HLH Syndrome in a Community Hospital: The Challenge of an Early Diagnosis.

Introduction: Hemophagocytic lymphohistiocytosis (HLH) is a potentially fatal hyperinflammatory cytokine storm. It can be secondary to infections, malignancies, autoimmune diseases, or the manifestation of genetic disorders, including primary immune deficiency. HLH requires a high index of suspicion and is challenging for community hospitals. Methods: Medical records of children with HLH admitted to the Meir Medical Center in Israel between 2014 and 2017 were reviewed. Results: Nine children met ≥5/8 HLH-2004 criteria. The median age was 1.1 year, and 78% of the patients were aged <2 years. All patients had prolonged fever, cytopenia, and elevated soluble interleukin-2 receptor, and 89% had elevated ferritin levels. Of three children who underwent gene panel evaluation, one had heterozygote genetic variants of UNC13D and STXBP2 of unclear significance, whereas the other two had no variants. Infection was identified in 8 of 9 patients: adenovirus, HHV6, EBV, and Streptococcus Group A. Only 2 patients received HLH-2004 therapy (dexamethasone, etoposide, cyclosporin-A) and the others received dexamethasone and/or intravenous gamma globulins (IVIG), with rapid resolution of fever (median 2 days). One patient (11%) died of Pseudomonas septicemia and multiorgan failure. At a median follow-up of 7 years (range 2.6-8.1 years), all others (8/9) are long-term survivors with no recurrent HLH, but 2 patients developed adenovirus-related bronchiolitis obliterans. Conclusion: Children presenting with prolonged fever and abnormal blood counts should be evaluated with ferritin, triglycerides, and fibrinogen levels which indicate possible HLH. Early intervention with corticosteroids and/or IVIG may prevent deterioration, spare them from chemotherapy and provide time for more elaborate testing to identify true HLH. Unfortunately, mortality remains a significant risk for these children.

In the emergency department, children with common infections may have a severe complication called Hemophagocytic Lymphohistiocytosis or HLH. HLH can be life threatening if not rapidly recognized. HLH is rare and challenging for doctors in community hospitals. We describe nine patients who presented to a community hospital who were later diagnosed with HLH, posing a dilemma for physicians. Most (78%) were less than 2 years, all had prolonged fever, abnormal blood counts, elevated marker of HLH called soluble interleukin­2 receptor and 8 of 9 had elevated ferritin, which can be a marker of HLH. HLH could be genetic therefore three children had genetic studies, with one having minor abnormalities, but the contribution to HLH is unclear. Infection as cause for HLH was identified in 8 of 9 patients. Chemotherapy that is used for severe HLH was required for 2 patients and the others received steroids and/or intravenous gamma globulin with rapid improvement. One patient who received chemotherapy and had suppressed immunity died of a severe bacterial infection. Others (8 of 9) are long-term survivors with no evidence of recurrent HLH. Two patients developed a pulmonary complication from adenovirus known as bronchiolitis obliterans. We conclude that children presenting with prolonged fever and abnormal blood counts should be evaluated with ferritin and other markers of possible HLH. Early intervention may prevent deterioration, may spare them from chemotherapy, and allow further assessment of true HLH. However, the death of one (11%), demonstrates the significant risks to these children.

Subcutaneous fat necrosis and hypercalcemia following therapeutic hypothermia--a patient report and review of the literature.

Subcutaneous fat necrosis (SCFN) of the newborn is an uncommon dermatologic disorder characterized by firm, palpable subcutaneous nodules or plaques with or without erythema. Despite its benign course, SCFN may become complicated by extracutaneous manifestations. Hypercalcemia is considered a rare complication, but it is potentially fatal if unrecognized. During the last several years therapeutic hypothermia (TH) became an essential new therapeutic modality for severe neonatal asphyxia. We report a neonate who presented with SCFN and hypercalcemia following hypothermia therapy for hypoxic ischemic encephalopathy (HIE) and provide a review of the contemporary literature on the topic. We believe that this is important since the use of TH is rapidly increasing, and therefore, the possible side effects including SCFN and hypercalcemia may also become more prevalent. This prompts the need for awareness by treating physicians for this complication.

Juvenile polymyositis associated with ureteral necrosis: a diagnostic and therapeutic dilemma-case report and review of the literature.

