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Sepsis and organ dysfunction: an ongoing challenge.

In recent years the problem of infection has become increasingly significant, especially in intensive care hospital wards such as Intensive Care Units (ICU), emergency medicine, surgery and critically ill patient care departments. Sepsis is a complex, multifactorial syndrome that can develop into conditions of different severity, described as severe sepsis or septic shock. In these conditions the triggering event may coincide with the functional impairment of one or more vital organs or systems, thus leading to poorer prognosis in patients with overt signs of sepsis or systemic inflammation syndromes. The available data are quite alarming, as most prevention and treatment is performed empirically and requires considerable human and technological resources. Clinical signs are often misleading and, in some circumstances, it may be difficult or even impossible to identify the source of the infection which might otherwise be removed relatively simply, using proper antimicrobial treatment or a less invasive surgical removal of the area from which the infection originates based on needle-guided radiology. In addition, the complex pathophysiological mechanisms involved can be an obstacle to gaining a full understanding of the various biohumoral interactions or mediators action mechanisms. It may not be easy to enroll patients belonging to homogeneous groups in terms of age, underlining disease, immune profile or genetic predisposition, although the use of specific severity indexes has proved helpful also to establish the prognosis. Although the interpretation of generalised inflammation as a warning sign also in the absence of clear signs of infection or a state of overt inflammation has to rely largely on simple intuition, it has helped to drive experimental and clinical research work towards the investigation of interaction between different factors such as infection and sepsis, or inflammation and coagulation. An additional useful tool is the possibility of modulating the endothelial response which may support the process of disseminated thrombosis typical of sepsis evolution. In this context the improvement of standards of care can shed light on the efficacy of different treatments.

Blood Coagulation↗

Diagnosis of vertical HIV-1 transmission using the polymerase chain reaction and dried blood spot specimens.

We have used the polymerase chain reaction (PCR) to detect HIV proviral sequences in minute amounts of peripheral blood collected onto newborn screening blotters. Forty-three newborns, infants, and children of HIV-infected mothers were serially studied: dried blood spot (DBS) specimens were processed for PCR; serum was assayed for HIV antibodies, p24 antigen, and immunoglobulins; mononuclear cells were cultured and CD4 cells were quantitated by immunofluorescence. There was excellent agreement between the results of blood spot PCR, viral culture, and clinical and immunological indicators of HIV infection. Eighteen of 19 infected children tested positive by both PCR and culture, including six asymptomatic infants who were less than 10 weeks of age. As expected, p24 antigen capture assays were insensitive, detecting only 13 of the 19 infected children. One infected infant tested positive by PCR, but negative by culture and antigen. This infant was seropositive at 27 months and had pronounced hypergammaglobulinemia in association with non-specific symptoms. Twenty-four of the 43 infants were asymptomatic with normal immune profiles, declining antibody levels and no evidence of infection. These children tested repeatedly negative by PCR, culture, and p24 antigen assays. Our results indicate that DBS PCR is a sensitive, specific, and cost-effective alternative to viral culture for the early diagnosis (or exclusion) of perinatal HIV infection. DBS sampling opens the way for large-scale prospective studies to determine the exact rates of vertical HIV transmission in industrialized, as well as, nonindustrialized countries.

Child, Preschool↗

Crossed immunoelectrophoretic analysis and viral neutralizing activity of five monospecific antisera against five different herpes simplex virus glycoproteins.

Crossed immunoelectrophoresis of Triton X-100 solubilized HSV-infected cells has identified several major HSV glycoprotein antigens in the precipitating profile. Immunization of rabbits with the corresponding precipitates resulted in the production of monospecific antisera against the antigen part of the precipitate. The immunological importance of five different HSV glycoproteins in respect of their representation on the outer virion envelope as targets for neutralizing antibodies was evaluated by comparison of immunoprecipitating activity and neutralizing potency of the corresponding monospecific antisera.

Antibodies, Viral↗

Health status of Air Force veterans occupationally exposed to herbicides in Vietnam. I. Physical health.

