BACKGROUND

In HIV infection, lymphoid tissue is disrupted by fibrosis. Angiotensin converting enzyme inhibitors have anti-fibrotic properties. We completed a pilot study to assess whether the addition of lisinopril to antiretroviral therapy (ART) reverses fibrosis of gut tissue, and whether this leads to reduction of HIV RNA and DNA levels.

METHODS

Thirty HIV-infected individuals on ART were randomized to lisinopril at 20mg daily or matching placebo for 24 weeks. All participants underwent rectal biopsies prior to starting the study drug and at 22 weeks, and there were regular blood draws. The primary end point was the change in HIV RNA and DNA levels in rectal tissue. Secondary outcomes included the change in 1) HIV levels in blood; 2) Gag-specific T-cell responses; 3) levels of T-cell activation; and 4) collagen deposition.

RESULTS

The addition of lisinopril did not have a significant effect on the levels of HIV RNA or DNA in gut tissue or blood, Gag-specific responses, or levels of T-cell activation. Lisinopril also did not have a significant impact on lymphoid fibrosis in the rectum, as assessed by quantitative histology or heavy water labeling.

CONCLUSIONS

Treatment with lisinopril for 24 weeks in HIV-infected adults did not have an effect on lymphoid fibrosis, immune activation, or gut tissue viral reservoirs. Further study is needed to see if other anti-fibrotic agents may be useful in reversing lymphoid fibrosis and reducing HIV levels.

BACKGROUND

It is unknown if extremely early initiation of antiretroviral therapy (ART) may lead to long-term ART-free HIV remission or cure. As a result, we studied 2 individuals recruited from a pre-exposure prophylaxis (PrEP) program who started prophylactic ART an estimated 10 days (Participant A; 54-year-old male) and 12 days (Participant B; 31-year-old male) after infection with peak plasma HIV RNA of 220 copies/mL and 3,343 copies/mL, respectively. Extensive testing of blood and tissue for HIV persistence was performed, and PrEP Participant A underwent analytical treatment interruption (ATI) following 32 weeks of continuous ART.

METHODS AND FINDINGS

Colorectal and lymph node tissues, bone marrow, cerebral spinal fluid (CSF), plasma, and very large numbers of peripheral blood mononuclear cells (PBMCs) were obtained longitudinally from both participants and were studied for HIV persistence in several laboratories using molecular and culture-based detection methods, including a murine viral outgrowth assay (mVOA). Both participants initiated PrEP with tenofovir/emtricitabine during very early Fiebig stage I (detectable plasma HIV-1 RNA, antibody negative) followed by 4-drug ART intensification. Following peak viral loads, both participants experienced full suppression of HIV-1 plasma viremia. Over the following 2 years, no further HIV could be detected in blood or tissue from PrEP Participant A despite extensive sampling from ileum, rectum, lymph nodes, bone marrow, CSF, circulating CD4+ T cell subsets, and plasma. No HIV was detected from tissues obtained from PrEP Participant B, but low-level HIV RNA or DNA was intermittently detected from various CD4+ T cell subsets. Over 500 million CD4+ T cells were assayed from both participants in a humanized mouse outgrowth assay. Three of 8 mice infused with CD4+ T cells from PrEP Participant B developed viremia (50 million input cells/surviving mouse), but only 1 of 10 mice infused with CD4+ T cells from PrEP Participant A (53 million input cells/mouse) experienced very low level viremia (201 copies/mL); sequence confirmation was unsuccessful. PrEP Participant A stopped ART and remained aviremic for 7.4 months, rebounding with HIV RNA of 36 copies/mL that rose to 59,805 copies/mL 6 days later. ART was restarted promptly. Rebound plasma HIV sequences were identical to those obtained during acute infection by single-genome sequencing. Mathematical modeling predicted that the latent reservoir size was approximately 200 cells prior to ATI and that only around 1% of individuals with a similar HIV burden may achieve lifelong ART-free remission. Furthermore, we observed that lymphocytes expressing the tumor marker CD30 increased in frequency weeks to months prior to detectable HIV-1 RNA in plasma. This study was limited by the small sample size, which was a result of the rarity of individuals presenting during hyperacute infection.

CONCLUSIONS

We report HIV relapse despite initiation of ART at one of the earliest stages of acute HIV infection possible. Near complete or complete loss of detectable HIV in blood and tissues did not lead to indefinite ART-free HIV remission. However, the small numbers of latently infected cells in individuals treated during hyperacute infection may be associated with prolonged ART-free remission.

The San Francisco Bay Area Regional Poison Control Center studied 189 cases of toxic workplace exposure occurring over a six-month period in the belief that Regional Poison Control Center reporting could be a useful surveillance measure for occupational disease. Dermatitis was a relatively uncommon occurrence, but systemic complaints were frequent, a pattern differing from that seen in standard occupational surveillance programs. As compared to chemically caused illness detected through a statewide physician reporting program in California, increases in proportional frequencies of certain industrial chemical causes were observed. A matching strategy utilizing the physician reporting system identified only 15.9 per cent of poison control center cases that appear to have been otherwise detected through established surveillance. A nationwide system of Regional Poison Control Centers already exists with a computerized data base in place. This study indicates that these centers could be utilized as a supplementary system for acute occupational illness related to chemical exposures.

