Management of an acute catecholamine-induced cardiomyopathy and circulatory collapse: a multidisciplinary approach.

A phaeochromocytoma (PC) is a rare, catecholamine-secreting neuroendocrine tumour arising from the adrenal medulla. Presenting symptoms of this rare tumour are highly variable but life-threatening multiorgan dysfunction can occur secondary to catecholamine-induced hypertension or hypotension and subsequent cardiovascular collapse. High levels of circulating catecholamines can induce an acute stress cardiomyopathy, also known as Takotsubo cardiomyopathy. Recent studies have focused on early diagnosis and estimation of the prevalence of acute stress cardiomyopathy in patients with PC, but very little is reported about management of these complex cases. Here, we report the case of a 38-year-old lady who presented with an acute Takotsubo or stress cardiomyopathy and catecholamine crisis, caused by an occult left-sided 5 cm PC. The initial presenting crisis manifested with symptoms of severe headache and abdominal pain, triggered by a respiratory tract infection. On admission to hospital, the patient rapidly deteriorated, developing respiratory failure, cardiogenic shock and subsequent cardiovascular collapse due to further exacerbation of the catecholamine crisis caused by a combination of opiates and intravenous corticosteroid. An echocardiogram revealed left ventricular apical hypokinesia and ballooning, with an estimated left ventricular ejection fraction of 10-15%. Herein, we outline the early stabilisation period, preoperative optimisation and intraoperative management, providing anecdotal guidance for the management of this rare life-threatening complication of PC. LEARNING POINTS: A diagnosis of phaeochromocytoma should be considered in patients presenting with acute cardiomyopathy or cardiogenic shock without a clear ischaemic or valvular aetiology.Catecholamine crisis is a life-threatening medical emergency that requires cross-disciplinary expertise and management to ensure the best clinical outcome.After initial resuscitation, treatment of acute catecholamine-induced stress cardiomyopathy requires careful introduction of alpha-blockade followed by beta-blockade if necessary to manage ß-receptor-mediated tachycardia.Prolonged α-adrenergic receptor stimulation by high levels of circulating catecholamines precipitates arterial vasoconstriction and intravascular volume contraction, which can further exacerbate hypotension. Invasive pressure monitoring can aid management of intravascular volume in these complex patients.

Survey of infection in patients receiving antibody replacement treatment for immune deficiency.

BACKGROUND: Primary antibody deficiency disorders are a heterogeneous group of disorders, which are treated by regular infusions of immunoglobulin. Despite replacement treatment, patients remain susceptible to infection. Effective management of infections is necessary to prevent the complications of chronic infection. AIMS: This retrospective survey of clinical practice examined the management of infections in patients who receive immunoglobulin replacement for immune deficiency. METHODS: Patients who received immunoglobulin replacement treatment in Newcastle during the year 2000 were identified. Medical records were reviewed. Basic clinical information and details of immunoglobulin replacement treatment were recorded. Episodes of infection were defined by documented symptoms, signs, or investigation results, and by the prescription of an antibiotic course. Details of episodes of infection and antimicrobial treatment were recorded. RESULTS: Thirty seven patients received immunoglobulin replacement during 2000. There were 101 episodes of infection. There was no correlation between the frequency of infection and the IgG trough value. Respiratory tract infections were most common (71 of 101). Where documented, 80% of infections were associated with clinical signs, 21% with pyrexia, and 64% with a raised C reactive protein value. Microbiological culture was performed in 30% of infections. Antimicrobial treatment was instituted along "best guess" lines in 99 of 101 episodes of infection. CONCLUSIONS: Management of respiratory tract infections represents the largest problem in antibody deficient patients. Greater use of microbiological culture might allow more effective prescription of antimicrobial treatment. The generation of treatment guidelines and improved communication with general practitioners could improve the management of all episodes of infection.

Regulation of T-cell apoptosis: a mixed lymphocyte reaction model.

Despite the capacity for antigen-specific activation and rapid clonal expansion, homeostatic mechanisms ensure that the mature immune system contains a relatively stable number of T cells. In recent years, it has become apparent that this stability is a consequence of apoptotic death of most of the specific T cells generated during an immune response. Clearly this process must be tightly regulated in order to retain sufficient T-cell progeny to mediate an effective response, whilst allowing the rapid deletion of these cells at the end of the response to prevent lymphadenopathy and cross-reactive autoimmunity. In this study, the factors that regulate the sensitivity of T cells to apoptosis were investigated in vitro after the induction of primary T-cell activation within a mixed lymphocyte reaction (MLR). It was found that activated T cells rapidly acquire the expression of both Fas and Fas ligand (FasL) on their surface and contain high levels of the precursor form of the pro-apoptotic enzyme, caspase 8 (FLICE). However, these T cells were resistant for up to 5 days to apoptosis following the stimulation of Fas; a maximal apoptotic response was observed after 7 days. This time point coincided with a marked reduction in expression of the FLICE inhibitory protein (FLIP) and maximal activity of caspase 8. At time points beyond day 7, the number of viable cells in the MLR decreased further despite a reduction in the expression of FasL. However, the expression of interleukin-2 (IL-2) at these late time points was low, resulting in a decrease in expression of the anti-apoptotic protein Bcl-2. This can produce apoptosis by allowing leakage of cytochrome-c from mitochondria resulting in direct activation of the caspase cascade. In this study, it is shown that T cells are resistant to apoptosis for the first 5 days after activation as a consequence of insensitivity of the Fas pathway and the presence of intracellular Bcl-2. After between 5 and 7 days, the cells become sensitive to Fas-mediated apoptosis while retaining Bcl-2 expression. At later time points, Fas ligation is reduced but the cells respond to a decreased availability of IL-2 by reducing Bcl-2 expression; this encourages further apoptosis by allowing the direct activation of caspase enzymes.

