltrative process. Her leukocytosis progressively increased to a WBC count of 93, 800/uL with worsening anemia (hemoglobin, 6.1 g/dL) and thrombocytopenia (platelet count, 12 x 103/uL) requiring transfusions. Oncology was consulted and performed a bone marrow biopsy, which revealed a markedly hypercellular marrow (nearly 100% cellularity) with trilinear hyperplasia. CD68 (PGM1) immunostaining demonstrated florid histiocytosis and hemophagocytosis in the marrow - pathognomonic of hemophagocytic lymphohistiocytosis (HLH) without evidence of malignancy. CD1 a staining for Langerhans cell histiocytosis (LCH) was negative. Herpes simplex virus 1 DNA was detected at a low titer in her serum; herpes simplex virus 2, human herpes virus 6, and cytomegalovirus DNA were not detected. IgG antibodies to parvovirus B19 were present, but there was no evidence of current infection. IgG antibodies to Epstein-Barr virus (EBV) were also found at a low titer in our patient (EBV viral capsid antigen, 1:80; EBV early antigen, 1:20 and Epstein-Barr nuclear antigen, 1:10), as was a very low copy number of EBV DNA by quantitative polymerase chain reaction (100 DNA copies/mL, assay range, 100 10 1 x 10^10 copies/mL). She had an elevated ferritin level. She was started on etoposide and dexamethasone for treatment of HLH, but soon died of multiorgan failure die to sepsis and disseminated intravascular coagulation despite cryoprecipitate and blood product support. Even though the patient had normal fibrinogen levels previously, she had low level (96mg/dL) on the morning of her death. The patient's family declined a postmortem examination. The authors concluded that the patient demonstrated no evidence of either autoimmunity or malignancy despite her marked leukocytosis, EBV was commonly reported to be associated with secondary HLH, but most herpes viruses had been reported to cause this rare syndrome so it was possible that either EBV or herpes simplex virus 1 might have bee the trigger for macrophage activation in this patient. It was of interest, however, that this patient developed a flulike illness 1 month after receiving the H1N1 vaccine. The authors further commented that HLH should be added to the differential diagnosis in a patient with new onset central diabetes insipidus, especially after febrile illness. Whether this patient's illness was related to the vaccination or was purely coincidental was speculative, but worth noting.