Israel Medical Association Journal

Heart failure (HF) accompanied by renal failure, termed cardiorenal syndrome (CRS), encompasses both the development and worsening of renal insufficiency secondary to HF as well as the harmful effects of impaired renal function on the cardiovascular system, and remains a universal clinical challenge. CRS was recently classified into subtypes depending on the etiologic and chronologic interactions between cardiac and renal dysfunctions. The mechanisms underlying the CRS are multifactorial, including hemodynamic alterations, neurohormonal effects, and inflammatory components. However, despite enhanced understanding and awareness of CRS, further elucidation of the mechanisms involved and the appropriate treatment approaches are clearly warranted. CRS is a difficult condition to manage, as treatment to relieve congestive symptoms of HF is limited by a further decline in renal functions, itself a major independent predictor of long-term cardiac morbidity. In order to perform a proper clinical investigation and implement appropriate treatment that will minimize subsequent progression of heart and kidney injury, a comprehensive approach to these two pathologies is crucial. In the present review we discuss current theories behind the mechanistic evolution of the CRS as well as therapeutic issues regarding this multifaceted condition.
 

The DRESS syndrome (drug reaction with eosinophilia and systemic symptoms), also known as DIHS (drug-induced hypersensitivity syndrome), presents clinically as an extensive mucocutaneous rash, accompanied by fever, lymphadenopathy, hepatitis, hematologic abnormalities with eosinophilia and atypical lymphocytes, and may involve other organs with eosinophilic infiltration, producing damage in several systems, especially kidney, heart, lungs, and pancreas. The pathogenesis is related to specific drugs (especially the aromatic anticonvulsants), altered immune response, sequential reactivation of herpes virus, and association with some HLA alleles. Glucocorticoids are the basis for the treatment of the syndrome, which may be given with intravenous immunoglobulin and, in selected cases, ganciclovir. This article reviews current concepts regarding the interaction of drugs, viruses and immune responses during this complex adverse-drug reaction.
 

Background: Autoimmune neutropenia of infancy is caused by neutrophil-specific autoantibodies. Primary AIN[1] is characterized by neutrophil count < 500 ml and a benign self-limiting course. Detecting specific antibodies against the polymorphic human neutrophil antigen usually confirms the diagnosis. Current available tests, however, are expensive and inapplicable in many laboratories as they require the use of isolated and fixed granulocytes obtained from donors pretyped for their distinct HNA[2] alloform.

Objectives: To assess the performance of a modified test to identify by FACS-analysis granulocyte-specific antibodies in the sera of neutropenic children.

Methods: We evaluated 120 children with a clinical suspicion of AIN, whose sera were analyzed by flow cytometry for the presence of autoantibodies using the indirect granulocyte immunofluorescence test. In contrast to the traditional tests, the sera were tested against randomly selected untyped neutrophils derived from a batch of 10 anonymous healthy subjects, presumably including the common HNA alloforms. Control sera samples were from patients with chemotherapy-induced, familial or congenital neutropenias. To further assure the quality of the new test, we retested six samples previously tested by the gold standard method. All medical files were screened and clinical outcomes were recorded.

Results: Our method showed specificity of 85%, sensitivity of 62.5%, and a positive predictive value of 91.8%, values quite similar to those obtained by more traditional methods.

Conclusions: The new method showed high specificity for detection of anti-neutrophil antibodies in the appropriate clinical setting and could be an effective aiding tool for clinical decision making.

Objectives: To compare leukocyte counts and blood levels of various inflammatory cytokines in children and adults diagnosed with community-acquired bronchopneumonia.

Methods: We prospectively evaluated all pediatric and adult patients admitted for bronchopneumonia based on clinical and chest X-ray findings.. Blood was drawn for complete blood count and serum concentration of the following cytokines: granulocyte colony-stimulating factor, interleukins-6, 8 and 10, interferon-gamma, tumor necrosis factor, as well as matrix metalloproteinase-9 and intercellular adhesion molecule-1.

Results: There were 31 children and 32 adults. The patients in both groups had similar parameters of infection severity. None of them required admission to the Intensive Care Unit. Mean (± SD) leukocyte counts in the pediatric and adult groups were 21,018/mm (± 10,420) and 12,628/mm (± 6735) respectively (P = 0.02). Age was inversely correlated with leukocytes in the pediatric group (P = 0.0001). A significant inverse correslation was also found between age and platelet counts. Although cuytokine levels in both groups were not significantly different, age was

Conclusions: The immune response in community-aquired bronchopneumonia is, at least partly, age-dependent.

Anti-neutrophil cytoplasm antibodies are important markers of certain small vessel necrotizing vasculitides, but the optimal use of laboratory results in daily clinical practice necessitates collaboration between clinicians and laboratory specialists. Physicians must familiarize themselves with ANCA tests in ANCA-related vasculitides as well as in differential diagnostic patient populations in order to define cutoff values. Indirect immunofluorescence with a consensus-agreed technique combined with standardized enzyme immunoassays is the modality for detecting the main SSV-associated ANCA specificities using cutoff values that can sufficiently distinguish SVV from non-SVV patients. The combined use of IF and direct EIA to demonstrate proteinase 3-ANCA and myeloper­oxidase-ANCA at significant levels leads to a very high diagnostic specificity towards SVV conditions such as Wegen­er’s granulomatosis, microscopic polyangiitis, Churg-Strauss syndrome, and limited forms of these such as renal-limited focal necrotizing glomerulonephritis. A strong reactivity of ANCA against several azurophil granule components indicates a drug-induced syndrome. ANCA-related SVV and drug­induced vasculitis or lupus syndromes have characteristic ANCA profiles that can help distinguish these conditions from other inflammatory diseases.

Objectives: To help clinicians and laboratory scientists recognize and utilize vasculitis-related ANCAs as an aid in diagnostic workup and patient follow-up, and be aware that ANCAs with different characteristics are commonly found in other chronic inflammatory conditions that persistently engage neutrophils in the inflammatory process.

Methods: Indirect immunofluorescence and enzyme immunoassay methods were used to detect ANCAs with both known and unknown neutrophil autoantigenic targets.

Results: Primary necrotizing small vessel vasculitides such as Wegener’s granulomatosis, Churg-Strauss syndrome, microscopic polyangiitis, and renal-limited rapidly progressive necrotizing glomerulonephritis target either the serine protease proteinase 3 or myeloperoxidase  in azurophilic granules. In ulcerative colitis and rheumatoid arthritis, we found multiple ANCA targets contained in azurophilic and specific granules, the cytosol and the nucleus, whereas PR3² and MPO³ were not, or only weakly, recognized.

Conclusions: ANCAs typically found in active SVV⁴ are demonstrable both by indirect immunofluorescence and antigen-specific enzyme immunoassay, and strong reactivity to either PR3 or MPO is characteristic. Strong ANCA with MPO reactivity is also found in some patients with drug-induced syndromes (lupus, vasculitis). Intermediate to strong perinuclear ANCAs are found in a substantial proportion of patients with UC⁵ (40–60%) and RA⁶ (30–70%), but in these conditions the ANCAs have many antigen targets that are only weakly recognized.

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¹ ANCA = anti-neutrophil cytoplasm antibody

² PR3 = protease proteinase 3

³ MPO = myeloperoxidase

⁴ SVV = small vessel vasculitides

⁵ UC = ulcerative colitis

⁶ RA = rheumatoid arthritis