Immune selection in neoplasia: towards a microevolutionary model of cancer development.

The dual properties of genetic instability and clonal expansion allow the development of a tumour to occur in a microevolutionary fashion. A broad range of pressures are exerted upon a tumour during neoplastic development. Such pressures are responsible for the selection of adaptations which provide a growth or survival advantage to the tumour. The nature of such selective pressures is implied in the phenotype of tumours that have undergone selection. We have reviewed a range of immunologically relevant adaptations that are frequently exhibited by common tumours. Many of these have the potential to function as mechanisms of immune response evasion by the tumour. Thus, such adaptations provide evidence for both the existence of immune surveillance, and the concept of immune selection in neoplastic development. This line of reasoning is supported by experimental evidence from murine models of immune involvement in neoplastic development. The process of immune selection has serious implications for the development of clinical immunotherapeutic strategies and our understanding of current in vivo models of tumour immunotherapy.

Bladder cancer immunogenicity: expression of CD80 and CD86 is insufficient to allow primary CD4+ T cell activation in vitro.

Transitional cell carcinomas (TCC) of the urinary bladder are known to express proteins which can yield potentially immunogenic peptide epitopes for expression in the context of cell surface class I or class II MHC antigens. However, additional costimulatory ligands must also be expressed before such a cell might directly induce full activation and proliferation of resting, antigen-specific T lymphocytes. Intravesical therapy might be used to manipulate T cell costimulation in order to promote specific rejection of TCC cells. This in vitro study examined the potential of such a strategy by transfection of the prototypical TCC line J82 with the important costimulatory molecules CD80 (B7-1) and CD86 (B7-2). Untransfected J82 cells expressed class I and II MHC antigens, a range of cell adhesion molecules, though did not induce T cell proliferation in a robust, allogeneic co-culture system. Transfected J82 cells expressed CD80 or CD86 at levels comparable to an antigen-presenting B cell line. Furthermore, functional surface expression of CD80 and CD86 was demonstrated in a mitogen-dependent assay of costimulation. However, neither CD80+ nor CD86+ transfectant J82 cells could induce significant proliferation of antigen-specific CD4+ T cells. Further analysis showed that bystander J82 cells could inhibit independent T cell activation in an effect dependent on direct cell contact. This inhibitory effect was associated with increased cell death in the responding lymphocyte population and is concordant with surface expression of CD95L by the J82 cell line.

Examination of the sensitivity of T cells to Fas ligation: induction of allospecific apoptosis.

BACKGROUND: Alloantigen-reactive T cells represent the major barrier to successful organ transplantation. However, it has been shown that cotransplantation of Fas ligand (FasL)-expressing cells can induce functional allograft tolerance in some model systems. In this study, the basis for this tolerance was investigated using a sensitive in vitro assay system. METHODS: T lymphocytes were activated by coculture with an allogeneic Epstein Barr virus-transformed B-cell line. Samples of the lymphocytes were taken daily and treated with agonistic anti-Fas antibodies or FasL-expressing cells. The time in culture required for development of optimal sensitivity to Fas-mediated apoptosis was assessed by Tdt-mediated nick end labeling (TUNEL) staining and the JAM assay of DNA fragmentation. After the induction of optimal apoptosis, a series of experiments was performed to assess the response of the T-cell population to antigen-specific rechallenge. RESULTS: Treatment of the allospecific lymphocyte population with anti-Fas antibodies or Fas-L-expressing cells did not induce apoptosis efficiently until between 6 and 7 days after initiation of the mixed lymphocyte culture; this time corresponded with decreases in the ambient interleukin 2 concentration and in Bcl-2 expression. In addition, induction of apoptosis by treatment with the agonistic anti-Fas antibody reduced the lymphoproliferative response of the T-cell population after antigen-specific rechallenge. CONCLUSIONS: These results give an important indication of the mechanism by which FasL-expressing third-party cells can reduce an allospecific T-cell response by an apoptotic mechanism. Furthermore, they demonstrate that apoptotic tolerance in vivo may only occur after the prolonged period of potentially graft-damaging T-cell activation required for acquisition of sensitivity to Fas-mediated apoptosis.