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Opportunistic infections and retrovirus-induced immunodeficiency: studies of acute and chronic infections with Toxoplasma gondii in mice infected with LP-BM5 murine leukemia viruses.

Mice infected with LP-BM5 murine leukemia viruses develop a syndrome, termed mouse AIDS (MAIDS), characterized by increasingly severe immunodeficiency and progressive lymphoproliferation. Virus-infected mice were examined for the ability to resist acute infection and to control chronic infection with the protozoan Toxoplasma gondii, a major opportunistic pathogen of individuals infected with human immunodeficiency virus. Mice infected with the retroviruses for 2 or 4 weeks responded normally to challenge with the parasite, but mice inoculated with the protozoan 8 or 12 weeks after viral infection died with acute disease due to T. gondii. Increased sensitivity to acute infection was associated with a reduced ability to produce gamma interferon (IFN-gamma) and with established changes in CD4+ T-cell function. Mice latently infected with T. gondii and then inoculated with the retrovirus mixture were found to reactivate the parasite infection, with 30 to 40% of dually infected animals dying between 5 and 16 weeks after viral infection. Reactivation was associated with reduced proliferation and impaired production of IFN-gamma in response to stimulation with soluble T. gondii antigens or to concanavalin A. Continuing resistance to lethal reactivation in the remaining mice was shown to require CD8+ T cells and expression of IFN-gamma. In addition, it was found that chronic infection with T. gondii altered the course of MAIDS by inhibiting the progression of splenomegaly and immunodeficiency and reducing the expression of both the helper and etiologic defective viruses. These results support previous studies which indicate that infection with T. gondii is controlled by synergistic interactions between CD4+ and CD8+ T cells, the functions of which are progressively impaired during the course of MAIDS.

Acute Disease

Interactions between HIV-infected monocytes and the extracellular matrix: increased capacity of HIV-infected monocytes to adhere to and spread on extracellular matrix associated with changes in extent of virus replication and cytopathic effects in infected cells.

Monocytes express cell surface receptors for extracellular matrix (ECM) proteins of basement membranes. These receptors are engaged during extravasation of cells through capillary endothelium into tissue. The number of human immunodeficiency virus (HIV)-infected monocytes that adhered to ECM over 2 h was threefold higher than that of uninfected control cells. This difference was ECM specific and was not observed with a bovine serum albumin substrate. Enhanced adhesion to ECM was evident in monocytes by 4 days after HIV infection and increased through 10 days. Monocytes exposed to a T cell-tropic HIV strain that binds to but does not replicate in monocytes showed no changes in adherence to ECM. Thus, productive infection of monocytes by HIV induces a significant increase in the capacity of these cells to interact with ECM. Enhanced adhesion of HIV-infected monocytes to ECM was associated with increased spreading: at 12 h, sixfold more HIV-infected monocytes were spread on ECM than were uninfected control cells. Cell processes of HIV-infected monocytes formed a complex network on ECM: many of these cells expressed HIV proteins as detected by indirect immunofluorescence. HIV-associated cytopathic effects and levels of virion-associated reverse transcriptase activity depended on the substrate to which monocytes were attached. Virus replication and cytopathic effects in monocytes adhered to ECM, fibronectin, or plastic alone were comparable. In contrast, HIV-infected monocytes attached to laminin showed a significant increase in virus replication and in extent of cytopathic effects through 2 weeks after infection. The lowest levels of HIV replication and cytopathic effects were in monocytes attached to collagen IV. Interactions between monocytes and ECM profoundly affect the manner in which these cells control HIV infection: HIV infection changes the capacity of infected monocytes to attach and spread on ECM; attachment to ECM alters the extent of virus replication in infected cells.

Cell Adhesion

Bovine respiratory syncytial virus infection of bovine embryonic lung cultures: enhancement of infectivity with diethylaminoethyl-dextran and virus-infected cells.

The effects of incorporating diethylaminoethyl-dextran (DEAE-D) in the inoculum with bovine respiratory syncytial virus (BRSV) on the infectivity of BRSV was evaluated. A concentration of 40 microgram DEAE-D/ml provided maximal enhancement of infection as determined by the time of onset of cytopathic effect (CPE), the percentage of cells infected by the inoculum, and the amount of virus produced. When DEAE-D was used in the inoculum, the CPE appeared a day earlier, the percentage of cells infected by the inoculum, as determined by the fluorescent antibody test, was increased 11 times, and the viral titer was increased 2 times as compared to results obtained without DEAE-D. Bovine respiratory syncytial virus-infected cultures contained much cell-associated virus which could be liberated by sonication to increase the titer of virus stocks. The use of BRSV-infected cells rather than supernates from BRSV-infected cells increased the rate at which a cytopathic effect developed, although it did not substantially increase the titer of virus which was harvested. The use of DEAE-D in the inoculum and the passage of BRSV-infected cells instead of viral suspensions was found to be the quickest and most effective method of consistently obtaining BRSV with a titer of about 10(5.5) TCID50/ml.

