Carla Saenz

Granulocyte Colony-Stimulating Factor (G-CSF) Administration in Individuals with Sickle Cell Disease: Time for a Moratorium?

Granulocyte colony-stimulating factor (G-CSF) is used commonly in an attempt to reduce the duration of neutropenia and hospitalization in patients undergoing chemotherapy and to obtain hematopoietic stem cells (HSC) for transplantation applications. Despite the relative safety of administration of G-CSF in most individuals, including subjects with sickle cell trait, severe and life-threatening complications have been reported when used in individuals with sickle cell disease (SCD), including those who were asymptomatic and undiagnosed prior to administration. The administration of G-CSF has now been reported in a total of 11 individuals with SCD. Seven developed severe adverse events, including vaso-occlusive episodes, acute chest syndrome, multi-organ system failure and death. Precautions, including minimizing the peak white blood cell count, dividing or reducing the G-CSF dose and red blood cell transfusions to reduce sickle hemoglobin (HbS) levels, have been employed with no consistent benefit. These reported data indicate that administration of G-CSF in individuals with SCD should be undertaken only in the absence of alternatives and after full disclosure of the risks involved. Unless further data demonstrate safety, routine usage of G-CSF in individuals with SCD should be avoided.

The epidemic of chronic kidney disease in Central America

Immediate and coordinated action is needed to address the epidemic of chronic kidney disease sweeping across Central America. The disorder, known as CKDnT, is not related to traditional causes such as hypertension and diabetes, and mainly aff ects young male agricultural workers, the highest mortality being in El Salvador and Nicaragua (fi gure). However, CKDnT also aff ects women and non-agricultural workers living in farming communities. Mortality estimates from the Pan American Health Organization (PAHO) show that chronic kidney disease coded as N18 in WHO’s International Classifi cation of Diseases revision 10—a proxy for CKDnT—in men younger than 60 years has been responsible for thousands of deaths in the past decade in Central America. CKDnT is characterised by a tubulointerstitial nephropathy with low-grade proteinuria, which has a long subclinical period that tends to progress to end-stage renal disease in a short period of time. The scarcity of coverage and access to health services might contribute to the clinical course and high mortality rates of CKDnT. Health authorities, for example in El Salvador, responded to this poor coverage by increasing access to health services; however, the large number of patients and absence of adequate infrastructure and trained personnel led to overloaded hospitals. Similar epidemiological and clinical patterns of CKDnT have been reported in other countries, such as Sri Lanka. Causes of the CKDnT epidemic are not clear, although a consensus exists among researchers on its multifactorial character and relation to social, environmental, and economic determinants. Most commonly postulated causes include exposure to pesticides, heat stress with recurrent dehydration, and an excessive intake of high-sugar drinks. Exposure to heavy metals, use of non-steroidal anti-infl ammatory drugs and alcohol, and infectious diseases have similarly been postulated as causes for the CKDnT epidemic. Research to identify determinants of the epidemic is necessary, but the moral duty to address an epidemic cannot be postponed until its causes are identifi ed. A coordinated response from the public health sector and other related sectors is urgently needed. In addition to health services required to treat aff ected people, public health bodies need to consider environmental and occupational health measures. The two main hypotheses for the high incidence and excess mortality—ie, the use of pesticides and heat stress along with dehydration—are strongly related to the absence of a regulatory system to control agrochemical use and the poor compliance with rules and standards to protect the labour force’s health. Almost all Central American countries are signatories to the Stockholm Convention on Persistent Organic Pollutants and the Rotterdam Convention on Prior Informed Consent. Compliance, however, is far from

Chronic Kidney Disease Epidemic in Central America: Urgent Public Health Action Is Needed amid Causal Uncertainty