We describe an 11-year-old girl, diagnosed with juvenile polymyositis (JPM), who developed right ureteral obstruction secondary to necrosis. We emphasize the dilemmas regarding optimal timing for surgical intervention and medical treatment. Vascular involvement, which could be a part of juvenile dermatomyositis, may also be a feature of JPM. We discuss the association between vasculopathy and ureteral necrosis and review the literature regarding similar conditions. Whether the ureteral necrosis is a specific feature of vasculopathy, or a result of visceral calcinosis, needs to be further explored.

Rhinovirus infections in infants suggest that early detection can prevent unnecessary treatment.

BACKGROUND: Human rhinoviruses (hRV) are small, RNA viruses of the Picornaviridae family, which are divided into three subtypes (A, B, C). hRVs are among the most common causes for acute respiratory illnesses (ARI) involving both the upper and lower respiratory tract. OBJECTIVES: This study aimed to assess the magnitude and characteristics of hRV infections in hospitalized children, aged less than 5 years, hospitalized in Israel during 2011-2012. STUDY DESIGN: The 2503 respiratory samples were subjected to real-time PCR, to detect hRV and other respiratory viruses. Rhinovirus-positive samples were further tested by sequencing to identify the infecting species. RESULTS: Of these 2503 respiratory samples, 422 tested positive for hRV, of them, 243 were from children under 5 years of age (58% of all rhinoviral-positive samples). We also found that among the ARI-associated hospital admissions, 16% were positive for rhinovirus. hRV type A was the most common species. Laboratory data showed monocytosis in 51%, hypercalcemia in 61% and lower respiratory tract involvement in 75% of patients. CONCLUSIONS: We thus recommend including rhinovirus testing as part of the routine testing performed in young children presenting with ARI.

Henoch-Schonlein purpura antecedent to Crohn's disease.

We report a 13-year-old youth who initially presented with the typical rash of Henoch-Schonlein purpura followed a month later by a nephrotic syndrome and hematuria. Renal biopsy revealed crescentic IgA nephropathy. The patient was aggressively treated with steroids leading to a remission of his nephrotic syndrome. Three years after his initial presentation, he developed bloody diarrhea and Crohn's disease was diagnosed.

Increased sodium concentrations in drinking water increase blood pressure in neonates.

BACKGROUND: In a previous study, we found that increased sodium concentrations in the drinking water led to an increase in mean arterial pressure (MAP) and systolic blood pressure (SBP) in fourth- and fifth-grade school children. Milk powder formulae have a low content of sodium, almost identical to that of breast milk. However, the final sodium concentration in the milk formula depends upon the concentration of sodium in the diluting water, which varies remarkably. OBJECTIVE: To evaluate changes in blood pressure during the first 2 months of life in neonates receiving low-sodium mineral water (LSMW), high-sodium tap water (HSTW), or breast milk. DESIGN: A randomized, prospective study in a teaching hospital. METHODS: Fifty-eight Jewish term infants maintained on milk formula were randomly assigned to two groups. Group 1 consisted of 25 infants whose formula was diluted with LSMW (Eden Spring Mineral Water) having a sodium concentration of 32 mg/l (1.4 mmol/l). Group 2 contained 33 infants whose formula was diluted with HSTW having a sodium concentration of 196 mg/l (8.5 mmol/l). Fifteen breastfed babies served as the control group (group 3). Weekly weight, height, head circumference, heart rate, and systolic (SBP), diastolic (DBP) and mean (MAP) blood pressures were recorded for each infant for 8 consecutive weeks after birth. After 8 weeks, group 1 reverted to a diet similar to that of group 2. At 6 months of age (week 24), a follow-up blood pressure measurement was performed in 11, 20 and seven infants in groups 1, 2 and 3, respectively. Blood pressure was measured during sleep. Urinary sodium : creatinine ratio was determined monthly during the initial 2 months. RESULTS: Increases in weight and height were equal in all groups. Heart rate did not differ between groups during the entire study period. From the age of 6 weeks until week 8, MAP, SBP and DBP were found to be significantly greater in the group 2 (HSTW). In parallel, the urinary sodium : creatinine ratio was significantly greater in this group. At week 24, blood pressure values in group 1 increased towards those of group 2. CONCLUSIONS: Diluting milk formula with tap water containing a high concentration of sodium will result in the infant being fed a high-salt diet. To equilibrate with breast milk, formula should be diluted with low-salt water. Blood pressure in the neonate is increased by a high sodium intake via drinking water.

Urinary tract infection in very low birth weight preterm infants.

