I. Schedel

Treatment of gram-negative septic shock with an immunoglobulin preparation: a prospective, randomized clinical trial.

Objective:To evaluate the effectiveness of a polyclonal immunoglobulin (Ig) preparation containing IgG, IgM, and IgA as an adjunctive therapy for septic shock. Design:Prospective, randomized clinical trial. Setting:A clinical immunology ward at the center for internal medicine in a university hospital. Patients:Fifty-five patients with septic shock were randomly allocated to two groups according to criteria of septic shock. Intervention:One group of patients (n = 27) received a commercially available immunoglobulin preparation (containing high titers of antibodies specific for determinants to bacterial endotoxin) during the first 3 days after inclusion in the study. The other randomized group (n = 28) did not receive any immunoglobulin preparation. Measurements and Main Results:During the period of ≤6 wks after the beginning of clinically apparent septic shock, death related to the septic process occurred in one (4%) of 27 patients who received immunoglobulin. By comparison, nine (32%) of 28 control group patients died during this period (p <.01 ). Within the first 48 hrs after onset of the clinically apparent septic process, significantly increased activity of circulating endotoxin and simultaneously decreased specific IgG serum titers to lipid A were detected in the group of nonsurvivors. Conclusions:Administration of a polyclonal immunoglobulin preparation in the early phase of septic shock was associated with significantly improved survival.

Resting energy expenditure and weight loss in human immunodeficiency: Virus-infected patients☆

Resting energy expenditure (REE) and body composition were investigated in 60 clinically stable patients with human immunodeficiency virus (HIV) infection varying with respect to immune impairment. REEs differed significantly from predicted values (> or < 10% of the Harris-Benedict [HB] equation) in 40% of patients. Seven percent of patients showed markedly increased REE (> +20% of HB prediction), whereas REE was decreased in 13% (< -10%). Increased REE was found during all clinical stages of the disease (Walter Reed [WR] 2 through 6) and was not strictly associated with the degree of immune impairment, presence of diarrhea or Kaposis sarcoma, nutritional state, or anamnestic wasting. Twenty-seven patients were evaluated for a mean period of 319 days; 11 lost more than 5% of their initial body weight during the observation period. Weight-losing patients were normometabolic before but showed a significantly increased REE (+7% of predicted values or +8% when compared with previous measurements) during weight loss. The degree of deviation from estimated REE was strongly associated with the degree of weight loss. We summarize that increased REE is not a constant feature of HIV infection. It is not associated with clinical and laboratory parameters of immune deficiency, but may occur during weight loss. Thus increased REE represents an inadequate adaptation to malnutrition and contributes to wasting.

Serum antibodies against common antigens of bacterial lipopolysaccharides in healthy adults and in patients with multiple myeloma

SummaryThe incidence of infections caused by gramnegative bacteria is increased in patients with multiple myeloma due to secondary humoral immunodeficiency. In order to diagnose patients with increased susceptibility to gram-negative infections, serum antibodies against common determinants of lipopolysaccharides (lipid A and core-polysaccharide) were determined by a rapid enzyme-linked immunosorbent assay (ELISA). It was possible to define a group of patients at high risk of contracting gram-negative infections using this test. Intravenous IgG preparations used as a substitute were shown to contain antibodies against these common antigens. However, it is suggested that the clinically recognized efficacy of these preparations could be due to their containing anti-LPS antibodies.ZusammenfassungAufgrund ihres sekundären humoralen Immundefektes treten bei Patienten mit multiplem Myelom gehäuft Infektionen durch gramnegative Bakterien auf. Um Patienten mit einer erhöhten Anfälligkeit für gramnegative Infektionen zu diagnostizieren, wurden die Serum-Antikörper gegen gemeinsame Determinanten der Lipopolysaccharide (Lipid A und zentrales Polysaccharid) in einem schnellen enzymverbundenen Immunbindungstest (ELISA) bestimmt. Mit diesem Test-system war es möglich, eine Gruppe von Patienten mit einem hohen Risiko für gramnegative Infektionen zu definieren. Es wurde gezeigt, daß IgG-Präparationen, die zur intravenösen Substitution verwendet werden, Antikörper gegen diese gemeinsamen Antigene enthalten. Dabei ist zu vermuten, daß die klinisch gefundene Wirksamkeit dieser Präparationen auf ihrem Gehalt an anti-LPS-Antikörpern beruhen könnte.