The 52nd Directing Council of the Pan American Health Organization (PAHO), in response to a call for action of the Minister of Health of El Salvador, recognized chronic kidney disease from nontraditional causes (CKDnT) affecting agricultural communities in Central America as a serious public health problem that requires urgent, effective, and concerted multisectoral action [1]. Most Central American countries do not have surveillance systems capable of detecting chronic kidney disease (CKD). However, many reports [2]–[4] and data from PAHO show the epidemiological magnitude of the disease. A proxy for CKDnT mortality, the age standardized mortality rate due to chronic kidney disease—coded as N18 (CKD-N18) by the 2010 International Classification of Diseases—is notably higher for men and women in Nicaragua and El Salvador compared to other countries in the region and has been since at least 2000 (http://www.paho.org/hq/index.php?option=com_content&view=article&id=9402). CKD-N18 data also show disproportionate mortality from the disease in males compared to females (Figure 1). Mortality due to CKD in El Salvador and Nicaragua exhibited a pattern of excess mortality in young adults (Figure 2), which is consistent with many other clinical and epidemiological reports [2]–[4]. Figure 1 Chronic kidney disease (N18; International Classification of Diseases, tenth revision [ICD-10]) age-standardized mortality rate, selected countries, 2000–2009. Figure 2 Chronic kidney disease (N18, ICD-10) age-specific mortality rate, selected countries, around 2008. CKDnT has been largely reported in some clustered farming communities traditionally burdened by socioeconomic disadvantages from northern Nicaragua [2], the Pacific coast of El Salvador [3], and other countries such as Costa Rica, Guatemala, Honduras, and the south of Mexico [4]. The disease affects mostly young adult male agricultural workers, e.g., sugarcane cutters. CKDnT has also been described in agricultural workers in Sri Lanka and India [5]–[6]. Studies reveal that patients affected by CKDnT show a clinical and pathologic pattern of a tubule-interstitial disease [7]–[8], which seems to progress to end-stage renal disease in a relatively short time. This clinical pattern explains at least in part the high burden imposed on the affected countries for the delivery of health services. For example, a 50% increase in hospitalizations for CKD from 2005 to 2012 was reported in El Salvador, making CKD the leading cause of death in El Salvadors main hospital [1]. CKDnT is a chronic and multifactorial condition that has been neglected for quite some time. The causes of this epidemic have not been elucidated yet. Several potential etiological factors have been considered [7]. Given the diseases higher prevalence in agricultural communities and its clinical and epidemiological characteristics, which are similar to CKDnT in Sri Lanka [5], it is reasonable to draw attention to two interdependent factors: the misuse of agrochemicals and the working conditions of the labor force. The misuse of pesticides has been widespread in Central America for a long time [9]. This region imported 33 million kg of active ingredient per year with an increase of 33% during 2000–2004. From a total of 403 pesticides (13 of which constitute 77% of the total pesticides that were imported), 22% were highly/extremely acutely toxic, 33% were moderately/severely irritating or sensitizing, and 30% had multiple chronic toxicities. Out of 41 banned or highly regulated pesticides as per international treaties, 16 were imported to Central America, four of which are among the 13 most imported pesticides [10]. Although the specific mechanisms to explain the nephrotoxicity of some pesticides are still under investigation, the nephrotoxicity of several of them is already known [11], [12]. Harsh working conditions, especially regular exposure to very hot temperatures and extreme physical effort, lead to heat stress and dehydration. Along with exposure to pesticides, these seem to play an important role in the occurrence of the disease, particularly among sugarcane cutters [13]. The weakness of regulatory systems [10], along with the agriculture dependency of local economies [14] and cultural agricultural practices [9], contribute to poor compliance with international safety and health standards for the use of agrochemicals and for occupational hygiene. Many questions related to these potential causative agents remain unanswered. For example, why is there such an important difference in the distribution of CKD between countries? Are there differences in the agricultural practices and work processes in areas with the same climatic characteristics and devoted to the same type of plantations (e.g., sugarcane)? Which types of agrochemicals have been used in the affected areas? How do we explain cases in nonsugarcane cutters, as well as in women? Other hypothesized causal agents merit further investigation. Nonsteroidal anti-inflammatory drugs, alcohol, and sugary beverage consumption have been associated with the disease [7], but their role remains controversial in current scientific evidence. The potential role of heavy metals and contamination of fertilizer has not been investigated in depth in the region and deserves more research. It has been argued that infectious diseases such as leptospirosis and dengue, which are prevalent in the region, could also play a role in the CKDnT epidemic [7]. However, these hypothesis have not been supported by evidence. Indeed, the human transmission of the West Nile virus, which has been associated with CKD [15], has not been documented in Central America until now. A CKDnT regional research agenda is imperative not only to drive efforts to determine the epidemics causative agents but also to bridge the gap between research and public health interventions. However, much-needed research must not delay action to address CKDnT. The resolution on CKDnT in Central America approved by PAHOs Directing Council [1] commits to coordinated and evidence-informed action to implement public policies, programs, and regulatory mechanisms to improve the social, environmental, occupational, and economic conditions of the affected communities and to strengthen surveillance and CKD-relevant health services. The resolution of PAHO [1] also highlighted the relevance of multisectorial actions outside of the health sector—for instance, agriculture, trade, environment, occupational safety, affected communities, academia, and civil society, among others—to coordinate efforts, mobilize resources, prioritize the sustainability of actions to promote evidence-based public policies, and to reach the high level of commitment to reduce environmental risk factors to mitigate, on an urgent basis, the health, social, and economic consequences of this disease. An effective and urgent response to address and ultimately stop the epidemic is a moral duty not only for Central America but for the whole Pan American community.

