Jeffrey A. Gelfand

Interleukin 1 induces a shock-like state in rabbits. Synergism with tumor necrosis factor and the effect of cyclooxygenase inhibition.

In addition to activating T and B lymphocytes, interleukin 1 (IL-1) induces several hematologic and metabolic changes typical of host responses to infection and injury. We now report a new biological property, namely, the induction of hypotension. Rabbits given a single intravenous injection of recombinant human IL-1-beta (5 micrograms/kg) rapidly developed decreased systemic arterial pressure, which reached the lowest levels after 50-60 min and slowly returned to pre-IL-1 values after 3 h. Associated with the hypotension, systemic vascular resistance and central venous pressure fell, while cardiac output and heart rate increased. These responses were prevented by ibuprofen given 15 min before the IL-1. A bolus injection of IL-1 followed by a 2-h infusion sustained the hypotension and was associated with leukopenia and thrombocytopenia. Ibuprofen given at the mid-point of the infusion reversed the changes in all hemodynamic parameters, but had no effect on the leukopenia or thrombocytopenia. Tumor necrosis factor (TNF) also induced a shock-like state in rabbits. When the dose of IL-1 or TNF was reduced to 1 microgram/kg, no hemodynamic changes were observed; however, the combination of these low doses of both cytokines resulted in a profound shock-like state including histological evidence of severe pulmonary edema and hemorrhage. Pretreatment with ibuprofen prevented the hemodynamic, leukocyte, and platelet changes induced by the low-dose cytokine combination, and ameliorated the pulmonary tissue damage. These results demonstrate that IL-1, like TNF, possesses the ability to induce hemodynamic and hematological changes typical of septic shock, and that the combination of IL-1 and TNF is more potent than either agent alone. These effects seem to require cyclooxygenase products, and suggest that intravenous cyclooxygenase inhibitors may be of therapeutic value in patients with IL-1/TNF-mediated shock.

Treatment of Hereditary Angioedema with Danazol

Abstract Danazol, an androgen derivative, was evaluated for its effectiveness in preventing attacks of hereditary angioedema in a double-blind study with nine patients. Of 47 placebo courses, 44 ended with attacks, but during 46 danazol courses only one attack occurred. Side effects were minimal, and virilization was not observed in the women studied. C1 esterase inhibitor levels increased three to four times, and levels of the fourth component of complement (C4) increased 15 times. These changes began during the first day of therapy and were maximal by one to two weeks. After therapy was stopped, C1 esterase inhibitor and C4 levels rapidly decreased. Danazol effectively prevents attacks in hereditary angioedema and acts to correct the underlying biochemical abnormality. (N Engl J Med 295:1444–1448, 1976)

Hereditary Angioedema: the Clinical Syndrome and Its Management

Hereditary angioedema is manifested by attacks of swelling of the extremities, face, trunk, airway, or abdominal viscera, occurring spontaneously or secondary to trauma. It is inherited as an autosomal dominant trait and is due to deficient activity of the inhibitor of the activated first component of complement. The clinical diagnosis can be confirmed by the findings of low levels of C4 or C1 esterase inhibitor activity, or both. Therapy may be divided into three phases: long-term prophylaxis of attacks, short-term prophylaxis of attacks, and treatment of acute attacks. Long-term prophylaxis may be achieved with antifibrinolytic agents and androgens. Short-term prophylaxis with these agents and plasma transfusions has been successful. Specific therapy for acute attacks is not available, but good supportive care, together with a knowledge of the course of the disease, can prevent asphyxiation from airway obstruction. Before the advent of therapy, mortality was reported as high as 30%.

A specific receptor antagonist for interleukin 1 prevents Escherichia coli-induced shock in rabbits.