Malnutrition and immune dysfunction in patients infected with human immunodeficiency virus.

SummaryStudy objective: To determine forms of malnutrition and basal metabolism at different stages of immunological impairment in clinically stable patients infected with Human Immunodeficiency Virus (HIV).Design: Cross sectional study.Setting: 53 outpatients with HIV-infection classified according to the Walter Reed staging system (WR1 to WR6).Measurements and main results: 87% of the patients showed some evidence of malnutrition. Reduced body weight was found in 53%, 68% and 25% had decreases in fat and body cell mass, 17% had visceral protein deficiency, whereas extracellular mass and serum triglyceride concentrations were increased in 58% and 30%, respectively. Reduced serum albumin and transferrin closely paralleled immunological depression, whereas alterations in body composition were manifest early during HIV-infection (WR3) and remained unchanged during the transition to the Acquired Immune Deficiency Syndrome itself. Resting metabolic rate increased from WR1 to WR3; it remained within the expected range during later stages (WR4-WR6), but was not appropriately reduced in response to the loss in body cell mass.Conclusions: HIV-infected patients display both, calorie and protein malnutrition. Immunological depression was independent of loss of body mass, but was closely associated to decreases in serum albumin values. Nutritional assessment and intervention should therefore be performed at an early stage of HIV-infection.

Cytomegalovirus infection in HIV-1-infected individuals

SummaryUrinary excretion of Cytomegalovirus and the presence of serum antibodies against CMV were examined in 79 HIV-1-infected patients at different stages of the disease, as well as in 27 heterosexual and 52 male homosexual controls and correlated to clinical and laboratory results. HIV-1-infected and healthy individuals differed significantly with regard to cutaneous delayed type reactions, absolute numbers of CD4+ cells and CD4+/CD8+ ratios. IgG antibodies against CMV were found in 87% of homosexual and in 52% of heterosexual controls, and in all HIV-1-infected homosexuals. CMV excretion in the urine was exclusively found in HIV-1-infected individuals where the incidence correlated with the CDC-defined disease stage (stage II: 6%, stage III/IV A: 22%, stage IV B/C: 55%). HIV-1-infected patients excreting CMV in the urine also exhibited distinctly decreased numbers of CD4+ cells and significantly decreased CD4+/CD8+ ratios compared to those without CMV viruria.ZusammenfassungDie Ausscheidung von Cytomegalievirus im Urin und Serumantikörper gegen CMV wurden bei 79 HIV-1-Infizierten in verschiedenen Krankheitsstadien sowie bei 27 heterosexuellen und 52 männlichen homo-/bisexuellen Kontrollpersonen untersucht und zu klinischen und immunologischen Befunden in Beziehung gesetzt. Zwischen HIV-1-Infizierten und gesunden Probanden bestand hinsichtlich der Hautreaktion vom verzögerten Typ (Typ-IV-Reaktion), der absoluten Zahl der CD4+-Lymphocyten und des CD4+/CD8+-Quotienten ein signifikanter Unterschied. IgG-Antikörper gegen CMV wurden bei 87% der homosexuellen und 52% der heterosexuellen Kontrollpersonen und bei allen HIV-1-infizierten Homosexuellen gefunden. Eine CMV-Ausscheidung im Urin fand sich ausschließlich bei HIV-1-infizierten Personen. Ihre Häufigkeit korrelierte mit dem CDC-Stadium der Krankheit (Stadium II: 6%, Stadium III/IV A: 22%, Stadium IV B/C: 55%). CMV-Ausscheider zeigten gegenüber HIV-1-Infizierten ohne CMV-Ausscheidung eine signifikant erniedrigte Zahl von CD4+-Zellen sowie einen signifikant erniedrigten CD4+/CD8+-Quotienten.

