Emilio Dirlikov

Update: Ongoing Zika Virus Transmission — Puerto Rico, November 1, 2015–July 7, 2016

Zika virus is a flavivirus transmitted primarily by Aedes aegypti and Aedes albopictus mosquitoes, and infection can be asymptomatic or result in an acute febrile illness with rash (1). Zika virus infection during pregnancy is a cause of microcephaly and other severe birth defects (2). Infection has also been associated with Guillain-Barré syndrome (GBS) (3) and severe thrombocytopenia (4,5). In December 2015, the Puerto Rico Department of Health (PRDH) reported the first locally acquired case of Zika virus infection. This report provides an update to the epidemiology of and public health response to ongoing Zika virus transmission in Puerto Rico (6,7). A confirmed case of Zika virus infection is defined as a positive result for Zika virus testing by reverse transcription-polymerase chain reaction (RT-PCR) for Zika virus in a blood or urine specimen. A presumptive case is defined as a positive result by Zika virus immunoglobulin M (IgM) enzyme-linked immunosorbent assay (MAC-ELISA)* and a negative result by dengue virus IgM ELISA, or a positive test result by Zika IgM MAC-ELISA in a pregnant woman. An unspecified flavivirus case is defined as positive or equivocal results for both Zika and dengue virus by IgM ELISA. During November 1, 2015-July 7, 2016, a total of 23,487 persons were evaluated by PRDH and CDC Dengue Branch for Zika virus infection, including asymptomatic pregnant women and persons with signs or symptoms consistent with Zika virus disease or suspected GBS; 5,582 (24%) confirmed and presumptive Zika virus cases were identified. Persons with Zika virus infection were residents of 77 (99%) of Puerto Ricos 78 municipalities. During 2016, the percentage of positive Zika virus infection cases among symptomatic males and nonpregnant females who were tested increased from 14% in February to 64% in June. Among 9,343 pregnant women tested, 672 had confirmed or presumptive Zika virus infection, including 441 (66%) symptomatic women and 231 (34%) asymptomatic women. One patient died after developing severe thrombocytopenia (4). Evidence of Zika virus infection or recent unspecified flavivirus infection was detected in 21 patients with confirmed GBS. The widespread outbreak and accelerating increase in the number of cases in Puerto Rico warrants intensified vector control and personal protective behaviors to prevent new infections, particularly among pregnant women.