The Air Force Health Study is a 20-year comprehensive assessment of the health of Air Force veterans of Operation Ranch Hand, the unit responsible for aerial spraying of herbicides in Vietnam. The study compares the health and noncombat mortality of Ranch Hand veterans with a comparison group of Air Force veterans primarily involved with cargo missions in Southeast Asia but who were not exposed to herbicides. This report summarizes the health of these veterans as determined at the third in a series of physical examinations. Nine hundred ninety-five Ranch Hands and 1299 comparison subjects attended the second follow-up examination in 1987. The two groups were similar in reported health problems, diagnosed skin conditions, and hepatic, cardiovascular, and immune profiles. Ranch Hands have experienced significantly more basal cell carcinomas than comparison subjects. The two groups were not different with respect to melanoma and systemic cancer.

2,4,5-Trichlorophenoxyacetic Acid↗

[Evaluation of immunologic status in mandibular fractures].

Immunity state was assessed in patients with uncomplicated course of mandibular fractures with resorption and regeneration of osseous tissues. The data allowed one to characterize the relevant disorders as a syndrome of immune system overload. This is a potent criterion for evaluation of the fractures' severity. Under the overload general shifts are detected most pronouncedly in the local oral cavity immunity. Characteristic profiles of immunity interrelations are combined with the immunity strain changes within the interconnection system. This is of major prognostic importance for the course of mandibular fractures and inflammatory complications.

Adolescent↗

Murine immune response to the Neisseria meningitidis group C capsular polysaccharide. I. Ontogeny.

The immune response to polysaccharide Ag develops late in ontogeny and the underlying mechanisms of the infant unresponsiveness are poorly understood. The development of vaccines that will prove efficacious in infants has been hindered by the lack of animal systems suitable for studying immunity to human pathogens. We have examined the BALB/c murine response to the capsular polysaccharide of Neisseria meningitidis group C (MCPS), a homopolymer of alpha(2----9) sialic acid, as a model system for the development of immunity to bacterial polysaccharides in man. We have observed the appearance of natural antibody of both IgM and IgG classes which increases with age, and the transfer of maternal IgG to the offspring. Both the naturally occurring and postimmunization serum responses are restricted to the IgM and IgG3 isotypes, and include antibody titers to both MCPS as well as a natural O-acetyl-negative variant (OAc-). The preimmune anti-OAc- antibodies, in contrast to anti-MCPS, were restricted to the IgM class, whereas after immunization with MCPS both IgM and low titers of IgG3 antibodies to OAc- were produced. These studies demonstrate that the BALB/c mouse strain shows a markedly similar immune profile to that observed in man.

Aging↗

Epidemiologic features of influenza in a large urban centre (B.) in Romania, in 1987.

The study presents the peculiarities of influenza evolution in 1987 in a large town in Romania. These features were defined by a complex methodology, based on clinical, epidemiologic and laboratory investigations, used in the active control of the epidemiologic process kinetics. The influenza viruses type A (H1N1 and H3N2) had a major role in the infecting and immunizing contacts in all age groups whereas the influenza virus type B had a reduced circulation. The epidemiologic influenza impact in 1987 is discussed from the point of view of the complex relationships between the antigenic structure of circulating influenza viruses and the anti-influenza immune profile of the population under the influence of extremely complex economic, social and natural factors.

Age Factors↗

Models for assessing the effect of toxicants on immunocompetence in mice. II. Effect of cyclophosphamide on the antibody responses to type III pneumococcal polysaccharide and tetanus toxoid in BALB/c female mice.

A mixture of antigens was used to detect alterations in immunocompetence. Type III pneumococcal polysaccharide (S3) and tetanus toxoid (TT) stimulate different cellular components, and can therefore be used to assess different compartments of the immune mechanism. Cyclophosphamide (CP), a known immunosuppressant, had a potent effect upon the antibody responses to both S3 and tetanus toxoid. All doses of CP administered within 2 days of priming with S3 resulted in a dose-related immunosuppressive action which persisted even after reinjection of S3. 300 mg/kg of CP given up to 14 days prior to or following primary immunization resulted in a marked suppression of antibodies to S3. Doses of S3 which were partially tolerogenic were made even more so by injections of CP. The effect persisted over a 96 day experimental period. CP also suppressed the formation a memory cells necessary for induction of a secondary-type IgG response to TT. The time of injection for maximum suppression was days 10 to 14 after priming. Therefore, the suppression must involve cellular mechanisms different from those responsible for S3 antibody suppression. In addition, there was a difference in the degree and persistence of the suppressive effect, since the suppressed animals were able to mount an immune response to subsequent injections of TT. Double injections of a high dose (300 mg/kg) of CP 4 weeks after priming completely suppressed the acquired immunity to both S3 and TT. Low and moderate doses of CP appeared to induce a mild augmentation of S3 antibody response when given 4 weeks after priming. However, an immunosuppressive effect occurred if the primed animals were reinjected with S3 or challenged with TT within a period of 2 days prior to or after receiving the CP treatment. Doses of CP, injected prior to challenge and resulting in suppressed tetanus antitoxin production, elevated the titers of specific IgE antibody. This class of antibody is associated with adverse hypersensitivity reactions. These data provided background for the development of models to assess immunocompetence in mice, based on a study of immune profiles following exposure to selected T-dependent and T-independent antigens. Such models may be used to detect potentially hazardous chemicals found in the environment of incorporated into foods, drugs, or cosmetics.