Animals

Course of antibody production by the DIG-ELISA method in neonatally infected and juvenile infected rats after primary infection with Breinlia booliati (Filarioidea: Onchocercidae).

The course of antibody production in Wistar neonatal and juvenile rats after primary infection with Breinlia booliati was studied by the DIG-ELISA technique using filter papers impregnated with capillary blood drawn from the infected rat tails at 7, 14, 28, 60 and 90 days post infection. Sera of neonatally infected rats did not react with adult worm antigen until day 7 and the titers of antibody remained at very low levels for the next 7 days. There was little tendency to eliminate the filarial larvae during this time. The antibody levels then rose rapidly throughout the next fortnight and increased to a maximum at day 60 after which the titer leveled out at a constant high value until early patency at day 90. On the other hand, antibodies could be detected in sera of juvenile infected rats as early as day 7 and the levels of antibody rose markedly to a maximum at day 28. During the period from day 60 to day 90 at early patency, the antibodies declined gradually to lower levels. The humoral immune responses of 42 neonatally infected rats and 53 juvenile infected rats of 3 strains (Lewis, Wistar and Sprague Dawley) were tested against soluble B. booliati antigens from both female (1:50) and male (1:10) worm extracts by the DIG-ELISA method. Antibodies were detected in sera from all the microfilaremic and amicrofilaremic rats belonging to neonatally and juvenile infected groups. Sera of clean neonatal rats did not give a positive reaction zone.

Age Factors

Herpes simplex virus type 2 infection, syphilis, and hepatitis B virus infection in Haitian women with human immunodeficiency virus type 1 and human T lymphotropic virus type I infections. The Johns Hopkins University (JHU)/Centre pour le Developpement et la Santé (CDS) HIV Study Group.

Antibodies to herpes simplex virus type 2 (HSV-2), antibodies to hepatitis B virus (HBV) core antigen (anti-HBc), and VDRL antibodies (serologic evidence of syphilis) were evaluated in women known to be infected with human immunodeficiency virus type 1 (HIV-1) (n = 95) or human T lymphotropic virus type I (HTLV-I) (n = 45) and controls (n = 89). HIV-1-seropositive women were more likely than controls to have antibodies to HSV-2 (88% vs. 54%; P less than .001), anti-HBc (67% vs. 43%; P = .008), and VDRL antibodies (21% vs. 8%; P = .02). Similarly, HTLV-I-seropositive women were more likely than controls to have antibodies to HSV-2 (82% vs. 54%; P = .003) and anti-HBc (67% vs. 43%; P = .008). There was no evidence that HIV-1 or HTLV-I predisposed to chronic hepatitis B virus infection. The stronger associations between HIV-1 and HTLV-I with HSV-2 than the associations with syphilis or HBV are consistent with the hypothesis that recurrent disruptions of mucous membranes caused by HSV-2 infections predispose to sexual transmission of HIV-1 and HTLV-I.

Adolescent

Consensus paper on the surveillance of surgical wound infections. The Society for Hospital Epidemiology of America; The Association for Practitioners in Infection Control; The Centers for Disease Control; The Surgical Infection Society.

A Surgical Wound Infection (SWI) Task Force was convened by The Society for Hospital Epidemiology of America (SHEA) to evaluate how SWI surveillance should be done and to identify where more information is needed. The Task Force reached consensus in the following areas. The Centers for Disease Control (CDC) definitions of SWI should be used for routine surveillance because of their current widespread acceptance and reproducibility. The CDC definitions have been clarified in an accompanying article ("Report From the CDC"). Direct observation of wounds and traditional infection control surveillance techniques are acceptable methods of case finding for hospitalized patients. The optimal method for case finding postdischarge or after outpatient surgery is unknown at this time. SWI rates should be stratified by surgical wound class plus a measure of patient susceptibility to infection, such as the American Society of Anesthesiology (ASA) class, and duration of surgery. Surgeon-specific SWI rates should be calculated and reported to individual surgeons.

Centers for Disease Control and Prevention, U.S.

Studies on the infectivity of Fasciola hepatica miracidia to Lymnaea truncatula. Attachment and penetration of miracidia into non-infected and infected snails.