BACKGROUND: The prevalence of urinary tract infection (UTI) in preterm neonates ranges between 4 and 25%. The need for a radiologic investigation has not yet been established in very low birth weight premature newborns (<1500 g birth weight). PATIENTS AND METHODS: For an 11-year period (1990 to 2001), medical records of 62 very low birth weight premature infants admitted to a Level III neonatal intensive care unit and who developed UTI were reviewed retrospectively. Results of renal ultrasound and voiding cystourethrograms were compared between extremely low birth weight infants (birth weight, <1000 g) (Group A, Patient 34) and premature infants with birth weight between 1001 and 1500 g (Group B, Patient 28). RESULTS: UTI was more common in Group A (12.2%) than in Group B (5.7%) infants. Renal ultrasound detected mild renal pelvic dilatation (unilateral or bilateral) in 9 infants in Group A (26%) and in 1 infant in Group B (3.5%). Voiding cystourethrograms were performed in 26 of 34 (76%) infants in Group A and in 17 of the 28 (61%) premature infants in Group B. Vesicourethral reflux (VUR) was observed in 6 infants, 2 in group A (7.7%) and 4 in Group B (23%). CONCLUSIONS: We found that the rate of VUR was lower in very low birth weight premature newborns than that reported in the medical literature among term newborns who developed UTI. VUR was less frequent in extremely low birth weight infants who developed UTI than in infants weighing 1001 to 1500 g.

Effect of tetrahydrobiopterin on blood pressure in rats after subtotal nephrectomy.

BACKGROUND: Previous studies have shown that endothelial dysfunction after 5/6 nephrectomy (5/6 Nx) in rats is associated with decreased nitric oxide (NO) bioavailability and increased vascular superoxide production. Blood pressure is significantly increased by day 10 after surgery. Tetrahydrobiopterin (BH4) is a key cofactor of NO synthase. Suboptimal levels of BH4 result in uncoupling of NO synthase, low NO synthesis and augmented production of superoxide anions. The aim of this study was to evaluate whether BH4 supplementation may improve NO production and prevent the increase of blood pressure after 5/6 Nx. METHODS: Three groups were evaluated: 5/6 Nx (untreated rats), BH4 (5/6 Nx rats treated with BH4, 10 mg/day i.p. for 10 days) and L-ARG (5/6 Nx rats treated with L-arginine, 260 mg/kg BW, p.o for 10 days). Systolic blood pressure (SBP), urinary nitrate excretion (UNO(3)) and creatinine clearance (CCR) were measured before surgery and on days 3 and 10 after surgery. Endothelial NO synthase (eNOS) protein content of mesenteric resistance vessels was measured at the end of the study. RESULTS: SBP increased from 107 +/- 2 to 127 +/- 4 mm Hg in untreated 5/6 Nx rats (p < 0.01). By contrast, rats treated with BH4 or L-ARG remained normotensive. Ten days after 5/6 Nx, creatinine clearance decreased similarly in all groups. Both BH4 and L-ARG supplementation markedly increased UNO(3) excretion. The mesenteric vascular expression of eNOs protein was significantly higher in BH4 but not in L-ARG, compared with Nx rats. CONCLUSIONS: BH4 supplementation prevents the earlier increase in blood pressure observed in rats after 5/6 Nx, possibly by upregulating eNOS in resistance vessels.

[Acute acquired non-traumatic torticollis in hospitalized children].

BACKGROUND: The inflammatory process in torticollis involves the cervical muscles, nerves, and/or the vertebral synovia causing painful and abnormal head position. Most cases of acute acquired non-traumatic torticollis are of benign etiology, but some patients may suffer from a serious disease requiring thorough investigation and hospitalization. OBJECTIVES: To describe the epidemiology, clinical features and the etiology of acute acquired non-traumatic torticollis in our center. METHODS: A retrospective chart review of 45 hospitalized children in the Sapir Medical Center over a 10 year period. RESULTS: We studied 45 children; 23 girls and 22 boys. Their mean age was 6 years (range 6 months to 16 years). All patients reported marked neck pain as their main complaint. Local infection was the most frequent etiology, and 33 (73%) patients were hospitalized during the fall-winter season. Twenty six patients underwent x-ray imaging, and of these, ten (38%) had pathology. The main findings were some degree of atlanto-axial subluxation, and widening of the prevertebral space. Treatment included analgesic and antibiotics for suspected bacterial infections. Two patients required surgical drainage. Cervical neck traction was performed on 15 patients. Mean admission time was 4.1 days and was shorter in the pediatric department compared to the ENT and orthopedic departments. CONCLUSIONS: Careful clinical and radiological evaluation for the wide spectrum of clinical entities should be done. Local infections of the respiratory tract are the most common etiology. Conservative treatment usually leads to complete resolution in a short time.