Animals↗

Transfer factor for adjuvant immunotherapy in cervical cancer.

In a prospective randomized double-blind study of 60 patients with invasive cervical cancer, 32 were treated with transfer factor (TF) derived from leukocytes of the patients' husbands, and 28 were treated with placebo. Within the first 2 years after radical hysterectomy, five out of 32 TF-treated patients and 11 out of 28 placebo-treated patients developed recurrence of malignancy. Excluding one further patient with intercurrent death this difference is significant (chi 2 = 3.9915; P less than 0.05). Subdividing the collectives, significant differences were found in patients aged below 35 years and in patients with stage I disease. Identical immune profiles were checked in leukocyte donors prior to leukophoresis and were serially checked in patients. Antigen-specific correlations were found between donors' and recipients' reactivities but not between donors' reactivity and recipient's course of the disease.

Clinical Trials as Topic↗

Study of lymphoid tissue in paediatric ENT practice.

This study comprises 2 groups of children; allergic (18) and non-allergic (36), having undergone tonsillectomy, adenoïdectomy or both. The humoral immunity profile' bacteriology and neutrophile and eosinophile cell populations of the lymphoid tissues removed were compared. No significant difference was brought into evidence. The bacteriology of the two groups did however show a preponderance of Haemophilus influenzae. This would appear to be in contradiction to the generally accepted theories.

Adenoids↗

Bullous pemphigoid refractory to recommended dosage of prednisolone in a dog.

Bullous pemphigoid in a dog was diagnosed on the basis of clinical, histopathologic, and immunologic criteria. There were widespread ulcerative lesions of the skin. Numerous ulcerative lesions and occasional bullous lesions were on the oral mucous membranes. Histopathologic changes included dermal-epidermal separation, with subepidermal production of bullae. Direct immunofluorescent staining of the skin revealed depositions of immunoglobulin G and of the 3rd component of the complement system. Indirect immunofluorescent staining of donor skin sections pretreated with patient's serum revealed antibasement membrane antibody in the patient's serum. Most of the data in the serum immune profile were within normal ranges. Prednisolone therapy did not effect remission at the dosage of 4.4 mg/kg/day, but led to the beginning of remission within 7 days at a dosage of 6.6 mg/kg/day. The dosage was gradually reduced to 1.1 mg/kg, at 30 days, after which the drug was given on alternate days at that dosage. The healing was complete within 35 days, without any remissions when the dog was last examined (ie, over 6 months).

Animals↗

Antibody response to recombinant 65-kDa, 70-kDa and 18-kDa mycobacterial antigens in leprosy patients and healthy contacts in a leprosy-endemic population.

