Polymyxin B Hemoperfusion in Pediatric Septic Shock: Single-Center Observational Case Series.

OBJECTIVES: To evaluate the use of direct hemoperfusion with polymyxin B-immobilized fiber (PMX-DHP) as adjunctive therapy during pediatric patients with septic shock. DESIGN: Prospective observational study. SETTING: Nine-bed PICUs at university referral hospital. PATIENTS: Children (30 d to 15 yr) with septic shock and Pediatric Logistic Organ Dysfunction (PELOD)-2 score greater than or equal to 10 or Pediatric Risk of Mortality (PRISM) 3 score greater than or equal to 15, who were also receiving at least one inotrope. INTERVENTION: Patients received 2-4 hour treatment with PMX-DHP 20R column on 2 consecutive days. MEASUREMENTS AND MAIN RESULTS: We enrolled six children aged 21-167 months old (median, 99-mo old), with a body weight of 10-50 kg (median, 28 kg). All six patients had both PELOD-2 greater than or equal to 10 and PRISM-3 greater than or equal to 15, required invasive mechanical ventilation, and received standard treatment for septic shock before enrollment. We observed significant improvement in PELOD-2 score from baseline to 72 hours after the start of PMX-DHP (mean [95% CI] from 14.3 [12.2-16.5] to 6.0 [0.3-11.7]; p = 0.006). The vasoactive inotropic score (VIS) and lactate concentration also significantly decreased from baseline to 72 hours (VIS, 60 mmol/L [25-95 mmol/L] to 4.0 mmol/L [44.1-12 mmol/L]; p = 0.003; lactate, 2.4 mmol/L [1.0-3.8 mmol/L] to 1.0 mmol/L [0.5-1.5 mmol/L]; p = 0.01). Five of six patients survived. There was no device-related adverse event in these patients. CONCLUSIONS: In this case series of treatment with PMX-DHP as adjunctive therapy in children with refractory septic shock and high baseline severity, we have shown that patient recruitment is feasible. We have also found that clinical hemodynamic and severity of illness scores at 72 hours may be potential end points for testing in future randomized controlled trials.

The clinical significance of antinuclear antibodies and specific autoantibodies in juvenile and adult systemic lupus erythematosus patients.

BACKGROUND: Juvenile systemic lupus erythematosus (JSLE) and adult SLE (ASLE) patients present with different clinical manifestations, but it is unknown if there are differences in their antinuclear autoantibody (ANA) profiles or if staining patterns are associated with specific autoantibodies and clinical manifestations. OBJECTIVE: To determine whether distinct types and numbers of ANA-staining patterns are associated with specific autoantibodies and clinical manifestations in JSLE and ASLE patients. METHODS: A retrospective study was performed in Thai children (n = 146) and adults (n = 180) diagnosed with SLE using the Systemic Lupus International Collaborating Clinics classification criteria. RESULTS: JSLE patients with a homogeneous pattern of staining and anti-dsDNA or anti-nucleosome antibodies in serum, developed renal involvement, leukopenia and acute/subacute cutaneous LE. Coarse speckled pattern with anti-RNP or anti-Sm showed thrombocytopenia and renal involvement in JSLE patients, but leukopenia in both groups. JSLE patients with fine-coarse speckled pattern and anti-RNP, anti-Sm, anti-Ro-52 or anti-SSA developed leukopenia, thrombocytopenia and renal involvement, whilst hemolytic anemia and serositis were commonly found in those with anti-Ro-52. Median SLEDAI score was higher in JSLE than ASLE patients. CONCLUSIONS: Detailed ANA-staining patterns with specific autoantibodies show particular clinical manifestations and hence prompt further clinical investigations in both JSLE and ASLE patients. Therefore, this study demonstrates that distinct patterns of ANA staining and specific autoantibodies are clinically important in both children and adults with SLE.

Early stage of vascular disease and diabetic kidney disease: an under-recognized entity.

Early stage of vascular disease and diabetic kidney disease (DKD stages 1 and 2) has been under-recognized, under common practice worldwide. The lack of sensitive diagnostic marker leads to late diagnosis and a progression of underlying vascular disease associated with chronic renal ischemia, which eventually intensifies the magnitude of DKD damage. Treatment at this late stage fails to correct the renal ischemia, or restore renal function, due to the altered vascular homeostasis associated with an impaired nitric oxide production. In contrast to the above information, early recognition of vascular disease and DKD with sensitive diagnostic markers would be able to implement an effective prevention of progression of vascular disease and DKD. Treatment at early stage under environment favorable for adequate vascular homeostasis is able to correct the renal ischemia and improve the renal function.

