James Yun

Poor positive predictive value of serum immunoglobulin G4 concentrations in the diagnosis of immunoglobulin G4-related sclerosing disease

Background Immunoglobulin G4 (IgG4)-related sclerosing disease is a recently described clinicopathological entity with diverse manifestations including, amongst others, autoimmune pancreatitis, sclerosing cholangitis, sclerosing sialadenitis and retroperitoneal fibrosis. Elevated serum IgG4 concentration has been described as the hallmark of this condition with reported good sensitivity and specificity. Objective We sought to establish the utility of serum IgG4 concentrations in the diagnosis of IgG4-related sclerosing disease by determining how many serum samples with elevated IgG4 from an unselected population would originate from patients who fulfilled criteria for this diagnosis. Methods The clinical features and laboratory characteristics of patients whose serum IgG4 concentration was greater than 1.30 g/L were analysed retrospectively from a total of 1,258 IgG subclass measurements performed in a tertiary hospital diagnostic laboratory. Results Eighty patients (6.4%) had elevated IgG4 concentrations greater than 1.30 g/L. Nine of 61 patients had the diagnosis of IgG4-related sclerosing disease, giving a poor positive predictive value of 15%. The median serum IgG4 concentrations of those with and without IgG4-related sclerosing disease were 2.16 g/L and 1.86 g/L, respectively (p = 0.22). Conclusion Serum IgG4 concentration has poor positive predictive value in the diagnosis of IgG4-related sclerosing disease and, therefore, the clinical significance of elevated serum IgG4 concentration alone must be interpreted with caution.

Multiple Drug Hypersensitivity

Multiple drug hypersensitivity (MDH) is a syndrome that develops as a consequence of massive T-cell stimulations and is characterized by long-lasting drug hypersensitivity reactions (DHR) to different drugs. The initial symptoms are mostly severe exanthems or drug rash with eosinophilia and systemic symptoms (DRESS). Subsequent symptoms due to another drug often appear in the following weeks, overlapping with the first DHR, or months to years later after resolution of the initial presentation. The second DHR includes exanthema, erythroderma, DRESS, Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN), hepatitis, and agranulocytosis. The eliciting drugs can be identified by positive skin or in vitro tests. The drugs involved in starting the MDH are the same as for DRESS, and they are usually given in rather high doses. Fixed drug combination therapies like sulfamethoxazole/trimethoprim or piperacillin/tazobactam are frequently involved in MDH, and 30-40% of patients with severe DHR to combination therapy show T-cell reactions to both components. The drug-induced T-cell stimulation appears to be due to the p-i mechanism. Importantly, a permanent T-cell activation characterized by PD-1+/CD38+ expression on CD4+/CD25low T cells can be found in the circulation of patients with MDH for many years. In conclusion, MDH is a drug-elicited syndrome characterized by a long-lasting hyperresponsiveness to multiple, structurally unrelated drugs with clinically diverse symptoms.