Twelve Years of Fogarty-Funded Bioethics Training in Latin America and the Caribbean: Achievements and Challenges

The landscape in research ethics has changed significantly in Latin America and the Caribbean over the past two decades. Research ethics has gone from being a largely foreign concept and unfamiliar practice to an integral and growing feature of regional health research systems. Four bioethics training programs have been funded by the Fogarty International Center (FIC) in this region in the past 12 years. Overall, they have contributed significantly to changing the face of research ethics through the creation of locally relevant training materials and courses (including distance learning), academic publications, workshops, and conferences in Spanish, and strengthening ethics review committees and national systems of governance. This paper outlines their achievements and challenges, and reflects on current regional needs and what the future may hold for research ethics and bioethics training in Latin America and the Caribbean.

Avances y retos en el registro de ensayos clínicos en América Latina y el Caribe

Clinical trial registries are one of the main sources of information concerning health research interventions that have been or are being carried out throughout the world. The World Health Organization (WHO) established a minimum data set to be recorded (20 items), which was agreed upon internationally with the stakeholders, and established a network of primary and associated records. In addition to the register ClinicalTrial.Gov (of the United States of America), there are currently two primary registries in the Americas (from Brazil and Cuba) that meet WHO requirements and provide data to WHO’s International Clinical Trials Registry Platform (ICTRP). Furthermore, there are important advances in the region related to the regulations, development and implementation of national registries and to the support of the ethics committees and editors to this initiative.

Ethics, regulation, and beyond : the landscape of research with pregnant women

Scarce research with pregnant women has led to a dearth of evidence to guide medical decisions about safe and effective treatment and preventive interventions for pregnant women and their potential offspring. In this paper, we highlight three aspects of the landscape in which pregnant women are included or, more frequently, excluded from research: international ethics guidance, regional and national regulatory frameworks, and prevailing practices. Our paper suggests that, in some cases, regulatory frameworks can be more restrictive than international ethics guidance, and that even when regulations permit research with pregnant women, practical challenges—as well as the prevailing practices of stakeholders, such as ethics review committees and investigators—may lead to the generalized exclusion of pregnant women from research.