Prevention of bone loss in children receiving long-term glucocorticoids with calcium and alfacalcidol or menatetrenone.

BACKGROUND: Long-term treatment with glucocorticoids can induce bone loss and increase fracture risks. AIM: To compare the efficacy of a 12-month treatment between alfacalcidol and menatetrenone in preventing bone loss in children treated with long-term glucocorticoids. PATIENTS AND METHODS: Twenty children on a stable dosage of glucocorticoids were randomly divided into two groups (alfacalcidol or menatetrenone). Each group received the assigned treatment along with 400 mg of elemental calcium daily for 12 months. Patients receiving medications affecting bone metabolism or patients with impaired kidney function were excluded. Bone density parameters, including lumbar spine bone mineral content (BMC), bone mineral density (BMD), and BMD Z-score were assessed by dual-energy X-ray absorptiometry at baseline and at 12-month follow-up. Bone mineral apparent density (BMAD) was calculated as a size-adjusted measurement of BMD in growing children. Baseline characteristics and bone density parameters were similar between both groups. RESULTS: After 12 months, BMC and BMD were significantly increased from baseline in both groups, but did not differ between the groups. The BMD Z-score at 12-month follow-up was significantly decreased from baseline in the menatetrenone group. BMAD was significantly increased from baseline in the alfacalcidol group. CONCLUSIONS: Administration of long-term glucocorticoids in children justifies an intervention to preserve bone mass. Calcium supplementation along with alfacalcidol can prevent further bone loss to a greater extent than menatetrenone in this group of patients.

Late sequelae of drug reaction with eosinophilia and systemic symptoms (DRESS) cause thyroid dysfunction and thyroiditis: review of literature.

Drug reaction with eosinophilia and systemic symptoms (DRESS) is one of the severe cutaneous adverse drug reactions (SCARs) with high mortality rate and variable long term sequelae, especially in thyroid dysfunction and thyroiditis. In this article, we review clinical course, culprit drugs, onset of diagnosis, and type of thyroid dysfunction in DRESS patients. There were a total of 51 cases including 12 children (aged less than 18 years old) and 39 adults from our review. The most common thyroid dysfunction was Hashimoto's thyroiditis (41/51=80.4%) including anti-thyroid antibody positive (29/51=56.9%), possible/compatible with Hashimoto's thyroiditis (12/51=23.5%) both in the children (n=12) and adult (n=39), Graves' disease/hyperthyroidism (7/51=13.7%) and non-specific hypothyroidism (3/51=5.9%), respectively. The most common culprit drugs and onset of thyroid dysfunction after DRESS diagnosis in children aged less than 18 years include antiepileptic drugs (phenytoin, phenobarbital, carbamazepine) (range 0-8 months, median 2 months) and sulfa groups (sulfasalazine, sulfamethoxazole, sulfonamide) (range 1-4 months, median 2 months). Data of prevalence, type, and clinical course of thyroid dysfunction from DRESS is important for clinicians to recognize for monitoring its sequelae and provide plans for treatment.

Low bone mineral density in Thai children with systemic lupus erythematosus: prevalence and risk factors.

Background: Improvement of disease recognition and management has increased the survival of children with systemic lupus erythematosus (SLE), but has shifted the morbidity focus toward long-term complications, such as low bone mass and osteoporosis. Studies in adults with SLE show older age, chronic inflammation, and corticosteroid therapy are risk factors for low bone mineral density (BMD) and osteoporosis. Objectives: To determine the prevalence of and identify risk factors associated with low BMD in Thai children with SLE. Methods: We conducted a retrospective review of demographic data and clinical variables for a cohort of 60 Thai children with SLE who underwent 2 dual-energy X-ray absorptiometry (DXA) at their initial examination and later follow-up. We considered a BMD z score ≤ -2.0 to indicate low BMD. Binary logistic regression was used to assess risk factors potentially associated with low BMD. Results: The prevalence of low BMD at the first visit was 40% and increased to 55% over follow-up. We found a significantly decreased hip BMD z score (median difference -0.25, 95% confidence interval [CI] -0.40 to -0.05; P = 0.016) and lumbar BMD z score (median difference -0.49, 95% CI -0.69 to -0.28; P < 0.001) over time. The cumulative steroid dose tended to be higher for patients with low BMD (adjusted odds ratio [OR] = 1.08, 95% CI 1.00 to 1.17; P = 0.050). Conclusion: Low BMD has a 40% prevalence in Thai children newly diagnosed with SLE and progresses significantly over time. Higher cumulative corticosteroid dose tended to be associated with a low BMD, but we did not find a significant risk in this small sample.