Mannitol-induced hyperosmolal hyponatraemia

Mannitol is a metabolically inert agent that can be used therapeutically to decrease intracranial pressure in cerebral oedema and intraocular pressure in glaucoma. This article reports a case of mannitol-induced hyperosmolal hyponatraemia. A 77-year-old woman with raised intraocular pressure after cataract surgery was admitted for multiple eye drops and mannitol infusion. Her past history included congestive cardiac failure, hypertension and mild renal impairment with baseline creatinine of 136 lmol/L. Her regular medications included captopril and frusemide. Over a period of 3 days, she received intravenously a total of approximately 2.5 L of 20%mannitol. Ibuprofen was also prescribed simultaneously for musculoskeletal pain. On day 4, she developed confusion, dyspnoea and anuria. Her clinical findings were consistent with that of acute pulmonary oedema. Investigations showed serum sodium of 112 mmol/L, urea of 13.3 mmol/L, creatinine of 282 lmol/L and calculated serum osmolality of 247 mOsm/kg. That same afternoon, she developed multiple seizures requiring urgent ventilation in an intensive care unit. She was treated with 3% hypertonic saline and i.v. frusemide. Her serum sodium increased to 119 mmol/L the next day, but she continued to have seizures and she became anuric. Her measured serum osmolality was 326 mOsm/kg, giving an osmolal gap (measured serum osmolality 2 calculated serumosmolality) of 79 mOsm/kg. This finding was consistent with hyperosmolal hyponatraemia secondary to mannitol intoxication. She was treated by haemodiafiltration over the next 48 h, and her serum sodium and measured osmolality gradually improved to 136 mmol/L and 316 mOsm/kg, respectively. Her seizures stopped, and she started to pass urine. She recovered completely without any neurological deficits and, on discharge, her serum creatinine had returned to baseline level. Mannitol accumulation in the blood leads to increased serum osmolality, osmotic movement of water out of cells and hyponatraemia secondary to dilution. As mannitol and glucose have a similar molecular weight, it is assumed that for every rise in3.5 mmol/Lof serummannitol, serum sodium will fall by 1 mmol/L. In our patient with an osmolar gap of 79, her expected serum sodium level was calculated to be 118 mmol/L (140(normal sodium level) 2 79/3.5(expected sodium level fall)), and this correlated verywell with the patient’s serum sodium of 119 mmol/L, thus supporting a diagnosis of mannitol-induced hyponatraemia. Thedevelopment of hyponatraemia in amannitol recipient should be an early warning sign of mannitol accumulation. It is important toappreciate that,unlikemanyothercauses of hyponatraemia, mannitol poisoning results in hypertonicity rather thanhypotonicity, and this canplace thepatient at risk of cerebral dehydration rather than cerebral oedema. Hence, administration of hypertonic solution may worsen cerebral dehydration. Thedefinitive treatment formannitol poisoning is urgent removal with haemodialysis. Themechanismof acuteoliguric renal failure inmannitol poisoning is unclear but may be because of a combination of intense mannitol-induced renal vasoconstriction and direct tubular toxicity. As mannitol is excreted exclusively by the kidney, its accumulation in renal failure will further worsen renal function, thus making prompt haemodialysis the most appropriate treatment in such a circumstance.

Dapsone-induced drug reaction with eosinophilia and systemic symptoms associated with HLA-B*13:01: Letters to the Editor

A 45-year-old Korean-born man presented with a 7-day history of a pruritic generalised maculopapular exanthema, sore throat and non-productive cough. The symptoms started 10 weeks after commencing dapsone 100 mg daily for acne. He ceased dapsone himself a few days prior to his hospital presentation as he felt ‘unwell’. On examination, he had fever 38.2 C, a maculopapular rash and widespread lymphadenopathy. His C-reactive protein was 37 mg/L (normal range < 5), his liver function tests were abnormal with alkaline phosphatase of 208 unit/L (normal range = 41–119), gamma glutamyl transferase of 317 unit/L (normal range = 12–64), alanine aminotransferase of 234 unit/L (normal range < 55) and AST of 76 unit/L (normal range = 12–36). He had a lymphocytosis at 9.9x10/L (normal range = 1.0–4.0) and significant eosinophilia at 2.7x10/L (normal range < 0.5). His blood film showed atypical lymphocytes. Blood and urine cultures were negative. After an initial clinical improvement with prednisone 60 mg daily, the patient had a partial relapse 2 weeks later due to rapid weaning of the prednisone. Subsequently, he was diagnosed with drug reaction with eosinophilia and systemic symptoms (DRESS). He was restarted on prednisone 35 mg daily with rapid symptomatic and biochemical improvement (Fig. 1). Prednisone was gradually weaned

Morphine and pholcodine‐specific IgE have limited utility in the diagnosis of anaphylaxis to benzylisoquinolines

Investigation of immediate hypersensitivity reactions in the perioperative setting involves skin testing and measurement of specific IgE (sIgE) as standard practice. In the case of the neuromuscular blocking agents (NMBAs), the main allergenic epitopes have been shown to be substituted ammonium groups. Commercial assays are available for detection of sIgE to these epitopes using morphine and pholcodine substrates but questions have been raised about the effectiveness of these assays in the diagnosis of benzylisoquinoline anaphylaxis. This study was therefore undertaken to assess the effectiveness of these assays in the diagnosis of hypersensitivity reactions to this group of NMBAs.

P44: SPECIFIC IGE TO GALACTOSE-ALPHA-1,3-GALACTOSE (ALPHA-GAL) DOES NOT ADD TO THE DIAGNOSIS OF MAMMALIAN MEAT ALLERGY IN A TICK-ENDEMIC POPULATION

Background: The clinical manifestations of mammalian meat allergy (MMA) are varied, encompassing urticaria, angioedema, gastrointestinal symptoms and anaphylaxis. Diagnosis is difficult based on clinical history alone as there are many differential diagnoses to exclude. Specific IgE (sIgE) to alpha-gal is considered a useful diagnostic test. Sensitisation to alpha-gal is considered a prerequisite to MMA. In Australia, one major mechanism is through tick bites from Ixodes holocyclus.