Luke Y. C. Chen

Hemophagocytic syndromes (HPSs) including hemophagocytic lymphohistiocytosis (HLH) in adults: A systematic scoping review.

Most knowledge of hemophagocytic syndromes (HPSs) including hemophagocytic lymphohistiocytosis (HLH) is derived from pediatric studies; literature on adult HPS/HLH predominantly consists of small retrospective studies with clinical and methodological heterogeneity. The aims of this systematic scoping review were to provide an overview of existing literature on adult HPS/HLH, describe current practices in diagnosis and treatment, and propose priorities for future research. Articles from Ovid Medline, Embase and Pubmed (1975-2015) describing 10 or more unique adults (age>15years) with HPS/HLH were included. 82 publications were eligible: 10 were prospective and 72 were retrospective. Of the six distinct diagnostic criteria, the HLH-2004 criteria were by far the most commonly used. A minority of studies tested for genetic abnormalities (12), soluble interleukin-2 receptor (11), and/or NK function (11) in a subset of patients. Most centers used steroids and either etoposide-based (HLH-94/HLH-2004) or doxorubicin-based (CHOP) initial therapy regimens. Allogeneic hematopoietic cell therapy for treatment of adult HLH has rarely been reported. Mortality in larger treatment focused studies ranged from 20 to 88%. Developing adult-specific diagnostic criteria based on widely evaluable features of secondary HPS/HLH and establishing standard initial therapies are priorities for future research.

IgG4‐related disease with hypergammaglobulinemic hyperviscosity and retinopathy

Immunoglobulin G4‐related disease (IgG4‐RD) is a recently described entity with protean manifestations. We describe a novel case of IgG4‐RD with hypergammaglobulinemic hyperviscosity responsive to fludarabine and rituximab. A 33‐year‐old Asian man developed bilateral lacrimal gland and submandibular salivary gland swelling with cervical lymphadenopathy. Biopsies of the affected tissues revealed reactive follicular hyperplasia. Seven years later, he presented with bilateral retinal hemorrhages due to hyperviscosity syndrome from profound polyclonal increase in IgG, including marked IgG4 elevation. Despite plasmapheresis, overproduction of IgG continued and he was refractory to systemic steroids, azathioprine, interferon alpha, and cyclophosphamide. IgG4‐RD was suspected following a myocardial infarction and detection of aneurysmal coronary arteries indicating large vessel vasculitis. Review of the cervical lymph node and lacrimal gland biopsies with immunohistochemical staining for IgG4‐positive plasma cells confirmed IgG4‐RD. B‐cell depletion with rituximab produced a partial response, but clinical symptoms and elevated protein levels persisted. Fludarabine was added to rituximab to suppress T‐cell activity, and this resulted in an excellent clinical and biochemical response. Combination therapy with fludarabine and rituximab in IgG4‐RD has not previously been reported and can be considered in patients with severe refractory disease.