Anti-neutrophil cytoplasmic antibodies and their clinical significance.

Anti-neutrophil cytoplasmic antibodies (ANCA) are a group of autoantibodies that cause systemic vascular inflammation by binding to target antigens of neutrophils. These autoantibodies can be found in serum from patients with systemic small-vessel vasculitis and they are considered as a biomarker for ANCA-associated vasculitis (AAV). A conventional screening test to detect ANCA in the serum is indirect immunofluorescence study, and subsequently confirmed by enzyme-linked immunosorbent assay. A positive staining of ANCA can be classified into three main categories based on the staining patterns: cytoplasmic, perinuclear, and atypical. Patients with granulomatosis with polyangiitis (GPA) mostly have a positive cytoplasmic staining pattern (c-ANCA) whilst a perinuclear pattern (p-ANCA) is more common in microscopic polyangiitis (MPA) and eosinophilic granulomatosis with polyangiitis (EGPA) patients. Atypical pattern (a-ANCA) is rarely seen in patients with systemic small-vessel vasculitis but it can be found in other conditions. Here, techniques for ANCA detection, ANCA staining patterns and their clinical significances are reviewed.

Oral Ulcers in Juvenile-Onset Systemic Lupus Erythematosus: A Review of the Literature.

Oral ulcers are the most common mucosal sign in juvenile-onset systemic lupus erythematosus (JSLE). The ulcers are one of the key clinical features; however, the terminology of oral ulcers, especially in JSLE patients, is often vague and ill-defined. In fact, there are several clinical manifestations of oral ulcers in JSLE, and some lesions occur when the disease is active, indicating that early management of the disease should be started. Oral ulcers are classified as lupus erythematosus (LE) specific, where the lesional biopsy shows a unique pattern of mucosal change in LE, and LE nonspecific, where the ulcers and their histopathological findings can be found in other oral diseases. Here, the clinical manifestations, diagnosis and management of oral ulcers in JSLE patients are reviewed.

Fractional excretion magnesium (FE Mg) in systemic lupus erythematosus.

BACKGROUND: Tubulointerstitial fibrosis is an index of clinical severity. FE Mg has been delineated to correlate directly with the magnitude of tubulointerstitial fibrosis in clinical setting of glomerulonephropathy. A correlation between FE Mg tubulointerstitial fibrosis has never been assessed in nephritis associated with systemic lupus erythematosus. MATERIAL AND METHOD: Thirty-six patients diagnosed of having lupus nephritis were included for the determination of renal functions namely creatinine clearance, FE Mg, urinary protein. Of these 36 patients, 18 patients were associated with intact tubulointerstitial structure (group I) and 18 age matched patients were associated with tubulointerstitial fibrosis (group II) RESULTS: The mean FE Mg observed in group I was 1.5 +/- 0.3 which differed significantly from that observed in group II; 2.6 +/- 1; p = 0.006. CCr, total urinary protein, systolic and diastolic pressure were not significantly different between the two groups. CONCLUSION: FE Mg is a sensitive marker for the detection of tubulointerstitial disease in lupus nephritis. It is useful in early screening of disease severity in systemic lupus erythematosus.

The protective effect of GM-CSF on serum-induced neutrophil apoptosis in juvenile systemic lupus erythematosus patients.