Fasciola hepatica miracidia labelled in vivo with radioselenium have been used in studies on the capacity of the miracidia to attach to and penetrate the tegument of infected compared with non-infected host snails (Lymnaea truncatula). The results show that the penetration of the larvae into the snail tissue is not influenced by an already existing infection, regardless of its developmental stage.

Animals

Ocular histopathology in animals experimentally infected with Mycobacterium leprae and M. lepraemurium. 1. Mycobacterium leprae and M. lepraemurium infections in the mouse. 2. Mycobacterium leprae infections in the 9-banded armadillo (Dasypus novemcinctus L.).

At varying periods of time following the successful establishment of systemic infections with Mycobacterium leprae or M. lepraemurium in the mouse and the nine-banded armadillo eyes were examined by light microscopy. Inoculation of bacilli was by the intravenous or intraperitoneal route or directly into the hind footpads; eyes were not directly inoculated in this study. During periods of up to 3 years under laboratory conditions no animal showed evidence of impaired vision or blindness, and the external appearance of both eyes was normal. The ocular histopathology and the sites of accumulation of bacilli are described. In immunologically normal mice infected with M. lepraemurium bacilli were much commoner in extraorbital tissues, but they were, nevertheless, found in various tissues within the orbit, including the ciliary body and sclera. In immunologically normal mice (and one rat) injected with M. leprae of human origin no bacilli were found in the eye, but in mice immunologically depressed by thymectomy and total body irradiation considerable numbers of bacilli were present in the iris and ciliary body and also in the limbal cornea. In the armadillo bacilli were found in large numbers in virtually all tissues except the lens, retina, optic nerve, and aqueous and vitreous humours, but the uveal tract was heavily involved. Findings are discussed in relation to the great frequency of ocular involvement and the importance of immune-complex disease in patients with lepromatous leprosy, and to factors wihch may favour the localisation and multiplication of Mycobacterium leprae in the eye.

Animals

Long term variations in trypanosome infection rates in highly infected tsetse flies on a cattle route in south-western Nigeria.

One thousand, nine hundred and ninety-seven male and 1988 female Glossina morsitans submorsitans were dissected at Ogbomosho, on a trade cattle route in south-western Nigeria, from June 1970 to August 1973. Of male flies, 1307 (65-45%) were infected by Trypanosoma vivax trypanosomes, 66 (3-31%) by the subgenus Nannomonas (congolense group) and three (0.15%) by the subgenus Trypanozoon (brucei group). Of flies, 1236 (62-17%) had T. vivax infections, 80 (4-02%) had infections of the subgenus Nannomonas and two (0.10%) had infections of the subgenus Trypanozoon, The great majority of T. vivax infections were mature, while a high proportion (10% in males and 22% in females) of infections of the subgenus Nannomonas were immature. No infection with the subgenus Trypanozoon was found after October 1971. Overall infection rates, for male and female flies respectively, rose from 77% and 80% in June 1970 to peak values of 91% ad 90% in April and June 1971 and thereafter declined to lowest values of 37% and 43% in 1973. The incidence of T. vivax infections was the major component of the rises and falls in overall infection rate. During the period of peak infection rates (April-June 1971), all female flies over about 40 days old were infected. It was assumed that all these had T. vivax infections; some also had subgenus Nannomonas infections and one also had an infection of the subgenus Trypanozoon. Of 72 specimens of G. tachinoides dissected at Ogbomosho from June 1970 to August 1972, 20 (27-8%) were infected by trypanosomes, 19 with T. vivax and one with immature subgenus Nannomonas. In this species, also, infection rate was related to the age of the fly. Of 43 specimens of G. m. submorsitans dissected at Ilorin, north of Ogbomosho on the same cattle route, in February 1975, seven (16-3%) had T. vivax infections. One of two specimens of G. tachinoides dissected here at the same time had an immature infection of the subgenus Nannomonas. In G. m. submorsitans, variations in age structure of the population did not account for the temporal fluctuations in infection rates. It appeared that since 1970 events further north, especially tsetse eradication and the natural decline of tsetse populations (due probably to drought) reduced the trypanosomiasis risk to cattle proceeding southwards. The declining infection rates at Ogbomosho, after 1971, reflected this.

Animals

Interaction of acute feline herpesvirus-1 and chronic feline immunodeficiency virus infections in experimentally infected specific pathogen free cats.

