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Bonaci-Nikolic B.,Institute of Allergy and Clinical Immunology | Bonaci-Nikolic B.,University of Belgrade | Andrejevic S.,Institute of Allergy and Clinical Immunology | Pavlovic M.,Institute for Infectious Diseases | And 3 more authors.
Clinical Rheumatology | Year: 2010

Chronic infections may mimic antineutrophil cytoplasmic antibody (ANCA)-associated vasculitides (AAV). We investigated which markers may help in the diagnosis and the prognosis of infections associated with proteinase 3 (PR3) and myeloperoxidase (MPO)-ANCA. In this study (1993-2008)-with an average follow-up of 5.1 years-we compared 66 AAV patients with 17 PR3 and/or MPO-ANCA-positive patients with protracted bacterial (11/17) or viral (6/17) infections. Seven of 17 patients had subacute bacterial endocarditis (SBE), while six of 17 patients had various autoimmune manifestations of chronic hepatitis C virus (HCV) infection. We determined ANCA, antinuclear antibodies, anti-PR3, anti-MPO, anticardiolipin (aCL), antibeta 2 glycoprotein I (β2-GP I), cryoglobulins, C3, and C4. Patients with infections were younger than AAV patients (p<0.01). There was no difference in frequency of renal and skin lesions. AAV patients more frequently had pulmonary and nervous system manifestations (p<0.01). Patients with infections more frequently had dual ANCA (high PR3, low MPO), aCL, anti-β2-GP I, cryoglobulins, and hypocomplementemia (pβ0.001). Immunosuppressive therapy (IST) was used in five 17 patients who had persistently high ANCA, cryoglobulinemia, and hypocomplementemia. There was no difference in frequency of lethality and renal failure in the two study groups. In patients who are PR3-and/or MPO-ANCA positive, SBE and HCV infection should be excluded. Although similar in renal and skin manifestations in comparison to AAV, only patients with infections developed multiple serological abnormalities. In patients with infections, concomitant presence of ANCA, cryoglobulins, and hypocomplementemia was associated with severe glomerulonephritis. The serological profile should be repeated after specific antimicrobial or surgical therapy, since some cases might require IST. © Clinical Rheumatology 2010.