Global Tuberculosis Control: Toward the 2015 Targets and Beyond

Tuberculosis (TB) remains a major health threat around the world. In 2013, an estimated 11 million prevalent cases (that is, the number of cases in a population at any given time) and 9.0 million incident cases (that is, the number of new cases that occur in a population in 1 year) occurred globally (1). Of the estimated cases, 3.3 million were missed by health systems, either by remaining undiagnosed or by being diagnosed but not reported (1). In the same year, an estimated 480000 new cases of multidrug-resistant (MDR) TB, defined as resistance to both isoniazid and rifampicin, emerged, but only 136000 were diagnosed and notified (1). An estimated 1.1 million incident cases occurred among people living with HIV, 550000 occurred among children, and 3.3 million occurred among women (1). Approximately 1.5 million deaths were caused by TB worldwide, of which 210000 were due to MDR TB and 360000 were among people living with HIV (1). Despite the continued severity of the epidemic, progress has been made in global TB control since 1990: The absolute number of cases globally declined at an average rate of 1.5% per year from 2000 to 2013 and 0.6% between 2012 and 2013 (1, 2). Countries have prioritized TB control by implementing internationally recommended strategies, increasing domestic funding, and incorporating TB into development agendas. Community-based organizations and other local groups have played an increasingly important role in TB care and prevention, aiding in providing comprehensive patient services. In this article, we review the progress toward the 2015 TB global targets since 1990 (Appendix). We detail current challenges to control efforts, including MDR TB and co-infection with HIV and TB, as well as broader socioeconomic issues. Beyond 2015, control strategies should quickly implement technical and operational innovations, as well as promote universal health care to improve access to services and avoid catastrophic expenditures. After 1990: The Road to the 2015 Policies and Targets Since 1990, several key events have shifted global strategies to control TB, and global epidemiology has also changed (Figure 1). In 1991, the World Health Assembly set global targets for 2000 (3), with a model-based goal of reducing prevalence and incidence by 5% to 10% annually (4, 5). Targets were based on the assumption that achieving a 85% cure rate and 70% case detection rate would reduce prevalence of active TB cases, thus leading to reduced transmission and the overall burden of illness and death (6, 7). To further increase international attention and political commitment, the World Health Organization (WHO) declared a global tuberculosis emergency in 1993 (8). The next year, WHO announced a new strategy focused on bacteriologic detection among persons spontaneously presenting with symptoms to health service points and the provision of standardized short-course chemotherapy. In 1995, this strategy was branded as DOTS (directly observed treatment, short-course) (9, 10). After initial positive results from China and elsewhere (11), the strategy was promoted aggressively worldwide, although a lack of funding and political commitment were major barriers for its adoption at the country level. Figure 1. Timeline of key events and epidemiologic shifts (left) and the evolving global strategies to control TB (right). BDQ = bedaquiline; DLM = delamanid; DOTS = directly observed treatment, short-course; EMA = European Medicines Agency; FDA = U.S. Food and Drug Administration; FIND = Foundation for Innovative New Diagnostics; Global Fund = Global Fund to Fight AIDS, Tuberculosis and Malaria; MDG = Millennium Development Goal; MDR = multidrug-resistant; TB = tuberculosis; TB Alliance = Global Alliance for TB Drug Development; UN = United Nations; WHA = World Health Assembly; WHO = World Health Organization. Recognizing the growing number of TB organizations at all levels, as well as its own financial constraints (12), WHO convened an ad hoc committee in London in 1998 (13). The event was a watershed moment toward more collaborative partnerships and coordinated global action. Since then, established health organizations (such as WHO, the International Union Against Tuberculosis and Lung Disease, the U.S. Centers for Disease Control and Prevention, and the KNCV [Koninklijke Nederlandse Chemische Vereniging] Tuberculosis Foundation) were joined by many bilateral organizations, private companies, nongovernment organizations, and newly formed research and funding institutions (including the Bill & Melinda Gates Foundation and the Global Fund to Fight AIDS, Tuberculosis and Malaria [Global Fund]). Formally founded in 2001, the Stop TB Partnership has served as a platform to facilitate collaboration among these organizations. Two important milestones occurred in 2000. In March, a ministerial conference held in Amsterdam sought to expand the global implementation of the DOTS strategy (14), and by year end, 148 countries had committed to scaling up the strategy (9, 15). In September, the United Nations Millennium Summit incorporated TB targets into the Millennium Development Goals, with 2015 set as the target year (16). After waning international interest in the 1970s and 1980s (10), TB moved back onto the global agenda during the 1990s. By the early 2000s, the Millennium Development Goal to halt and reverse the global incidence of TB was achieved. In 2006, the Stop TB Strategy was launched as an enhancement of DOTS, in line with a broader push toward the Millennium Development Goals (17, 18). The strategy explicitly addressed MDR TB and co-infection with HIV and TB while also promoting publicprivate mixed approaches and community engagement. After a 2009 ministerial meeting of the 27 countries with a high burden of MDR and extensively drug-resistant TB, drug resistance became a global priority, as galvanized by a World Health Assembly resolution (19, 20). Substantial gains have been made in TB research and development (21). New molecular diagnostics, such as the Xpert MTB/RIF (Cepheid) or GenoType MTBDRplus assay (Hain Lifescience), have been introduced, and existing funding mechanisms, such as the Global Fund and UNITAID, have allowed for the deployment of new diagnostics in complex, low-resource settings (22). Two new medicines, bedaquiline and delamanid, have gained conditional approval for use in MDR TB cases, and 16 new vaccine candidates are at various stages of clinical trials (2327). Global TB prevalence, incidence, and mortality rates have been declining since the early 2000s (Figure 2). New treatment options have been explored, with varying success (28, 29). Moving forward, control strategies must address social and economic determinants of disease, be integrated into development agendas, and promote universal health coverage as a means to mitigate barriers to accessing services (30). In 2014, the 67th World Health Assembly approved the WHO End TB Strategy, 20162035, which encapsulates broader approaches toward ending the TB epidemic as a major challenge to public health (31). Although the assessment of the epidemiologic effect of policy shifts is not an easy task, given that economic improvements contribute to reducing the burden of TB, robust control measures since 1990 have been concomitant to progress in epidemiologic indicators toward the 2015 targets. Figure 2. Global tuberculosis trends in prevalence, incidence, and mortality per 100000 population, 1990 to 2013. Shading indicates the lower and upper bounds of the 95% uncertainty interval. Data from reference 1. * Deaths due to tuberculosis among people living without HIV. Reaching the 2015 Targets Recent retrospective analysis estimates that overall TB mortality rates (not including people living with HIV) decreased from 30 cases per 100000 persons in 1990 to 20 cases per 100000 persons in 2009 (4). From 2000 to 2013, approximately 37 million lives were saved by TB prevention, diagnostic, and treatment interventions (1). Increased funding has been pivotal. Total domestic and international donor TB funding in 104 low- and middle-income countries increased from