A young woman with episodic angioedema, papilledema, and eosinophilia

A 21-year-old Chinese woman presented to the Emergency Department with a 6-week history of progressive headache, blurred vision, exertional dyspnea and limb claudication, mild epistaxis, and heavy menses. This was preceded by a 15-month history of episodic erythematous maculopapular rash and limb swelling. She had no fever, weight loss, or night sweats. Her past history was significant for glucose-6-phosphate dehydrogenase (G6PD) deficiency and she was on nortriptyline for headaches. She was not sexually active, had not traveled, and used no recreational substances. This syndrome of headache, visual disturbance, claudication, and mucosal bleeding suggests disruption of the microvasculature and platelet dysfunction such as seen in hyperviscosity syndrome. Increased serum viscosity may be due to hypergammaglobulinemia (monoclonal or polyclonal) or cryoglobulinemia and may lead to neurologic defects, mucosal bleeding, and thrombosis. Increased cellular viscosity is seen in conditions such as acute leukemia (leukostasis), myeloproliferative neoplasms, or sickle cell crisis and typically affects small vessels of the lungs and brain. The limb claudication, neurologic symptoms, and skin rash may also indicate a systemic vasculitis. Her transient limb swelling suggests angioedema. G6PD deficiency is typically an X-linked recessive disorder and therefore unusual in females but a hemolytic workup is appropriate if she is anemic. Physical examination revealed a pale thin young woman. Her temperature was 36.88C, blood pressure 115/65 mmHg (no pulsus paradoxus), heart rate 130 beats per minute, respiratory rate 20 breaths per minute, and oxygen saturation 98% on ambient air. Head and neck examination revealed multiple bilateral 1–2 cm soft, mobile cervical lymph nodes. Her jugular venous pressure (JVP) was at the angle of her jaw while at 908 and she had a loud pulmonic component of the second heart sound (P2), but no right ventricular heave. Her liver edge was palpable 6 cm below the costal margin, the span was 18 cm by percussion, and there was no splenomegaly. Fundoscopy revealed papilledema with tortuous ‘‘sausage’’ vessels, indistinct optic disk margins and absence of arterial pulsations. The rest of her neurologic exam was unremarkable. She had no rash, swelling, or joint effusions. Bloodwork done 1 week before revealed white-cells 13.9 3 10 per liter, eosinophils 3 10 9.1 3 10 per liter (normal 0.7), hemoglobin 75 g per liter, platelet count 205 3 10 per liter, total protein 137 g per liter (normal 62–82), albumin 31 g per liter, and gamma globulin 91 g per liter (normal 5.1–15) with a focally increased gamma-globulin peak. Immunofixation revealed predominantly IgG with corresponding lambda and kappa light chain bands of equal intensity. Creatinine was 82 lmol per liter, and urine was negative for blood and protein. An abdominal ultrasound 1 week before showed mild hepatomegaly of 17.9 cm with porta-hepatis lymphadenopathy measuring up to 2.7 cm, but no splenomegaly and no other intra-abdominal lymphadenopathy. The markedly elevated immunoglobulin G (IgG) levels and papilledema confirm the hypothesis of hyperviscosity syndrome. Equal kappa and lambda light chain intensity indicates a polyclonal gammopathy, although with such high levels, a monoclonal element cannot be excluded. Structural causes of raised intracranial pressure must be ruled out. Polyclonal hypergammaglobulinemia and eosinophilia may be associated with connective-tissue disease such as the Churg-Strauss syndrome, lymphoproliferative disorders such as angioimmunoblastic T-cell lymphoma (AILT), and idiopathic eosinophilia. Malignancy and parasitic infection with multiorgan involvement (such as strongyloides stercoralis) should be ruled out. Medication reactions, atopic disease, and adrenal insufficiency may be associated with reactive eosinophilia and/or hypergammaglobulinemia but are unlikely in this case. She has evidence of pulmonary hypertension with right ventricular failure (elevated JVP, loud P2, and hepatomegaly). This may be related to hyperviscosity. Hyperviscosity increases the risk of vascular thrombosis, so an electrocardiogram and cardiac enzymes should be done, as well as a computed tomography pulmonary angiogram to rule out

IgG4-related disease and lymphocyte-variant hypereosinophilic syndrome: A comparative case series

To compare the clinical and laboratory features of IgG4‐related disease (IgG4‐RD) and lymphocyte‐variant hypereosinophilic syndrome (L‐HES), two rare diseases that often present with lymphadenopathy, gastrointestinal symptoms, eosinophilia, and elevated immunoglobulins/IgE.

Resolution of Spurious Immunonephelometric IgG Subclass Measurement Discrepancies by LC-MS/MS

BACKGROUND The Binding Site immunonephelometric (IN) IgG subclass reagents (IgG1, IgG2, IgG3, IgG, BSIN) are used for assessment of both immunodeficiency and IgG4-related disease (IgG4-RD). In our laboratory, suspected analytic errors were noted in patients with increases in IgG4: The sum of the individual IgG subclasses was substantially greater than the measured total IgG concentrations (unlike samples with normal IgG4), and the IgG4 concentration was always less than the IgG2 concentration. METHODS We developed a tryptic digest LC-MS/MS method to quantify IgG1, IgG2, IgG3, and IgG4 in serum. Samples with IgG4 concentrations ranging from <0.03 g/L to 32 g/L were reanalyzed by LC-MS/MS, and a subset was also reanalyzed by Siemens IN (SIN) subclass measurements. RESULTS Multivariate linear regression identified 3 subclass tests with multiple predictors of the measured subclass concentration. For these 3 subclasses, the predominant predictors were (in terms of LC-MS/MS IgG subclass measurement coefficients) BSIN IgG1 = 0.89·IgG1 + 0.4·IgG4; BSIN IgG2 = 0.94·IgG4 + 0.89·IgG2; and SIN IgG2 = 0.72·IgG2 + 0.24·IgG4. CONCLUSIONS There is apparent IgG4 cross-reactivity with select IN subclass measurements affecting tests from both vendors tested. These findings can be explained either by direct cross-reactivity of the IN reagents with the IgG4 subclass or unique physicochemical properties of IgG4 that permit nonspecific binding of IgG4 heavy chain to other IgG immunoglobulin heavy chains. Irrespective of the mechanism, the observed intermethod discrepancies support the use of LC-MS/MS as the preferred method for measurement of IgG subclasses when testing patients with suspected IgG4-RD.