News Article
Site: news.mit.edu

After its emergency meeting on Zika virus two weeks ago, World Health Organization (WHO) Director-General Margaret Chan wrote in an official statement, “the Committee advised that the recent cluster of microcephaly cases and other neurological disorders reported in Brazil, following a similar cluster in French Polynesia in 2014, constitutes an ‘extraordinary event’ and a public health threat to other parts of the world.” Given these stakes, WHO declared Zika a “global public health emergency." The designation highlights immediate goals, such as “development of new diagnostics . . . prioritized to facilitate surveillance and control measures,” and longer-term measures, such as “appropriate research and development efforts . . . intensified for Zika virus vaccines, therapeutics and diagnostics.” MIT’s Institute of Medical Engineering and Science (IMES) is on the front lines of this research. Led by Professor Lee Gehrke, the MIT Gehrke Lab is at the vanguard of disease diagnostics. In recent years, lab members have developed a successful, noncross-reacting diagnostic test for Dengue virus, a close relative to Zika, as well as one for Ebola. “The Gehrke team is currently focused on developing sensitive, low-cost, rapid diagnostics to detect Zika, giving a result in 10 to 15 minutes, as well as on basic research needed to characterize Zika virus infections in advance of therapeutics and vaccine development,” says Gehrke, the Hermann von Helmholtz Professor in IMES and Professor of Microbiology and Immunobiology at Harvard Medical School. “Detection is needed from an epidemiological perspective . . . [and] to improve patient care. By detecting specific pathogens, a tailored treatment plan can be developed.” The threat is compounded by several factors, Gherke says: “Because there is little immunity against Zika virus infections in most parts of the world, Zika has the potential to spread anywhere that the mosquito vectors (Aedes aegypti and Aedes albopictus) are found. “Further, there are few available research reagents that can be used for scientific experimentation and study. Yet the development and characterization of reagents needed to detect Zika virus is underway at a rapid pace now, [and] we hope that the Zika test will be ready for field-testing in late spring or early summer 2016. Gehrke adds that his team has been indespensible in the work: “MIT graduate student Helena de Puig is developing nanoparticle surface chemistries to increase the sensitivity of the tests, and undergraduate Luis Mora is taking time from his work on the MIT Solar Car to precision-mold the cartridges that hold the device,” he says. Because Zika disease is often nonsymptomatic, several public health concerns are presently at play, Gehrke says. “There might be some danger from nonsymptomatic individuals serving as virus sources for mosquitoes, who could in turn infect other people,” he explains. “Once an individual has been infected, it’s reasonable to predict that they will have immunity, but no one knows the long term effects of Zika infections.” For this reason, Gehrke’s lab wants to provide health workers with a rapid test to detect who has Zika and does not, as well as who’s had it in the past. U.S. Centers for Disease Control Director Tom Friedan wrote for CNN: “Diagnosing prior infection with Zika is much more challenging. . . . This is a priority, and we are working to do in weeks what would usually take months or years.” “Identifying individuals who have been infected in the past is done by identifying anti-Zika IgM and IgG antibodies,” Gehrke says. “Advanced technology is available for examining the portfolio of pathogens that have infected an individual over time. However, as a practical matter with readily available reagents, the IgG and IgM tests can be non-specific. Our Dengue Fever device can identify IgG and IgM in patient serum, and we will develop the same capacity for Zika. Crossover interactions with nonspecific antigens are, however, a consideration.” Since reporting outbreaks is crucial to public health, technology is also being implemented to make diagnostics into messengers. “The detection technology is being linked to low-cost communication and data technologies that will analyze the test results and transmit them to personal care physicians and public health officials,” Gehrke explains. “[IMES researcher] Jose Gomez Marquez is adapting a 5-dollar Raspberry Pi single-board computer to invent a very low-cost reader that will quantify the rapid test data. More research is needed to determine how that data can be transmitted and stored to protect privacy while improving communication with physicians and public health officials.” Additionally, the Gehrke Lab wants to help officials to “develop a plan for a ‘smart’ mosquito trap that identifies mosquito species as they enter and transmits the data to a home base. We are also exploring technologies to screen mosquitoes directly for the presence of viruses, in an effort to provide advance warning of an impending epidemic.” Ultimately, the sudden, intensive focus on Zika could help the fight against other viruses, as well. Gehrke’s own lab is focused on detecting multiple RNA viruses, zeroing in on processes from innate immune signaling to gene expression. “Because the genomes and proteins of the flaviviruses (including Zika) are related, it is quite possible that studying Zika and comparing its replication strategies and pathogenesis to other viruses will be very informative,” Gehrke says. Daniel Anderson, an associate professor of chemical engineering and member of IMES, is working on a new type of vaccine: a customized, on-hand, single-dose RNA nanoparticle vaccine — that may have potential to fight the spread of Zika virus. “We have developed a nanoparticle vaccine that can be rapidly tuned for different diseases, including viruses. The speed of development allows us to make new vaccines in only seven days, allowing the potential to deal with sudden outbreaks, like Zika,” Anderson says. “Using a single injection, these nanoparticles deliver RNA, carrying instructions that ultimately help train the patient’s immune system to fight off infections.” The team at the Anderson Lab has successfully developed customized vaccines for all three classes of National Institute of Allergy and Infectious Disease’s “priority pathogens,” including Ebola virus (class A), H1N1 Influenza (class B), and microorganism parasite Toxoplasma gondii (class C), generating fully protective immunity in animals. “We have already started using the same process for Zika,” says postdoc Omar F. Khan, who works closely with Anderson at the Koch Institute for Integrative Cancer Research at MIT. “It’s possible that some of the antigens found in Zika are also present in other arboviruses [viruses caused by mosquito or tick bites], which broadens the vaccine’s applicability.” In fact, by designing the synthetic nanoparticle to “simultaneously deliver many different and unique RNAs,” the Anderson Lab’s vaccine innovation has the ability to target multiple diseases, reducing the burden on health care workers addressing large populations. “These can be multiple antigens from the same virus or different antigens from other viruses. We call this multiplexing,” Khan says. “In this way, it’s possible to make a pan-arbovirus vaccine that can simultaneously train the immune system to target [related viruses]. We are already doing this type of multiplexing for filoviruses. Our pan-filovirus nanoparticle vaccine is designed to simultaneously target Zaire Ebola, Sudan Ebola, and Marburg virus, and is currently being validated by our collaborators at the United States Army Medical Research Institute for Infectious Diseases.” The speed, cost, and on-demand, local production potential of a nanoparticle vaccine for Zika — or Zika combined with other arboviruses — makes it particularly compelling. “Once the unique Zika antigens have been identified by virology experts, it will take us about seven days to generate the Zika-specific RNA instructions and build the nanoparticle vaccines,” Anderson says. “We are working with labs and government agencies that study the Zika virus to validate the potential in preventing this disease.” The nanoparticle vaccine is, according to Anderson’s presentations, the “first and only nonviral replicon delivery system that has achieved protective immunity in lethal exposure experiments . . . [with] no side effects [and] no risk of anti-vector immunity” — in other words, no risk of being attacked by the patient’s immune system. And based on its success preventing other viruses, influenza, parasites, and even some cancers in animals, it offers promising potential as a formidable foe to Zika in the future, if clinical trials are prioritized.