Effect of honey on nocturnal cough and sleep quality: a double-blind, randomized, placebo-controlled study.

OBJECTIVES: To compare the effects of a single nocturnal dose of 3 honey products (eucalyptus honey, citrus honey, or labiatae honey) to placebo (silan date extract) on nocturnal cough and difficulty sleeping associated with childhood upper respiratory tract infections (URIs). METHODS: A survey was administered to parents on 2 consecutive days, first on the day of presentation, when no medication had been given the previous evening, and the following day, when the study preparation was given before bedtime, based on a double-blind randomization plan. Participants included 300 children aged 1 to 5 years with URIs, nocturnal cough, and illness duration of ≤ 7 days from 6 general pediatric community clinics. Eligible children received a single dose of 10 g of eucalyptus honey, citrus honey, labiatae honey, or placebo administered 30 minutes before bedtime. Main outcome measures were cough frequency, cough severity, bothersome nature of cough, and child and parent sleep quality. RESULTS: In all 3 honey products and the placebo group, there was a significant improvement from the night before treatment to the night of treatment. However, the improvement was greater in the honey groups for all the CONCLUSIONS: Parents rated the honey products higher than the silan date extract for symptomatic relief of their children's nocturnal cough and sleep difficulty due to URI. Honey may be a preferable treatment for cough and sleep difficulty associated with childhood URI.

Isolated severe renal injuries after minimal blunt trauma to the upper abdomen and flank: CT findings.

Renal injuries caused by blunt abdominal trauma are common in children. Serious renal trauma is associated with insult to other organs, whereas isolated renal injuries are usually minor. We present the cases of six male children (aged 7-17 years) with major isolated renal injuries due to minimal blunt trauma to the upper adbomen and/or the flank, out of a total of 21 children admitted with renal trauma in a 5-years period. On physical examination all patients had a painful, tender abdomen and/or flank with ipsilateral bruises and ecchymosis. Hematuria, either macro ( n=4) or micro ( n=2), was found in all. The injuries were left-sided in five and were of a variable severity (grade III: n=2; grade IV: n=3; grade V: n=1 according to the kidney injury scale of the American Association for the Surgery of Trauma). Four children underwent nephrectomy. This small series underlines that major kidney insult can occur after a minimal blunt trauma localized to the flank or upper abdomen. Abdominal CT should be performed when clinical or laboratory findings or the mechanism of trauma suggest renal injury.

Ambulatory blood pressure monitoring in children with isolated haematuria.

Ambulatory blood pressure monitoring (ABPM) was performed in 29 children, ages 8.5-10.5 years (mean 11.6+/-3.0) with isolated haematuria (IH) and in 27 age, sex, weight and height matched healthy controls (C). Isolated haematuria was defined as >or=5 RBC/HPF on three separate urinalyses over a 3-month period with normal renal function, a normal appearing ultrasound examination of the kidneys and the absence of hypercalciuria. Haematuria had been documented for at least 3 years prior to ABPM. Daytime and nighttime periods were 0800-2200 and 2200-0800 hours, respectively. The total number of successful blood pressure readings was 21.8 and 20.7 per subject (90.0 and 86.1% of all attempted measurements) in IH and C, respectively. Mean 24-h, daytime and nighttime heart rate, mean arterial pressure, and systolic and diastolic blood pressure in IH did not differ from that of controls. Nocturnal dipping was present in all IH patients and was of equal magnitude to C (9.5 vs 8.4 and 13.7 vs 10.3% for average systolic blood pressure (SBP) and diastolic blood pressure (DBP) dips, respectively). We conclude that normal blood pressure values, as well as the circadian rhythm of blood pressure, are maintained in children with IH of at least 3 years' duration.

Fetal urinoma as a sign of a dysplastic kidney.

We describe a female neonate in whom a urinoma was first diagnosed at 20 weeks of gestation without any evidence of underlying urinary tract obstruction. The urinoma became apparent following the performance of a "bloody tap" amniocentesis. Sequential ultrasonography, both fetal and up to 3 months after birth, showed eventual resorption of the urinoma in parallel with the development of a shrunken, non-functioning kidney. Except for the onset of high-renin hypertension, which spontaneously remitted at 1 year of age, the baby's postnatal course was uneventful. Renal function was normal. The presence of a fetal urinoma as a sign of a dysplastic kidney is discussed.