Soluble interleukin-2 receptor is a sensitive diagnostic test in adult HLH

Serum soluble interleukin-2 receptor (sIL-2r) is an important disease marker in hemophagocytic lymphohistiocytosis (HLH), but there are no published data on its diagnostic value in adults. We conducted a single-center retrospective study of 78 consecutive adults who had sIL-2r measured for suspected HLH. Serum sIL-2r levels were measured by enzyme-linked immunosorbent assay (adult reference range, 241-846 U/mL). There were 38 patients with HLH and 40 with a non-HLH diagnosis (such as sepsis, liver disease, histiocyte disorders, autoimmune disease, leukemia, or lymphoma). The receiver operating characteristic curve demonstrated that sIL-2r is a good to excellent diagnostic test for adult HLH, with an area under the curve (AUC) of 0.90 (95% confidence interval, 0.83-0.97) compared with AUC 0.78 (95% confidence interval, 0.67-0.88) for ferritin. The optimal threshold for sIL-2r was 2515 U/mL (sensitivity, 100%; specificity, 72.5%). Although there was a large indeterminate range for sIL-2r, a level of 2400 U/mL or less was helpful for ruling out HLH (sensitivity, 100%), and more than 10 000 U/mL was helpful for ruling in HLH (specificity, 93%). Higher mean sIL-2r levels were seen in malignancy-associated HLH (20 241 U/mL) compared with infection-associated HLH and macrophage activation syndrome (9720 and 5008 U/mL, respectively; P < .05). Levels above 10 000 U/mL were not associated with worse prognosis in patients with HLH. Serum sIL-2r is a sensitive test for diagnosis of adult HLH, but is not as specific as previously reported in children. Additional studies enriched with patients without HLH who have conditions associated with T-cell activation, such as lymphoma and autoimmune lymphoproliferative syndrome, are needed.

Atypical autoimmune hemolytic anemia

The recent report by Alidjidi et al. provides valuable prospective data on a large cohort of children with autoimmune hemolytic anemia (AHA).[1][1] Their inclusion criteria were designed to capture typical cases of AHA including patients with anemia, a positive direct antiglobulin test (DAT), and

Utility of Serum IgG4 Levels in a Multiethnic Population

Background: IgG4‐related disease (IgG4‐RD) is a recently recognized condition defined by characteristic histopathologic findings in affected organs. Serum IgG4 concentration is often but not always elevated. The sensitivity and specificity of serum IgG4 vary greatly across studies and has been anecdotally associated to ethnicity. Our study was conducted to investigate the difference in serum IgG4 levels between Asian and non‐Asian patients with IgG4‐RD. Methods: This is a single‐center retrospective study of 26 Asian and 10 non‐Asian patients with histologically confirmed IgG4‐RD. Serum IgG4 levels, clinical features and other laboratory findings were compared between the 2 groups, 31 Asian and 11 non‐Asian patients with non‐IgG4‐RD rheumatic diseases were randomly identified to evaluate test characteristics of serum IgG4 measurement. Results: Median serum IgG4 at time of diagnosis was significantly higher in Asian (median = 11.2 g/L, interquartile range: 4.6‐19.7) than non‐Asian patients (median = 2.9 g/L, interquartile range: 0.7‐5.4, P = 0.0094), as well as the median serum IgG and total protein. Asian patients had more eosinophilia and polyclonal hypergammaglobulinemia than non‐Asian patients (P = 0.016 and 0.001, respectively). Test sensitivity was higher in Asian (96%) than non‐Asian patients (67%), whereas test specificity was higher in non‐Asian patients (91% versus 71%). Conclusion: Asian patients with IgG4‐RD have more exuberant serum IgG4, IgG and polyclonal hypergammaglobulinemia than non‐Asian patients; the mechanism of this difference requires further study. These findings have significant clinical importance and must be accounted for in the diagnostic workup of patients in multiethnic settings.

Hemophagocytic Syndromes in Adult Intensive Care Units: Response to Okabe et al:

A 19-year-old Japanese woman presented with fever, coryza, and abdominal pain progressing to respiratory, hepatic, and renal failure with shock requiring intensive care unit (ICU) admission. Her platelets were 20 giga/L, hemoglobin (Hb) 87 g/L, international normalized ratio (INR) 1.5, partial thromboplastin time (PTT) 80 seconds (normal 24-40 seconds), fibrinogen 2.3 g/L (normal 1.5-4.5), and ferritin 3312 mg/L (normal 20-300) with Epstein-Barr virus (EBV) DNA levels >100 000 copies/mL. Spleen size was on the upper limit of normal and a bone marrow biopsy revealed hemophagocytosis and increased T cells with absent natural killer (NK) cells on immunophenotyping. She received a modified Hemophagocytic Lymphohistiocytosis 2004 (HLH-2004) regimen consisting of high-dose dexamethasone and reduced-dose etoposide, cyclosporine, and 1 dose of rituximab. One dose of recombinant factor VIIa was given for severe intra-abdominal bleeding with immediate hemostasis. She improved and was able to return to Tokyo for further treatment.

A young woman with steroid-responsive, IgG4-positive plasma cell-enriched cystic lymphangioma and chylous ascites

Lymphangiomas are benign tumors of the lymphatic vessels, which can be inflammatory and occasionally steroid‐responsive. IgG4‐related disease (IgG4‐RD) is a recently defined fibro‐inflammatory condition. We describe a novel association between reactive IgG4+ plasma cells and cystic lymphangioma in a young woman who had a dramatic clinical response to steroids.