Jabara C.B.,Center for Research | Jabara C.B.,University of North Carolina at Chapel Hill | Jabara C.B.,Abbott Laboratories | Hu F.,Center for Research | And 15 more authors.
Antimicrobial Agents and Chemotherapy | Year: 2014

HIV coinfection accelerates disease progression in chronic hepatitis C and reduces sustained antiviral responses (SVR) to interferon- based therapy. New direct-acting antivirals (DAAs) promise higher SVR rates, but the selection of preexisting resistanceassociated variants (RAVs) may lead to virologic breakthrough or relapse. Thus, pretreatment frequencies of RAVs are likely determinants of treatment outcome but typically are below levels at which the viral sequence can be accurately resolved. Moreover, it is not known how HIV coinfection influences RAV frequency. We adopted an accurate high-throughput sequencing strategy to compare nucleotide diversity in HCV NS3 protease-coding sequences in 20 monoinfected and 20 coinfected subjects with well-controlled HIV infection. Differences in mean pairwise nucleotide diversity (π), Tajima's D statistic, and Shannon entropy index suggested that the genetic diversity of HCV is reduced in coinfection. Among coinfected subjects, diversity correlated positively with increases in CD4± T cells on antiretroviral therapy, suggesting T cell responses are important determinants of diversity. At a median sequencing depth of 0.084%, preexisting RAVs were readily identified. Q80K, which negatively impacts clinical responses to simeprevir, was encoded by more than 99% of viral RNAs in 17 of the 40 subjects. RAVs other than Q80K were identified in 39 of 40 subjects, mostly at frequencies near 0.1%. RAV frequency did not differ significantly between monoinfected and coinfected subjects. We conclude that HCV genetic diversity is reduced in patients with well-controlled HIV infection, likely reflecting impaired T cell immunity. However, RAV frequency is not increased and should not adversely influence the outcome of DAA therapy. Copyright © 2014, American Society for Microbiology. All Rights Reserved.

Hu Z.,Guangzhou No. 8 Peoples Hospital | Li Y.,Guangzhou University | Li C.,Guangzhou No. 8 Peoples Hospital | Huang C.,Guangzhou No. 8 Peoples Hospital | And 4 more authors.
Ultrasound in Medicine and Biology | Year: 2015

The correlation between liver stiffness (LS), measured by ultrasonic transient elastometry (FibroScan), and the presence and severity of esophageal varices (EV) in patients with viral cirrhosis of the liver has not been well documented to date. The study described here investigated the value of using FibroScan to predict EV. Patients with cirrhosis (200 patients: 167 cases caused by hepatitis B virus and 33 cases caused by hepatitis C virus) underwent both upper gastrointestinal endoscopy and FibroScan. Demographic, clinical, biochemical and endoscopic data and FibroScan-obtained LS parameters were collected. The mean LS value in patients with EV (33.2kPa) was significantly higher than the mean LS value in patients without EV (18.6kPa) (. p<0.05). The mean LS value in patients with grade 2 and 3EV (38.3kPa) was significantly higher than that in patients with grade 1EV (24.8kPa) (. p<0.05). Overall, FibroScan was 86.4% sensitive and 72.2% specific in predicting the presence of EV, with an area under the receiver operating characteristic curve (AUROC) of 0.84. The sensitivity and specificity for the patients with grade 2 or 3EV were 84% and 73% (AUROC=0.86). When FibroScan was combined with platelet count, the overall sensitivity and specificity of prediction increased to 84% and 80% (AUROC=0.88), respectively, and 84% and 75% (AUROC=0.89), respectively, in patients with grade 2 and 3EV. FibroScan alone or combined with platelet count might predict the presence and severity of EV in patients with hepatitis B or C-related viral cirrhosis. © 2015 World Federation for Ultrasound in Medicine & Biology.

Seale H.,University of New South Wales | Kaur R.,University of New South Wales | Wang Q.,University of New South Wales | Yang P.,Institute for Infectious Diseases | And 7 more authors.
Vaccine | Year: 2011

Due to the advent of the new influenza A (H1N1) strain in 2009, many countries introduced mass immunization programs. Healthcare workers (HCWs) were amongst the key groups targeted for the vaccine in these programs. However, experience with the seasonal influenza vaccine has shown that there are multiple barriers related to the attitudes and perceptions of the population which influence uptake. The aim of this study was to determine pandemic influenza A (H1N1) vaccination rate amongst a group of Chinese HCWs and the associated factors around acceptance. A cross-sectional investigation of HCWs (doctors, nurses and technicians) from 19 hospitals in Beijing, China was conducted in January 2010. The main outcome measures were awareness, risk perception of H1N1, preventive measures and uptake of H1N1 vaccination during the pandemic. A total of 1657 HCWs completed the survey. A quarter of the participants reported receiving the pandemic influenza A (H1N1) vaccine. Occupation (being a doctor), receiving seasonal flu vaccine and believing in the effectiveness of the vaccine were all strongly associated with accepting the pandemic influenza A (H1N1) vaccine. Over a thousand participants (61%, 1008/1657) agreed that they were 'concerned about the side effects of the swine flu vaccine', while 758 (46%) were 'concerned that the vaccine had not been tested adequately'. While studies reported high rates of willingness toreceive the vaccine,in reality these did not transpire. Aside from promoting seasonal flu vaccination, authorities need to start educational campaigns much earlier in a pandemic. Programs that are simultaneously launched with the introduction of the vaccine will not be as successful, as those which have built momentum alongside the pandemic. © 2011 Elsevier Ltd.

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