Antibody responses to recombinant Mycobacterium leprae 65-kDa (rML65) and 18-kDa (rML18), M. bovis BCG 65-kDa (rMB65) and M. tuberculosis 70-kDa (rMT70) antigens were measured by indirect ELISA in sera from leprosy patients and healthy contacts in a leprosy-endemic area in southern India. Antibody responses to M. leprae-specific epitopes on phenolic glycolipid-I (PGL-I) and a 35-kDa protein antigens also were measured simultaneously by PGL-I ELISA and the serum antibody competition test (SACT), respectively. Significantly higher levels of antibodies of the IgG isotype to rML65 and rMB65 were observed in bacterial index (BI)-positive, lepromatous (LBI+) patients but not in other groups of leprosy patients and endemic controls [healthy family contacts (HFC), healthy hospital contacts (HHC), and healthy non-contacts (HNC)]. LBI+ patients could be distinguished from LBI- patients on the basis of their higher levels of IgG antibodies to rML65, rMB65 and rMT70; lower levels of IgM antibodies to these antigens and higher levels of anti-PGL-I IgM levels. In the former group, 84% were SACT positive in contrast to 39% in the latter groups. Among lepromatous patients good positive correlations were observed between IgG antibody responses to rML65 and rMB65 and anti-PGL-I IgM levels, SACT ID50 titers as well as BIs. Among healthy controls, HFC had higher levels of IgG antibodies to rML65, but lower levels to rMB65 than did HNC. Thirty-nine percent of the HFC were seropositive to anti-PGL-I IgM antibodies in contrast to 4% in the HNC. On the basis of these criteria, the immune profile of the HFC appears to be distinctly different from that of the HNC, even though both groups are from the same endemic area. It is therefore possible that antibody response to defined protein antigens of mycobacteria is influenced by the lesional bacterial load in leprosy patients and by exposure to homologous proteins of M. leprae and/or related environmental mycobacteria in the case of healthy contacts and noncontacts. The above results are discussed in relation to T- and B-cell activity toward M. leprae antigens and the immunoregulatory mechanisms of antibody production in leprosy.

Antibodies, Bacterial↗

High versus ultra-high purity factor VIII concentrate therapy: prospective evaluation of immunological and clinical parameters in HIV seronegative and seropositive hemophiliacs.

This study aimed at evaluation of the immunological status and the clinical course of both HIV seronegative and seropositive hemophiliacs treated with either an ultra-pure factor VIII product (UP-F VIII), or a high-purity F VIII (HP-F VIII) concentrate. Eighteen HIV seronegative patients were divided into two groups of therapy and their immune status was followed for 2 years. During the second year of the study 8 patients of the HP-F VIII and 6 from the UP-F VIII therapy groups were switched to the alternative F VIII concentrates. Eighteen asymptomatic HIV seropositive patients were also divided into therapy groups and their immune status and any development of HIV-related symptoms were followed for 4 years. Evaluation of the HIV seronegative patients during the first year did not reveal any differences between the groups in the CD4 or CD8 cell counts, in natural killer cell (NK) activity, or in the mitogenic responses of T lymphocytes to Phytohemagglutinin (PHA), and of B lymphocytes to Pokeweed mitogen (PWM). The switch of 8 patients from the HP-F VIII and 6 from the UP-F VIII groups to the alternative concentrate did not yield any changes in their immune profile during the second year of the study. The HIV seropositive groups differed in the initial CD4 count, with a lower CD4 count (193 +/- 126 vs 437 +/- 142) and a higher F VIII consumption (63,000 +/- 17,000 vs 26,000 +/- 10,000) in the UP-F VIII group.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗

Vaccines directed against HIV: preventive and therapeutic strategies.

Vaccine therapy studies in HIV-seropositive volunteers over the next year should provide additional insights into whether different vaccine viral strains (LAI, IIIB, MN, SF2), different protein sources (whole virus particles, recombinant protein, peptides), different expression systems (baculovirus, mammalian), or different adjuvants (incomplete Freund's, MTP-PE, MF59, alum) generate significantly different immune responses at the cellular and humoral level. In addition, differences in the ability of each vaccine to induce humoral immune responses to epitopes in the constant regions vs. variable regions, contiguous or noncontiguous "conformational" epitopes, with high vs. low antibody affinity can be evaluated. The roles of antibody-dependent cellular cytotoxicity (ADCC), cellular recognition, nonspecific natural killing, and MHC-restricted cytotoxicity can also be explored. To date, the majority of the immunogens have proven to be safe. Many induce new humoral and cellular immune responses against HIV. The final important question remains, whether any of these vaccines used as therapeutic immunogens generate immune responses that induce an altered disease course with a prolonged asymptomatic period without immunodeficiency, whether vaccines can affect increased viral clearance, or decreased transmission/infectivity? There remains no in vitro assay known to correlate with lack of disease progression, no immune profile consistent with a prolonged asymptomatic period. The vaccine therapy trial researchers seek the answers to these important questions. No single research organization can begin to address all the possibilities, so the overall pace of exploration of this therapeutic concept is likely to be dictated by the level of cooperation between the many groups involved in these studies. Open collaboration between researchers and open exchange of reagents, immunogens for in vitro experiments, and sera will allow faster dissection of the many questions and issues raised in this chapter. Whether vaccine therapy proves to have a useful role in the treatment of HIV-1-induced disease, these studies will ultimately lead to the development of useful techniques and provide new insights into the nature of the immunological responses, as the investigation of vaccine therapy did over a century ago.