Despite antibiotic therapy, the septic shock syndrome continues to have a high mortality. Tumor necrosis factor (TNF) and interleukin 1 (IL 1), two polypeptide cytokines produced during sepsis, are thought to mediate the hypotension and tissue damage of shock. In the present studies, rabbits were infused with Escherichia coli organisms to produce shock. The IL 1 receptor antagonist (IL 1ra), which competes with IL 1 for occupancy of the IL 1 cell‐surface receptors without agonist properties, was given 15 min before the bacterial infusion and during the subsequent 4 h. In saline‐treated controls, hypotension was sustained for 4 h and death occurred for two of five rabbits; in rabbits treated with the IL 1ra, however, blood pressure was only transiently decreased, returned to pre‐E. coli levels, and no deaths occurred. The associated leukopenia was also reduced by treatment with the antagonist (P < 0.05). Histological examination of lung tissues showed reduced infiltrating neutrophils in the IL 1ra treatment group. Despite the attenuated responses in animals treated with the IL 1ra, circulating TNF and IL 1 levels were nearly identical in both groups. We conclude that specific blockade of IL 1 at the receptor level demonstrates an essential role for this cytokine in the pathogenesis of septic shock.—Wakabayashi, G.; Gelfand, J. A.; Burke, J. F.; Thompson, R. C.; Dinarello, C. A. A specific receptor antagonist for interleukin 1 prevents Escherichia coli‐induced shock in rabbits. FASEB J. 5: 338–343; 1991.

Staphylococcus epidermidis induces complement activation, tumor necrosis factor and interleukin-1, a shock-like state and tissue injury in rabbits without endotoxemia. Comparison to Escherichia coli.

Tumor necrosis factor (TNF) and IL-1 are thought to mediate many of the pathophysiologic changes of endotoxemia and Gram-negative bacteremia. In these studies, heat-killed Staphylococcus epidermidis were infused into rabbits to determine whether an endotoxin (LPS)-free microorganism also elicits cytokinemia and the physiologic abnormalities seen in Gram-negative bacteremia. S. epidermidis induced complement activation, circulating TNF and IL-1, and hypotension to the same degree as did one-twentieth the number of heat-killed Escherichia coli. Circulating IL-1 beta levels had a greater correlation coefficient (r = 0.81, P less than 0.001) with the degree of hypotension than TNF levels (r = 0.48, P less than 0.02). Leukopenia, thrombocytopenia, diffuse pulmonary capillary aggregation of neutrophils, and hepatic necrosis with neutrophil infiltration were observed to the same extent after either S. epidermidis or E. coli infusion. However, S. epidermidis infusion did not induce significant (less than 60 pg/ml) endotoxemia, whereas E. coli infusion resulted in high (11,000 pg/ml) serum endotoxin levels. S. epidermidis, E. coli, LPS, or S. epidermidis-derived lipoteichoic acid (LTA) induced TNF and IL-1 from blood mononuclear cells in vitro. E. coli organisms and LPS were at least 100-fold more potent than S. epidermidis or LTA. Thus, a shock-like state with similar levels of complement activation as well as circulating levels of IL-1 and TNF were observed following either S. epidermidis or E. coli. These data provide further evidence that host factors such as IL-1 and TNF are common mediators of the septic shock syndrome regardless of the organism.

Replacement Therapy in Hereditary Angioedema: Successful Treatment of Acute Episodes of Angioedema with Partly Purified C1 Inhibitor

Although considerable progress has been made during the past two decades in the use of androgens to prevent attacks of hereditary angioedema, replacement of the deficient C1-inhibitor protein would provide a useful menas of treatment once an attack has begun. We studied the clinical use of C1 inhibitor that was partly purified on a large scale from pooled plasma. The in vivo efficacy and safety of this protein concentrate were evaluated during 11 intravenous infusions in eight patients with hereditary angioedema. Three patients received the C1-inhibitor preparation during an asymptomatic period. Increases in serum C4 activity provided evidence of the biologic activity of the infused inhibitor. Intravenous administration of the concentrate during acute abdominal or laryngeal attacks of hereditary angioedema in five patients resulted in abatement of symptoms in addition to increased serum C4 activity. No untoward effects of the intravenous administration of the C1 inhibitor were observed in these eight patients. Thus, this C1-inhibitor preparation seems to offer the potential for safe, effective replacement therapy and may provide a means of controlling an attack of hereditary angioedema that is in progress.