The contribution of workplace exposures to the prevalence of asthma in adults has been minimized in the epidemiology of this illness. Analysis of the 1978 Social Security Disability Survey provides a population-based assessment as a novel approach utilizing self-attributed, occupationally related asthma as a measure of disease. Of 6,063 respondents, 468 (7.7 percent) identified asthma as a personal medical condition; 72 (1.2 percent [15.4 percent of all those with asthma]) attributed it to workplace exposures. These subjects were older and included more men and cigarette smokers than groups of both asthmatic and nonasthmatic subjects. The relative risk for occupationally attributed asthma was elevated among industrial and agricultural workers as compared with white collar and service occupations. Analysis of disability benefit status did not indicate that this introduced major reporting bias in this survey. This study suggests that occupational factors may have a greater role in adult asthma than previously thought.

We studied the roentgenograms, pulmonary function tests, and physical findings of 294 shipyard workers to evaluate asbestos exposure-cigarette smoking interactions. Roentgenographic parenchymal opacities, decreased pulmonary diffusing capacity for carbon monoxide, decreased flow at low lung volume, rales, and clubbing were each significantly related to the number of years elapsed since first exposure to asbestos and cigarette smoking status when analyzed by logistic regression. A dose-dependent cigarette smoking response that was consistent with synergism was present only for parenchymal opacities and decreased flow at low lung volume. These findings suggest that decreased flow at low lung volume, possibly reflecting peribronchiolar fibrosis, may be a functional corollary to smoking-associated parenchymal roentgenographic opacities among some asbestos-exposed individuals.

Whether cigarette smoking can cause radiographic opacities indistinguishable from those due to pneumoconiosis remains controversial. The situation becomes clearer when one limits the abnormalities to those that can be standardized under the International Labour Office (ILO) classification system. The bulk of the evidence indicates that, using the ILO system, cigarette smoking alone is not associated with radiographic opacities that would be mistaken for pneumoconiosis with sufficient frequency to be of any practical importance. The effects of cigarette smoking, as a cofactor, in conjunction with occupational dust exposure depend on the type of dust. No relationship has been convincingly demonstrated for coal dust or silica. Only with asbestos exposure does there appear to be a significant cigarette smoking-associated increase in the frequency of irregular radiographic opacities. This increase does not appear to translate into a restrictive impairment in pulmonary function. The limited information available indicates that the features of asbestosis on high-resolution computed tomography are not similarly related to cigarette smoking. Additional research is needed to substantiate the relationship between smoking and occupational exposure to dust of many types, and also the possible imaging and pathophysiologic significance of their interactions.

In the Negev region of Israel, I tested a model approach to occupational health planning. This model included components assessing exposures, measuring adverse health outcomes, and evaluating health services. I analyzed employment survey data, compiled an exposure data base, and carried out site visits covering 10,707 employees (over 50% of the regional industrial work force). Site visits identified exposure hazards of inorganic and organic dusts, heavy metals, chemicals, pesticides, and noise. I identified elevated relative regional injury rates by Standard Morbidity Ratios (SMRs) in a variety of industries, including sixfold increases for mining and non-metallic minerals manufacture (SMR 6.8, 99% CI 6.1-7.7). Review of biological monitoring data suggested deficiencies in pesticide and heavy metals surveillance. A survey of primary care clinics estimated 13,707 cases of occupational injury and illness untreated by existing occupational medical services. Based on these findings, I formulated regional occupational health planning goals, including targeting high-risk industries for increased preventive activities. This regional approach, combining multiple measures of occupational health status, can serve as a model for assessing local public health planning needs.

STUDY OBJECTIVE

To evaluate the usefulness of poison control center detection in occupational illness surveillance.

DESIGN

Case series of all occupationally related exposures referred for poison control center consultation over 6 months. Follow-up structured interviews were done of exposed persons and health care providers. Cases were traced under established occupational illness reporting programs.

SETTING

A regional poison control center.

PATIENTS

Consecutive sample of 461 symptomatic occupational exposure cases. After exclusions and losses to follow-up, interview of 301 patients and the treating physician, physician's assistant, or nurse practitioner for the 223 of the patients under direct medical care.

MEASUREMENTS AND MAIN RESULTS

One hundred and fifty-five persons (61%; CI, 55% to 67%) had systemic or respiratory illness; 109 (36%; CI, 31% to 41%) had eye or skin conditions. Work practices were associated with exposures more often than technical failure; 118 persons (39%; CI, 33% to 45%) reported lack of respirators or other appropriate personal protective equipment. For 223 persons who received direct medical care, only five treating health care providers (2%; CI, 0.2% to 4%) reported occupational specialization, although occupational care was a regular practice activity for 128 of the health care providers (57%; CI, 51% to 63%). Sixty-seven cases (22%; CI, 17% to 27%) were detected by the Doctor's First Report surveillance program; 97 cases (32%; CI, 27% to 37%) comprised the maximal detection estimated for Occupational Safety and Health Administration surveillance.

CONCLUSIONS

Poison control center detection provides a useful surveillance measure for occupational illness. The proportion of case detection failures by established surveillance programs suggests that the incidence of occupational illness in the United States, which is calculated from these incomplete programs, may be three to five times greater than previously estimated.

In a study of occupational illness reported to a regional poison control center and to gauge the center's outreach and services, we did follow-up interviews of 301 case contacts over a 6-month period. We ascertained referral routes, reasons for contacting the poison control center, and awareness of the center's function. For 122 cases a nonphysician was the initial poison control center contact. Of the nonphysician contacts, 41 had already consulted a health care provider and been referred to the poison control center for assistance. Of the 70 persons with exposure, only 21 had been aware before their exposures that poison control center services might include occupational chemical illness consultation. Physicians and nonphysicians expressed similar reasons for contacting the poison control center, with 118 of 301 identifying the need for an exposure hazard risk assessment. These data suggest that although those contacting a poison control center because of occupational illness include a variety of cases, they have many similar service needs.