AIDS Vaccines↗

Immunological actions of cyclosporin A in rheumatoid arthritis.

Rheumatoid arthritis is present in a population which is heterogeneous both clinically and immunologically. A variety of cells including lymphocytes, macrophages and fibroblasts play important roles in its pathogenesis, but the T cell appears to be a common thread throughout the disease process. Treatments aimed at reducing these lymphocytes mechanically and specifically result in a good clinical response in many patients. The mechanism of action of cyclosporin A (CyA) in inhibiting T lymphocytes presents a more specific form of therapy. Though limited, studies including immune profiling suggest that certain subgroups of RA patients are more likely to respond to CyA. Further studies are required to test these findings, but targetted therapy with CyA could result in enhanced and longer-lasting efficacy.

Arthritis, Rheumatoid↗

[Hormonal-metabolic and immune status in recurrent laryngeal papillomatosis in children].

Clinical, biochemical and immunological findings in 12 children with recurrent laryngeal papillomatosis evidence for defects in hormonal--metabolic and immune profiles in terms of depressed sympathoadrenal, adrenocortical functions and secondary immunodeficiency. To correct the above disorders it is advisable to practice immunocorrective therapy and drugs (prospidin) stimulating adrenal function.

Adjuvants, Immunologic↗

Evaluation of cow-level risk factors for the development of winter dysentery in dairy cattle.

OBJECTIVE: To identify exposures to etiologic agents and to identify characteristics that could explain risk of disease for adult cattle in herds affected by winter dysentery (WD). ANIMALS: 229 lactating and nonlactating adult cattle (125 case and 104 control cattle) selected from 12 dairy herds. PROCEDURE: A case-control study, using multivariate conditional logistic regression and controlling for herd effects, was used to develop a model for risk factors associated with disease for each cow. RESULTS: Likelihood of developing disease increased as the ELISA value for bovine coronavirus (BCV) antigen detectable in feces increased (odds ratio [OR] = 2.94 for each 0.100 increase in BCV antigen ELISA value). Pregnant cattle were less likely to develop WD, compared with nonpregnant herdmates. Cows with high acute BCV antibody titers that seroresponded had greater odds of developing disease, compared with seroresponding cows with low acute titers. However, among those cows that did not serorespond, high acute antibody titers were associated with lower odds of developing the disease. CONCLUSION: In herds affected by WD, ill cows were more likely to shed detectable amounts of BCV antigen in their feces, and pregnancy appeared to protect cattle from the disease. The measured interaction between BCV seroresponse and acute BCV antibody titer may be evidence of an immunopathologic condition, but could also have been attributable to dynamics of the ELISA or study design. CLINICAL RELEVANCE: Factors that explained a cow's risk for illness within WD-affected herds may have been surrogate measures for that cow's nonspecific and BCV-specific immune profile.

Animals↗

Generalized cutaneous reactions to the anthrax vaccine: preliminary results of anthrax vaccine-specific cell mediated immunity and cytokine profiles.

Over two years, the Vaccine Adverse Event Reporting System reported that 0.042% of all anthrax vaccine (Biothrax, Bioport Corporation) doses administered were associated with cutaneous reactions, half of which were eczematous. This case series attempts to immunologically detail this eczematous reaction in four patients by measuring anthrax vaccine-specific cell mediated immunity (ASCMI), profiling TH1 and TH2 cytokine response to the anthrax vaccine in vitro, and analyzing of skin biopsy specimens. Results demonstrated that (1) ASCMI was variable and likely unrelated to this reaction; (2) a lack of TH1 cytokine response to anthrax vaccine may be associated with an increased risk of this eczematous reaction; and (3) skin biopsy findings were nonspecific but supportive of a clinical diagnosis of eczema. Future studies with more patients may yield data to further characterize the ASCMI response and cytokine profiles among patients with this type of reaction.

Adult↗