Abstract

California's Public Health Laboratories: Inter-organizational cooperation models to bolster laboratory capacity

Background: California has 61 local health departments that are currently served by 37 local public health laboratories. These laboratories act as the first line of defense against health threats by providing community disease surveillance, food and environmental safety testing, newborn disease screening, identification of causal agents during an outbreak, and national disease screening for biological agents of warfare, resulting in a decreased burden on the health care system. In January 2009, the Little Hoover Commission released a report "First Year Checkup: Strategies for a Stronger Public Health Department" to address ways in which the California Department of Public Health can improve public health and safety. One of the five major recommendations made was for the California Department of Public Health to continue to provide leadership to strengthen the state's laboratory capacity by helping to facilitate consolidation of county public health laboratories into regional laboratories. Due to the California budget crisis and the shortage of public health laboratory directors qualified to run laboratories, regionalization has been proposed as a strategy to address resource constraints as well as to obtain economies of scale in the provision of laboratory services. However, there is resistance from a subset of county public health laboratory directors as well as county health officers to regionalize local public health laboratories. In addition, neither the California Department of Public Health nor the state has the legal authority or financial resources to enforce county public health laboratory regionalization. The rationale and the feasibility of implementing the Little Hoover Commission's recommendation need to be more thoroughly explored. Purpose: This dissertation research was conducted to incorporate the perspectives of county public health laboratory directors, county health officers, and state public health officials in order to assess whether reorganization of county public health laboratories is a feasible solution to bolster California's public health laboratory capacity. Methodology: Case studies of inter-organizational forms of cooperation among public health laboratories in California were conducted to assess necessary "factors of success" when engaging in an inter-organizational partnership between public health laboratories. Qualitative interviews were also conducted with public health laboratory directors, health officers, and state public health officials to assess 1) the feasibility of public health laboratories engaging in inter-organizational partnerships and 2) the impact that an inter-organizational partnership will have on addressing the state's insufficient PHL capacity. Lastly, policy options aimed at bolstering the state's laboratory capacity were proposed based on findings from the case studies and the interviews. Findings: Analysis of the data collected through the case studies and qualitative interviews with public health laboratory directors, county health officers and state public health officials suggests that an inter-organizational form of cooperation such as a regionalization effort of local county public health laboratories led by the state is not a feasible solution to help bolster laboratory capacity. However, a consolidation effort of public health laboratories led by county administrators and public health laboratory directors through a joint powers agreement is a potential solution for 1) ensuring affordable and continuous provision of public health laboratory testing services for all public health departments and 2) a short-term measure to address the shortage of board certified, doctoral level public health laboratory directors available to supervise laboratories located in rural counties. The three policy options that would be effective at addressing the state's insufficient laboratory capacity include 1) amend the state PHLD requirements, 2) promote locally driven PHL consolidation efforts through utilization of joint powers agreements and 3) provide state funding for PHL services in rural counties.

Public health laboratories are the first line of defense in the fight against communicable diseases and bioterrorism. The local public health laboratories in particular serve important functions including the identification and monitoring of pathogens in the community. They have the ability to respond to individual challenges within their jurisdictions with creative and innovative solutions. Unfortunately, instead of investing in and expanding the functions of their public health laboratory, many jurisdictions are forced by budget cuts, workforce shortages, and competition with private/commercial laboratories, to consider downsizing or closure of these essential facilities.2-4 California has been especially targeted by reorganization approaches, including regionalization, consolidation and privatization, because it has a unique, decentralized system consisting of one state- and 35 local laboratories, many more than other states.5 Reorganization, however, might be applicable only in a few isolated settings and faces opposition from many lab directors and health officers.2 It would result in further public health laboratory closures to the detriment of the overall mission of public health.

It would be imperative to strengthen the local public health laboratories, improve their cost-effectiveness and maintain their quality service. This could be achieved through specimen volume increases in certain testing areas. Economies of scale would arise due to costs being distributed over more samples, and quality might be improved. One strategy to achieve volume increases is specialization, or the sharing of testing services amongst several neighboring public health laboratories. If focused on the particularly cost-inefficient low-to-moderate volume tests, specialization might be able to achieve the greatest benefits. It was the goal of this research to identify the current level of support for and the prevalence of specialization in low-to-moderate volume tests in the local jurisdictions of California and to examine how feasible wider implementation would be. Additionally, a Cost-Effectiveness Evaluation Model was developed to evaluate past or future service changes, such as volume increases or service sharing, based on their effect on the cost, revenue and quality of testing. Overall, this alternative strategy to strengthen the public health laboratories was examined so that public health policy makers, administration, and lab directors can make a more informed decision about the future of their public health laboratory.

Breast cancer is a leading cause of morbidity and mortality worldwide. About 5-10% of breast cancer cases are associated with hereditary factors (such as mutations of the BRCA-1 or BRCA-2 gene), but the exact causes for most breast cancers are unknown. The remaining 90% of breast cancer cases may potentially be caused by external initiators such as radiation, chemical carcinogens, or infectious agents. Infectious agents cause about 23% of all malignancies in developing countries, and approximately 8% of malignancies in developed countries. Currently, six viruses are causally associated with human cancers: Epstein-Barr virus (EBV), human T-lymphotropic virus type 1 (HTLV-1), hepatitis B virus (HBV), hepatitis C virus (HCV), human papilloma virus (HPV), and human herpes virus 8 (HHV-8). No infectious agent has yet been causally associated with human breast cancer. One candidate virus is bovine leukemia virus (BLV), a retrovirus closely related to HTLV and the causative agent of enzootic bovine lymphosarcoma. In cattle, BLV is transmitted by transfer of infected lymphocytes via blood or milk. Humans are potentially exposed to BLV by consumption of cow's milk and meat.