Cats with or without chronic feline immunodeficiency virus (FIV) infection were exposed to feline herpesvirus, type 1 (FHV-1). FIV infected cats became sicker than non-FIV infected cats and required more supportive treatment. However, there were no differences in the length of their illness or in the levels and duration of FHV-1 shedding. FHV-1 infection caused a transient neutrophilia at Day 7 with a rapid return to preinfection levels. The neutrophilia coincided with a transient lymphopenia that was accompanied by a decline in both CD4+ and CD8+ T-lymphocytes. A brief decrease in the CD4+/CD8+ T-lymphocyte ratio occurred at Day 14 in both FIV infected and non-infected cats. This decrease was mainly the result of an absolute and transient increase in CD8+ T-lymphocytes. CD4+ and CD8+ T-lymphocyte numbers and CD4+/CD8+ T-lymphocyte ratios returned to baseline within 4-8 weeks in both FIV infected and non-infected cats. FIV infected cats produced less FHV-1 neutralizing antibodies during the first 3 weeks of infection than non-FIV infected animals. The IgM FHV-1 antibody response was depressed in FIV infected cats whereas the IgG antibody response was unaffected. FHV-1 infection evoked a comparable transient loss of lymphocyte blastogenic responses to concanavalin A and pokeweed mitogen in both FIV infected and non-infected cats. However, response to pokeweed mitogen took longer to return to normal in FIV infected animals. Lymphocytes from FIV infected cats had a greater and more sustained proliferative response to FHV-1 antigen than non-FIV infected cats. The ongoing IgG antibody response to FIV was not affected by FHV-1 infection.

Acute Disease

The epidemiology of 2056 remote site infections and 1966 surgical wound infections occurring in 1865 patients: a four year study of 40,923 operations at Rush-Presbyterian-St. Luke's Hospital, Chicago.

Over a 4-year period 40,923 operations and 44,716 surgical admissions were monitored for both community and hospital onset infections. One thousand eight hundred sixty-five patients had 1966 surgical wound infections and 2056 remote infections including 1652 hospital onset and 404 community onset infections. One thousand one hudnred forty-four patients with multiple infections averaged 40 days in the hospital contrasted with 24 days for 721 patients with a single wound infection. The total excess cost of hospitalization for these patients was $951,150. A statistically significant reduction occurred for urinary tract infections, lower respiratory infections and clean and contaminated surgical wound infections. It is suggested that these are all inter-related and a significant reduction in surgical wound infections can be achieved through control of infections at remote sites, particularly those associated with medical devices. The coagulase positive staphylococcus is still the most important single bacterial species in the primary etiology of surgical wound infections. When the gastrointestinal tract is entered or "supra" infecting organisms appear, gram negative bacteria and mixed gram negative and gram positive infections are dominant. Reduction in remote site infections occurring in surgical patients is necessary to reduce the incidence of surgical wound infections, suggest preventive and control measures, and document the effectiveness of such measures.

Adolescent

Prophylactic intravenous immunoglobulin in HIV-infected children with CD4+ counts of 0.20 x 10(9)/L or more. Effect on viral, opportunistic, and bacterial infections. The National Institute of Child Health and Human Development Intravenous Immunoglobulin Clinical Trial Study Group.

OBJECTIVE: To evaluate the efficacy of intravenous immunoglobulin (IVIG) for prevention of viral, opportunistic, and minor bacterial infections in children infected with human immunodeficiency virus (HIV). DESIGN: Randomized, double-blind, placebo-controlled, outpatient clinical trial comparing subjects treated with 400 mg of IVIG per kilogram of body weight every 28 days with those given albumin placebo. SETTING: Twenty-eight clinical centers in mainland United States and Puerto Rico. PATIENTS: Three hundred seventy-six children infected with human immunodeficiency virus with clinical or immunologic evidence of HIV disease, 313 of whom had entry CD4+ counts of at least 0.20 x 10(9)/L (greater than or equal to 200/mm3). MAIN OUTCOME MEASURES: The incidence of laboratory-proven and clinically diagnosed viral, opportunistic, and bacterial infections. MAIN RESULTS: Viral infections and minor bacterial infections contributed more frequently to morbidity in children with entry CD4+ counts of at least 0.20 x 10(9)/L (together over five times as frequent) than did serious bacterial infection, the primary outcome measure of the trial. Opportunistic infections occurred at a similar rate as laboratory-proven serious bacterial infections. In this group of children, IVIG was significantly associated with a decrease in the rate of viral infections and minor bacterial infections per 100 patient-years (36.0 vs 54.0 episodes of viral infection per 100 patient-years, IVIG vs placebo, P = .01; and 115.1 vs 159.7 episodes of minor bacterial infection per 100 patient-years, IVIG vs placebo, P = .02), as well as a decrease in the rate of serious bacterial infections per 100 patient-years (26.4 vs 48.2 episodes per 100 patient-years; P = .002). There was no apparent difference in the rate of opportunistic infections between treatment arms. CONCLUSIONS: Beneficial effect of IVIG was seen across multiple infectious outcome measures, with reductions in serious and minor viral and bacterial infections observed in children with entry CD4+ counts of at least 0.20 x 10(9)/L.