Persistent and Relapsing Babesiosis in Immunocompromised Patients

BACKGROUND Human babesiosis is a tickborne malaria-like illness that generally resolves without complication after administration of atovaquone and azithromycin or clindamycin and quinine. Although patients experiencing babesiosis that is unresponsive to standard antimicrobial therapy have been described, the pathogenesis, clinical course, and optimal treatment regimen of such cases remain uncertain. METHODS We compared the immunologic status, clinical course, and treatment of 14 case patients who experienced morbidity or death after persistence of Babesia microti infection, despite repeated courses of antibabesial treatment, with those of 46 control subjects whose infection resolved after a single course of standard therapy. This retrospective case-control study was performed in southern New England, New York, and Wisconsin. RESULTS All case patients were immunosuppressed at the time of acute babesiosis, compared with <10% of the control subjects. Most case patients experienced B cell lymphoma and were asplenic or had received rituximab before babesial illness. The case patients were more likely than control subjects to experience complications, and 3 died. Resolution of persistent infection occurred in 11 patients after 2-10 courses of therapy, including administration of a final antimicrobial regimen for at least 2 weeks after babesia were no longer seen on blood smear. CONCLUSIONS Immunocompromised people who are infected by B. microti are at risk of persistent relapsing illness. Such patients generally require antibabesial treatment for >or=6 weeks to achieve cure, including 2 weeks after parasites are no longer detected on blood smear.

Concentrations of immunoreactive human tumor necrosis factor alpha produced by human mononuclear cells in vitro

The concentrations of tumor necrosis factor (TNF) produced by human peripheral blood mononuclear cells (MNC) were measured using a radioimmunoassay (RIA) for human TNF. This was developed using a rabbit antiserum against human recombinant TNF (Hu rTNF), and Hu rTNF labeled with Na1251 by a modification of the chloramine T method. This RIA does not detect human lymphotoxin, interieukin‐1 alpha or beta, interleukin 2, interleukin 6, interferon alpha or gamma, granulocyte‐macrophage‐colony stimulating factor, and C5a des arg. A good correlation (r = 0.89) was found between the RIA and the cytolytic bioassay for TNF. The sensitivity of the RIA is between 3 and 78 pg/ml (median 11 pg/ml).

Acquired C1 esterase inhibitor deficiency and angioedema: a review.

A case of acquired C1INH deficiency with angioedema is described. Fifteen cases are thus far recorded. The clinical syndrome of angioedema in these patients closely resembles hereditary angioedema (HAE). Most cases are associated with a paraprotein, cryoglobulin, or autoantibody, which presumably initiates C1 activation and C1 Inhibitor consumption. C1INH, C4 and C2 levels are low in acquired C1INH deficiency, as in HAE. A distinguishing feature is that C1 titers are very low in the acquired disease and only minimally depressed, if at all, in HAE. Most cases have appeared in patients with an underlying lymphoproliferative or autoimmune disease. Therapy is directed at the underlying disorder, but androgen therapy may be helpful in preventing attacks. Future potential therapeutic approaches are discussed.

Systemic capillary leak syndrome and monoclonal IgG gammopathy; studies in a sixth patient and a review of the literature.

The clincical and laboratory features of a sixth patient with periodic systemic capillary leak syndrome are reported. During an attack metabolic studies demonstrated a marked shift of plasma (10 to 70%) from the intravascular to the extravascular space resulting in hemoconcentration (highest hematocrit of 82). At the termination of the attack there was a return of the electrolytes, water and proteins to the intravascular compartment. The cardiovascular, renal and endocrine compensation was appropriate to this insult and no underlying abnormalities were demonstrated in these systems. The effector pathways of coagulation, complement, bradykinin generation, prostaglandins and histamine metabolism did not appear to be responsible for the altered capillary permeability. The patient was not missing inhibitors of these same pathways. The only persistently abnormal finding was a monoclonal IgG gammopathy. However, further studies of this paraprotein did not uncover a link between it and the abnormal capillary permeability. Five similar cases are reviewed; at least four and possibly all of these patients also had an IgG paraprotein. Treatment of these attacks was unsuccessful. Attemps to prevent the episodes with a wide variety of therapeutic agents failed. Treatment of the acute attacks with administration of intravenous fluids, did not maintain an adequate intravascular volume and may lead to fluid overload upon return of normal capillary integrity. Pressor agents were of no apparent value and may cause increased cardiac irritability. Although the clinical features and pathophysiology of the capillary leak syndrome have been defined, the etiology remains unknown.