One part of the process of proving that an infectious agent causes a particular disease is proving that the organism infects humans. Production of immunoglobulins specific to the organism is often evidence of infection. Utilizing an immunoblot assay with a chemiluminescent endpoint, Buehring et al. demonstrated the presence of anti-BLVp24gag IgG, IgM, and IgA in human sera. Competition studies with pre-immune and immune goat sera further verified the human anti-BLV specificity. Since immunoblotting is a labor-intensive and inefficient method compared to ELISA, an ELISA assay was developed in this study to detect anti-BLVp24gag IgG and IgM in human serum and plasma samples. Receiver operator curve analysis was used to compare the ELISA to the immunoblot. The ELISA method developed here has poor ability (IgG AUC=0.51, IgM AUC= 0.56) to discriminate between people with and without antibodies to BLV p24gag, compared to immunoblot. ROC analysis is concordant with the unimodal IgG and IgM frequency distributions.

The cut-off value derived from ROC analysis for IgG is 77800 RLUs, which gives a sensitivity of 76.47% and a specificity of 26.1%. The cut-off value for IgM is 26244 RLUs, giving a sensitivity of 80.9% and a specificity of 28.05%. Initial competition studies with a monoclonal anti-human secondary antibody indicates that the Assay may show specificity for the BLV p24 protein. However, an appropriate antigen control was not available to rule out non-specific reactions with the antigen matrix. Therefore, this ELISA needs further development to assure specificity of the assay for the recombinant BLV p2gag protein before solid conclusions can be made regarding the seroprevalence of BLV antibodies in humans.

However, this developmental stage ELISA was used to estimate the frequency of anti-BLVp24gag IgG and IgM in our study population, using the ROC derived cut-off points. In the 0-3 month age category, the frequency of IgG is 14.2%, declining to 0% by the age of 6 months. The frequency of IgM in the 0-3 month age group is 23.9%, increasing to 70% by 6 months of age. The presence of IgG in the 0-3 month age group is most likely maternal IgG that wanes by age 6 months, while IgM is indicative of the child's own immune response to a new antigen. The level of IgG peaks at 30-39 years of age, plateaus, and then begins to decrease at 60 years of age. IgM peaks in adolescence and then begins a slow decline after 30 years of age, but never falls below 60% prevalence. Continuing high IgM titers may be indicative of constant reexposure to BLV via dairy and meat consumption, or to episodes of viral reactivation. The relatively high overall percentage of IgM seropositivity (73.3%) compared to IgG seropositivity (49.3%) may be due to the low median age of the study population.

Using the preliminary ELISA method being developed here, this study may indicate that both vertical and sexual transmission of BLV potentially occur. However, presence of antibodies to the BLV p24gag protein do not necessarily indicate infection, but may result from exposure to the antigen from consumption of dairy products. In addition, confirmation of the specificity of this ELISA is necessary to make firm conclusions. Further prospective studies are warranted in order to determine precisely at what point(s) in the perinatal period vertical transmission could occur, and to elucidate whether sexual transmission is truly occurring. Prospective studies may also permit a study sample more representative of the target population to be developed.

In conclusion, widespread consumption of BLV-contaminated dairy and beef may potentially be responsible for a significant proportion of breast cancer cases worldwide. If the pathogenicity of BLV for humans is established, the implications are far-reaching and may indicate the need for primary preventative measures to avert continuing infection of humans.

Background

Methods

Results

Conclusions

Background

Bovine leukemia virus (BLV) infection is widespread in cattle globally and is present in marketed beef and dairy products. Human infection with BLV has been reported in breast and lung cancer tissues and was significantly associated with breast cancer in 3 case-control studies. The purpose of this current research was to determine if BLV is present in human blood cells and if antibodies to BLV are related to blood cell infection.

Methods

Standard liquid PCR and Sanger DNA sequencing were used to test for BLV in buffy coat cells (leukocytes and platelets) of blood specimens from 95 self-selected female subjects.

Enzyme-linked immunosorbent assay (ELISA) for IgG, IgM, and IgA was used to detect antibodies to BLV in the plasma of the corresponding blood samples.

Results

BLV DNA was detected in the buffy coat cells of blood in 33/95 (38%) of the subjects by PCR and DNA sequencing. IgG antibodies were detected in 30/95(32%), IgM in 55/95(58%), and IgA in 30/95(32%) of the subjects. There was no significant correlation between presence of the antibodies and presence of BLV DNA.

Conclusions

This first report of BLV in human blood raises the question of whether infection of leukocytes could conceivably lead to leukemia as it does in infected cattle. Also, system wide circulation of infected blood cells could facilitate BLV transit to various internal tissues/organs with potential for their infection and subsequent development of cancer. The most likely route of BLV transmission to humans would be zoonotic, as a foodborne infection. Although eradicated from cattle in some countries, BLV still has a high rate of infection in the Americas, the Middle East, and parts of Europe and Asia. This report of BLV in the blood layer containing human leukocytes/platelets adds important information which could be useful to elucidate possible routes of transmission of BLV to humans and to prevent further human infection.