Bacterial Infections

Prospective controlled study of four infection-control procedures to prevent nosocomial infection with respiratory syncytial virus.

To determine the most effective infection control procedure in preventing nosocomial infection with respiratory syncytial virus (RSV), we did a prospective controlled study of four infection-control strategies in four wards in a large paediatric hospital in the west of Scotland. All children under two years old admitted to four general wards during three winter RSV epidemics (1989-92) were screened for RSV infection (by nasopharyngeal aspirate and direct immunofluorescence) within 18 hours of admission. The main outcome measure was the occurrence of nosocomial infection, defined as the number of children initially RSV negative who became RSV positive 7 days or more after hospital admission (incubation period for RSV infection is 5-8 days). Without special precautions, there was a high rate of nosocomial RSV infection (26%). Nosocomial infection was significantly reduced by the combination of cohort nursing with the wearing of gowns and gloves for all contacts of RSV-infected children (p = 0.0022). Neither the use of gowns and gloves alone nor cohort nursing alone produced a significant reduction in cross-infection. In the final year, general clinical use of a policy of cohort nursing with gowns and gloves resulted in a reduction in the cross-infection rate by two-thirds of its original value (9.5% vs 26%). Combined with rapid laboratory diagnosis, cohort nursing and the wearing of gowns and gloves for all contacts with RSV-infected children can significantly reduce the risk of nosocomial RSV infection.

Antibodies, Viral

Evaluation of new anti-infective drugs for the treatment of intraabdominal infections. Infectious Diseases Society of America and the Food and Drug Administration.

These guidelines deal with the evaluation of anti-infective drugs for the treatment of intraabdominal infections. The clinical entities consist of infections arising from any part of the gastrointestinal tract, from the distal esophagus to the colon. These include surgical infections of the bowel, biliary tree, liver, spleen, and pancreas. Virtually all intraabdominal infections are due to multiple microorganisms resident in the gastrointestinal tract; these include aerobes and facultative and obligate anaerobes. Infections are classified as complicated (requiring an operative procedure), uncomplicated (managed medically), and postoperative wound (the operative procedure should be curative, but anti-infective drugs are used to prevent further infection at the site). Clinical criteria are paramount for entry into a study and for evaluation of efficacy. For complicated infections an adequate operation is an important determinant of outcome and needs assessment. Cultures of purulent intraabdominal fluid or abscess material are the only valid microbiologic indicators of infection. The acute physiology and chronic health evaluation score is useful in defining the severity of acute illness. The control regimen should consist of effective, established drugs and surgical procedures for the condition. Duration of therapy for complicated infections is usually 5-14 days; for uncomplicated infections, 3-7 days; and for postoperative wound infection, 2-5 days. Periodic assessment of safety and efficacy must be conducted during therapy. The outcome at final assessment is cure, failure, or indeterminate.

Anti-Infective Agents

Vaginal infection of mice with HSV type 2 variant ER-: a new animal model for human primary genital HSV type 2 infections.

Studying the pathogenesis of vaginal infections in mice with two variants of Herpes simplex virus type 2 (HSV-2) strain ER we observed that both variants ER+ and ER- caused severe vaginitis but only ER+ invaded the CNS leading to lethal neurological disease. In contrast, mice infected with ER- cleared the virus from the vagina and recovered from infection. ER+ and ER- expressed equal levels of thymidine kinase (TK) indicating a TK-independent difference in neurovirulence. Using the non-neurovirulent variant ER-, we were able to investigate humoral immune responses later after infection. Vaginal infection with ER- suppressed serum antibody formation after a secondary systemic HSV-1 infection. Fresh isolates of HSV-1 and HSV-2 caused uniformly a lethal neurological disease after vaginal inoculation of mice. However, some animals survived an intraperitoneal infection with these isolates. Infection with HSV-1 isolates stimulated a strong antibody production, whereas infection with HSV-2 isolates suppressed antibody formation, thus supporting earlier results from our group obtained with laboratory strains. Since suppression of antibody formation could be demonstrated with clinical HSV-2 isolates and likewise after vaginal infection with HSV-2 variant ER- we consider this phenomenon to be of relevance in human genital HSV-2 infections. Vaginal infection of mice with variant ER- represents a new model for primary genital HSV-2 infections; this model could be useful for histopathological, virological, immunological and drug testing studies.

Animals