Public Health Ethics: Global Cases, Practice, and Context

Introducing public health ethics poses two special challenges. First, it is a relatively new field that combines public health and practical ethics. Its unfamiliarity requires considerable explanation, yet its scope and emergent qualities make delineation difficult. Moreover, while the early development of public health ethics occurred in a western context, its reach, like public health itself, has become global. A second challenge, then, is to articulate an approach specific enough to provide clear guidance yet sufficiently flexible and encompassing to adapt to global contexts. Broadly speaking, public health ethics helps guide practical decisions affecting population or community health based on scientific evidence and in accordance with accepted values and standards of right and wrong. In these ways, public health ethics builds on its parent disciplines of public health and ethics. This dual inheritance plays out in the definition the U.S. Centers for Disease Control and Prevention (CDC) offers of public health ethics: “A systematic process to clarify, prioritize, and justify possible courses of public health action based on ethical principles, values and beliefs of stakeholders, and scientific and other information” (CDC 2011). Public health ethics shares with other fields of practical and professional ethics both the general theories of ethics and a common store of ethical principles, values, and beliefs. It differs from these other fields largely in the nature of challenges that public health officials typically encounter and in the ethical frameworks it employs to address these challenges. Frameworks provide methodical approaches or procedures that tailor general ethical theories, principles, values, and beliefs to the specific ethical challenges that arise in a particular field. Although no framework is definitive, many are useful, and some are especially effective in particular contexts. This chapter will conclude by setting forth a straightforward, stepwise ethics framework that provides a tool for analyzing the cases in this volume and, more importantly, one that public health practitioners have found useful in a range of contexts. For a public health practitioner, knowing how to employ an ethics framework to address a range of ethical challenges in public health—a know-how that depends on practice—is the ultimate take-home message.

Public Health Research

Having a scientific basis for the practice of public health is critical. Research leads to insight and innovations that solve health problems and is therefore central to public health worldwide. For example, in the United States research is one of the ten essential public health services (Public Health Functions Steering Committee 1994). The s of the Ethical Practice of Public, developed by the Public Health Leadership Society (2002), emphasizes the value of having a scientific basis for action. Principle five specifically calls on public health to seek the information needed to carry out effective policies and programs that protect and promote health.

Separate Goals, Converging Priorities: On the Ethics of Treatment as Prevention

Recent evidence confirming that the administration of antiretroviral drugs (ARVs) to HIV-infected persons may effectively reduce their risk of transmission has revived the discussion about priority setting in the fight against HIV/AIDS. The fact that the very same drugs can be used both for treatment purposes and for preventive purposes (Treatment as Prevention) has been seen as paradigm-shifting and taken to spark a new controversy: In a context of scarce resources, should the allocation of ARVs be prioritized based on the goal of providing treatment, or on the goal of preventing the spread of the HIV epidemic? Contributions to this discussion tend to assume that treatment and prevention constitute two divergent goals that entail conflicting priorities. We challenge that assumption on the basis of both conceptual and empirical examination. We argue that, as far as the provision of ARVs to HIV-infected persons is concerned, the goals of treatment and prevention do not entail conflicting priorities; to the contrary, they dictate converging strategies for the optimal allocation of ARVs. In light of the current evidence, the concept of Treatment as Prevention can indeed be seen as paradigm-shifting, yet in a novel way: Rather than extending the tension between the goals of treatment and prevention to the level of drug-allocation, it dissolves this tension by providing a rationale for a unified strategy for allocating ARVs.

Making Fair Choices on the Path to Universal Health Coverage: Applying Principles to Difficult Cases

Abstract Abstract—Progress toward universal health coverage (UHC) requires making difficult trade-offs. In this journal, Dr. Margaret Chan, the World Health Organization (WHO) Director-General, has endorsed the principles for making such decisions put forward by the WHO Consultative Group on Equity and UHC. These principles include maximizing population health, priority for the worse off, and shielding people from health-related financial risks. But how should one apply these principles in particular cases, and how should one adjudicate between them when their demands conflict? This article by some members of the Consultative Group and a diverse group of health policy professionals addresses these questions. It considers three stylized versions of actual policy dilemmas. Each of these cases pertains to one of the three key dimensions of progress toward UHC: which services to cover first, which populations to prioritize for coverage, and how to move from out-of-pocket expenditures to prepayment with pooling of funds. Our cases are simplified to highlight common trade-offs. Though we make specific recommendations, our primary aim is to demonstrate both the form and substance of the reasoning involved in striking a fair balance between competing interests on the road to UHC.