Überlegungen und Hochrechnungen zur Epidemiologie des Acquired Immunodeficiency Syndrome «in der» Bundesrepublik Deutschland

ZusammenfassungAufgeschlüsselt nach Bevölkerungskollektiven mit unterschiedlichen sexuellen Verhaltensweisen wird anhand der bisher bekannten bzw. größenordnungsmäßig abgeschätzten epidemiologischen Daten des „Acquired Immunodeficiency Syndrome“ eine Hochrechnung der Morbiditäts- und Mortalitätsziffern für die Bundesrepublik Deutschland mittels Computer-Simulation vorgenommen; danach könnten in den nächsten 15 Jahren bis ca. 41 000 Personen erkranken. Die Bedeutung der weiblichen Prostituierten und der männlichen Bisexuellen als „Vektoren“ der Infektion aus den bisherigen Risikogruppen in Bevölkerungsteile mit ausschließlich heterosexuellen Verhaltensweisen, der Einfluß infektiologischer Schutzmaßnahmen sowie der Effekt sexueller Verhaltensänderungen breiter Bevölkerungsschichten kann mit diesem Programm ebenfalls untersucht werden.SummaryA computer simulation of the morbidity and mortality rates of the “Acquired Immunodeficiency Syndrome” in the Federal Republic of Germany was performed. Since sexual intercourse is the main mode of transmission, the population was divided into six groups with different sexual behaviour. In several variations of the program it is demonstrated that during the next 15 years up to 41,000 AIDS patients can be expected. The importance of female prostitutes and male bisexuals as “vectors” who may transmit the infection into exclusively heterosexual groups is shown. Using this program, the effect of prophylaxis against infection as well as of changes of sexual behaviour within the population at large can also be examined.

Efficacy of intravenous immunoglobulins in patients with advanced HIV-1 infection. A randomized clinical study

Summary40 adults with symptomatic HIV-1 infection (AIDS related complex [ARC] WR 2B–4B or AIDS WR 5–6) were randomized into two groups, receiving either 200 mg of an i. v. immunoglobulin preparation (ivIg)/kg body weight every other week or no such treatment. Medical care and antibiotic therapy were comparable in the two groups. Frequency of opportunistic infections, “B”-symptoms, number of T-helper cells, change of disease stage (Walter Reed Classification, WR), delayed cutaneous hypersensitivity, onset and clinical course of Kaposis sarcoma, neurological manifestations and proportion of patients alive at the end of the observation period were evaluated. After an average observation period of 13.8 months, decreased mortality was observed in ivIg treated patients of WR 5–6 (p<0.004). Frequency and microbial spectrum of opportunistic infections, the most frequent cause of death, were not influenced significantly by ivIg treatment. No statistically relevant differences concerning the other parameters were observed. A similar beneficial effect of ivIg in WR 2B–4 patients has not become apparent so far.Zusammenfassung40 Erwachsene mit symptomatischer HIV-1 Infektion (AIDS related complex [ARC] WR 2B–4B oder AIDS WR 5–6) wurden in zwei Gruppen randomisiert und erhielten entweder 200 mg einer intravenös applizierbaren Immunglobulinpräparation (ivIg)/kg Körpergewicht alle 14 Tage oder keine solche Therapie. Die medizinische Versorgung und die antibiotische Therapie war in beiden Gruppen vergleichbar. Untersucht wurden die Häufigkeit opportunistischer Infektionen, der „B“ Symptome, der Anzahl von T-Helferzellen, Veränderungen des Krankheitsstadiums (Walter Reed Klassifikation [WR], die kutane Typ IV Reaktion vom verzögerten Typ, das Auftreten und der klinische Verlauf des Kaposi Sarkoms, neurologische Manifestationen und die Zahl überlebender Patienten am Ende der Studie. Nach einer durchschnittlichen Beobachtungszeit von 13,8 Monaten konnte eine verringerte Mortalität der ivIg behandelten Patienten der Stadien WR 5–6 festgestellt werden (p<0,004). Hingegen konnte durch die ivIg Behandlung die Häufigkeit und das Keimspektrum der opportunistischen Infektionen, der häufigsten Todesursache, nicht signifikant beeinflußt werden. Auch bei den anderen Parametern zeigten sich keine statistisch signifikanten Unterschiede. Eine Verbesserung des Krankheitsverlaufes bei Patienten im Stadium WR 2B–4 war nicht nachweisbar.

New aspects in the treatment of gram-negative bacteraemia and septic shock.