Guillain-Barré Syndrome and Healthcare Needs during Zika Virus Transmission, Puerto Rico, 2016

1.7 billion in 2002 to

Acute Zika Virus Infection as a Risk Factor for Guillain-Barré Syndrome in Puerto Rico

4.4 billion in 2011, and domestic funding alone increased from

Postmortem Findings in Patient with Guillain-Barré Syndrome and Zika Virus Infection

1.5 to

Human Rabies - Puerto Rico, 2015.

3.9 billion over this period (32). The Global Fund is the largest provider of international donor funding, disbursing

The Global Fund in China: Multidrug-resistant tuberculosis nationwide programmatic scale-up and challenges to transition to full country ownership

500 million in 2012 (1). Although progress has been substantial, major challenges remain (Figure 3). At the present rates, the goals of decreasing global prevalence by half by 2015 will not be met. Of the 22 designated high-burden countries, incidence is not yet decreasing in 7, 11 are unlikely to reduce the mortality rate from 1990 levels by half, and another 11 are unlikely to reduce the prevalence from 1990 levels by half (1). To reach the ultimate goal of eliminating TB by 2050 (defined as 1 case per 1 million persons), incidence rates must decrease by an average of 20% annually, a rate of decline that has never been empirically achieved (26). New technology and more effective service delivery are thus required to accelerate the decline toward elimination and confront challenges, such as co-infection with HIV and diabetes. Figure 3. Progress toward global TB targets set for 2015 (left) and other indicators of progress and major challenges (right). Light green means that the global targets were already met, medium green means that the global targets need acceleration to meet the 2015 deadline, and dark green represents major challenges. Circles with 1990 above them signify indicators compared with the 1990 baseline levels, and circles with 2013 above them show estimates for indicators for 2013, as reported in the WHO Global Tuberculosis Report. Data from reference 1. MDR = multidrug-resistant; TB = tuberculosis. Drug-Resistant TB Drug-resistant TB presents a complex and evolving challenge to future control efforts. It often indicates weak implementation of TB care and poor infection control pract

Clinical Features of Guillain-Barré Syndrome With vs Without Zika Virus Infection, Puerto Rico, 2016

To assist with public health preparedness activities, we estimated the number of expected cases of Zika virus in Puerto Rico and associated healthcare needs. Estimated annual incidence is 3.2–5.1 times the baseline, and long-term care needs are predicted to be 3–5 times greater than in years with no Zika virus.

Molecular Characterization of a Cluster of Imported Malaria Cases in Puerto Rico

Acute Zika Virus Infection as a Risk Factor for Guillain-Barré Syndrome in Puerto Rico Guillain-Barré syndrome (GBS) is an uncommon autoimmune disorder characterized by progressive weakness and diminished deep tendon reflexes following infection or, rarely, vaccination.1 Increased GBS incidence has been reported in countries affected by Zika virus,2 a flavivirus transmitted primarily by Aedes species mosquitoes.3 During the Zika virus epidemic in Puerto Rico, we conducted a casecontrol study to identify risk factors associated with GBS.

Guillain-Barré Syndrome During Ongoing Zika Virus Transmission — Puerto Rico, January 1–July 31, 2016

Postmortem examination results of a patient with Guillain-Barré syndrome and confirmed Zika virus infection revealed demyelination of the sciatic and cranial IV nerves, providing evidence of the acute demyelinating inflammatory polyneuropathy Guillain-Barré syndrome variant. Lack of evidence of Zika virus in nervous tissue suggests that pathophysiology was antibody mediated without neurotropism.