Juvenile systemic lupus erythematosus (JSLE) is one of the most common autoimmune diseases in children and can affect multiple organs and systems. The etiology remains unclear, and current management only suppresses rather than eliminates the disease. The pathogenesis is triggered by autoantigens that induce autoantibody production. Apoptotic neutrophils may be one source of autoantigens in JSLE, and increased numbers of apoptotic neutrophils in JSLE have been reported. This study aimed to determine if factor(s) in JSLE serum induce neutrophil apoptosis, to identify the most potent cytokine in delaying neutrophil apoptosis, and to investigate whether this cytokine can reverse the pro-apoptotic effects of JSLE serum. Blood neutrophils and sera were collected from JSLE patients, healthy children and adult controls. Neutrophils from healthy adult controls were incubated with 10 % serum from either JSLE patients or pediatric controls. Neutrophils from healthy adult controls were also incubated with 10 % JSLE serum with or without granulocyte-macrophage colony-stimulating factor (GM-CSF) supplementation. Neutrophil apoptosis was measured by flow cytometry (annexin-V/propidium iodide staining). Caspase-3, caspase-7 and caspase-8 protein expression was detected using Western blotting. Neutrophils incubated with JSLE sera had significantly increased apoptosis at 6 h compared to those incubated with control sera. Cleaved (active) forms of caspase-3, caspase-7 and caspase-8 were identified in neutrophils incubated with JSLE sera (that showed high rates of apoptosis) compared to control sera. GM-CSF had the most protective effect on neutrophil apoptosis, significantly preventing neutrophil apoptosis and caspase activation induced by JSLE serum. JSLE serum significantly induced neutrophil apoptosis in healthy adult neutrophils, activating the extrinsic pathway of apoptosis. The observation that GM-CSF prevents activation of apoptosis in response to JSLE serum should prompt further studies to evaluate the therapeutic potential of this cytokine for the treatment of JSLE.

Acute renal failure in a child with jellyfish contact dermatitis.

A 7-year-old boy suffered from jellyfish contact dermatitis and acute renal failure following a jellyfish sting. Three days before being admitted, he accidentally contacted a jellyfish on the left forearm, left thigh and trunk while wading at Pattaya beach, Eastern Thailand. Investigation revealed hemoglobinuria. Histologic findings of a renal biopsy indicated that acute tubular necrosis had caused acute renal failure in the present patient. Supportive treatments improved the dermatitis and renal function of this patient.

Novel AQP2 mutation causing congenital nephrogenic diabetes insipidus: challenges in management during infancy.

Congenital nephrogenic diabetes insipidus (NDI) is a rare inherited disorder, mostly caused by AVPR2 mutations. Less than 10% of cases are due to mutations in the aquaporin-2 (AQP2) gene. Diagnosis and management of this condition remain challenging especially during infancy. Here, we report two unrelated patients, a 6-month-old Thai boy and a 5-year-old Emirati girl, with a history of failure to thrive, chronic fever, polydipsia, and polyuria presented in early infancy. The results of water deprivation test were compatible with a diagnosis of NDI. The entire coding regions of the AVPR2 and AQP2 gene were amplified by polymerase chain reaction and sequenced. Patient 1 was homozygous for a novel missense AQP2 mutation p.G96E, inherited from both parents. Patient 2 harbored a previously described homozygous p.T126M mutation in the AQP2 gene. Both patients were treated with a combination of thiazide diuretics and amiloride. Patient 1 developed paradoxical hyponatremia and severe dehydration 2 weeks after medical treatment began. In conclusion, we report a novel mutation of the AQP2 gene and highlight an important role of genetic testing for definite diagnosis. Vigilant monitoring of the fluid status and electrolytes after beginning the therapy is mandatory in infants with NDI.

DcR3 mutations in patients with juvenile-onset systemic lupus erythematosus lead to enhanced lymphocyte proliferation.

OBJECTIVE: Previous studies suggested a role for the death decoy receptor 3 (DcR3) in the pathogenesis of adult systemic lupus erythematosus (SLE). We investigated the role of DcR3 in juvenile-onset SLE, to identify polymorphisms that might alter the function of this protein. METHODS: DcR3 was measured in the serum of 61 patients with juvenile SLE. The coding region of the DcR3 gene was sequenced in 100 juvenile and 103 adult patients with SLE, together with 500 healthy controls. RESULTS: DcR3 was elevated in the serum of juvenile patients with active SLE disease (440.8 ± 169.1 pg/ml), compared to patients with inactive disease (122.6 ± 28.05 pg/ml; p = 0.0014) and controls (69.27 ± 20.23 pg/ml; p = 0.0009). DNA sequencing identified 2 novel missense mutations: c.C167T (p.T56I) in an adult SLE patient and c.C364T (p.H122Y) in a juvenile patient. Recombinant proteins containing these mutations exhibited altered binding kinetics to FasL and they significantly increased lymphocyte proliferation, compared to the wild-type protein (p < 0.05). The adult patient with SLE carrying the p.T56I mutation had significantly increased lymphocyte proliferation compared to 3 SLE controls matched for age, sex, and disease severity. CONCLUSION: DcR3 may play an etiologic role in SLE through either elevated serum levels of wild-type DcR3 or normal levels of gain-of-function DcR3 proteins that increase lymphocyte proliferation.