Despite the development of a spectrum of new antimicrobial drugs, sepsis and septic shock have remained associated with a high mortality rate. A recent investigation reported by the Sloan Kettering Institute revealed a lethality of 31% in a group of non-neutropenic septic patients (n = 239) and a lethality of 52% in a group of patients (n = 158) with neutropenia before onset of septic complications. If more than one pathogen was found to be involved, lethality of the septic complication increased to 80%. This high lethality led to the search for additional modalities for the treatment of sepsis and septic shock during the last years. Characteristic symptoms of infections caused by gramnegative bacteria such as Escherichia coli, Pseudomonas spp., Salmonella or Shigella spp. are fever, headache, hypotension, changes in leukocyte counts, diarrhea, and in severe cases shock and death may follow. These effects of gram-negative pathogens are widely independent of bacterial viability and can also be elicited by the injection of killed bacteria or of preparations of endotoxins released from the wall of gram-negative cells after cell death (1). The obvious similarity between symptoms of gram-negative bacteraemia and the effects of endotoxin has consequently led to the assumption that endotoxin liberated from the bacterial cell wall during infection must be regarded as a causative agent of certain manifestations of septicaemia and septic shock (2, 3). The lipid A component of the lipopolysaccharide (LPS) molecule was shown to be responsible for the majority of the endotoxic activities (4-7). Lipid A expresses affinity to various humoral factors: Lipid A was shown to be capable of activating the complement cascade by the classical as well as the alternate pathway. The excessive complement activation may have a deleterious effect in gram-negative shock, especially through increased chemotaxis of polymorphonuclear leukocytes resulting in pulmonary leukostasis, leading to the acute respiratory distress syndrome (8). In this context, the liberation of anaphylatoxins may increase the inflammatory process and lead to vascular permeability disturbances. In addition, lipid A can activate factor XII (Hageman factor), a key factor for activation of the coagulation and flbrinolytic systems as well as the bradykinin system. Activation of these systems leads to disseminated intravascular coagulation with thrombosis and consumption of coagulation factors and platelets. This process again may lead to depletion of coagulation factors and to activation of the fibrinolytic system (9, 10). The interaction of LPS with high-density lipoprotein (HDL) is of special significance (7, 11). The HDL obviously serves as a carder for circulating LPS or lipid A and it appears to prevent the random attachment of LPS to cells and tissues. Rather, HDL may ensure a more specific transport of LPS to organs of clearance and metabolism. The most prominent organs involved in LPS accumulation are the liver and, to some extent, the spleen. To a lesser extent, LPS can also be detected in the lung. At these body sites, LPS may interact with reticuloendothelial cells, and this event is believed to play a decisive role in the mechanism of LPS action. Notably, macrophages and Kupffer cells have been shown to form and release, as a result of exposure to lipopolysaccharide, a variety of mediators that are endowed with distinct biologic activities (12). Well-studied examples of such endogenously produced mediators are endogenous pyrogen, tumor necrosis factor, glucocorticoid antagonizing factor, plasminogen activator, procoagulant activity, colony stimulating activity, interleukin-1, insulin-like activity, prostaglandine E 2 and F2, and others (1). These mediators can induce many of the typical endotoxin effects such as fever, hypotension, and shock. In vivo, these factors may act locally or they may be released into the circulation and transported to distinct susceptible target cells and organs such as the kidneys, the central nervous system and the skin. Thus, host-derived endogenous mediators may be finally responsible for the mediation of various effects observed after endotoxin injection in experimental animal models or even during the septic process in man. Gram-negative endotoxin may be introduced into the host by absorption from infected wounds, from the intestines, by the intermittent deliberation from a septic focus and by parenteral infusion of non-sterile medical devices. Since small amounts of endotoxin can cause severe clinical symptoms, the availability of a sensitive and specific assay system for gram-negative endotoxin is crucial for the diagnosis of endotoxinaemia. During the last ten years, considerable progress has occurred in the development of techniques for detecting endotoxin in many types of different samples and body fluids. These test systems also became applicable for routine clinical use. The limulus amoebocyte lysate-(LAL-)clotting test revealed disadvantages particularly for diagnostic use in septic patients because of its activation by many substances other then endotoxin, such as colony stimulating factor or heparin derivatives. The development of chromogenic peptide substrate could improve the LAL technique, increasing its specificity and sensitivity for gram-negative endotoxin (13). The chromogenic proce-