Two novel CTNS mutations in cystinosis patients in Thailand.

Cystinosis is an autosomal recessive disorder characterized by defective transport of cystine across the lysosomal membrane and resulting in renal, ophthalmic, and other organ abnormalities. Mutations in the CTNS gene cause a deficiency of the transport protein, cystinosin. We performed mutation analysis of CTNS in six cystinosis patients from four families in Thailand. Using PCR sequencing of the entire coding regions, we identified all eight mutant alleles, including two mutations, p.G309D and p.Q284X, that have not been previously reported. This study expands the mutational and population spectrum of nephropathic cystinosis.

A biomarker for detecting early tubulointerstitial disease and ischemia in glomerulonephropathy.

Present diagnostic tests such as serum creatinine determination and creatinine clearance are unable to reflect early tubulointerstitial disease. Because a kidney biopsy cannot be performed in every single patient, tubular epithelial function (namely, the fractional excretion of magnesium; FE Mg) that correlates directly with the degree of tubulointerstitial fibrosis would serve this purpose. FE Mg is normal in acute post-streptococcal glomerulonephritis and mesangial proliferative nephrosis with intact tubulointerstitial structure, and is abnormally elevated in nephrosis with focal segmental glomerulosclerosis (FSGS) and in chronic kidney diseases in which kidney biopsies have been obtained. FE Mg is useful in the screening of tubulointerstitial disease in patients when indication for kidney biopsy in not fulfilled, such as diabetic patients or patients with microscopic proteinuria, hematuria, and hypertension. Altered FE Mg is usually associated with a reduction in peritubular capillary flow. There is a linear correlation between FE Mg and peritubular capillary flow, which supports the chronic ischemic injury inducing altered tubular function and tubulointerstitial fibrosis.

Mucocutaneous findings in pediatric AIDS related to degree of immunosuppression.

The normal value of the absolute CD4-positive T-lymphocyte count is relatively high in normal infants and declines steadily until 6 years of age, whereas the CD4 percentage of the total lymphocyte count is constant. The immunologic categories according to the 1994 revised pediatric human immunodeficiency virus (HIV) classification, based on CD4-positive percentage of the total lymphocyte count, is classified into three categories: no evidence of suppression (> or =25%), moderate suppression (15-24%), and severe suppression (1-14%). Our objective was to determine the prevalence of mucocutaneous findings in pediatric acquired immunodeficiency syndrome (AIDS) related to the degree of immunosuppression. We prospectively examined 120 children less than 13 years of age who were born to HIV-seropositive women and developed definite HIV infection. The prevalence of mucocutaneous findings in those children who had severe, moderate, and no evidence of immunosuppression were 62%, 43%, and 20%, respectively. The mucocutaneous findings in patients in the moderate and severe suppression groups were significantly more common than in patients without evidence of immunosuppression (p < 0.001). In the moderate immunosuppression group, 11% had two mucocutaneous findings while 21% in the severe immunosuppression group had two or more mucocutaneous findings. The most common mucocutaneous finding was oral candidiasis (33%), which had a mean corresponding CD4 percentage of the total lymphocyte count of 11.3%. Herpes zoster was found in 6% of the patients (mean CD4 percentage of the total lymphocyte count = 13.5%). Chronic herpes simplex virus (HSV) stomatitis was found in 3% of the patients (mean CD4 percentage of the total lymphocyte count = 3%). Mucocutaneous manifestations are common in pediatric AIDS. The majority of these findings have an infectious etiology. The prevalence increases as the CD4-positive percentage of the total lymphocyte count decreases. More than one mucocutaneous finding can be found at the same time in patients with moderate or severe immunosuppression.