24 - PART 17 Global Medicine

• 01 - 485 Global Issues in Medicine
• 02 - 486 Emerging and Re-Emerging Infectious Diseases
• 03 - 487 Primary Care and Global Health

01 - 485 Global Issues in Medicine

485 Global Issues in Medicine

Joseph J. Rhatigan, Paul E. Farmer*

Global Issues in Medicine WHY GLOBAL HEALTH? Global health has emerged as an important field within medicine. Some scholars have defined global health as the field of study and practice concerned with improving the health of all people and achiev­ ing health equity worldwide, with an emphasis on addressing trans­ national problems. No single review can do much more than identify the leading problems in applying evidence-based medicine in settings of great poverty or across national boundaries. However, this is a moment of opportunity: only relatively recently have persistent calls for global health equity been matched by an unprecedented invest­ ment in addressing the health problems of poor people worldwide. To ensure that this opportunity is not wasted, we must strengthen health systems and improve health care delivery to address the true burden and distribution of disease. This chapter introduces the major interna­ tional bodies that address global health problems; identifies the more significant barriers to improving the health of people who to date have not, by and large, had access to modern medicine; and summarizes population-based data on the most common health problems faced by people living in poverty. Examining specific problems—notably HIV/ AIDS (Chap. 208) but also tuberculosis (Chap. 183), malaria (Chap. 231), Ebola (Chap. 216), COVID-19 (Chap. 205) and key “noncommunicable” chronic diseases (NCDs)—helps sharpen the discussion of barriers to prevention, diagnosis, and care as well as the means of overcoming them. This chapter closes by discussing global health equity, drawing on concepts of social justice. A BRIEF HISTORY OF GLOBAL HEALTH INSTITUTIONS Concern about illness across national boundaries dates back many centuries, predating the Black Plague and other pandemics. One of the first organizations founded explicitly to tackle cross-border health issues was the Pan American Sanitary Bureau, which was formed in 1902 by 11 countries in the Americas. The primary goal of what later became the Pan American Health Organization was the control of infectious diseases across the Americas. Of special concern was yellow fever, which had been running a deadly course through much of South and Central America and halted the construction of the Panama Canal. In 1948, the United Nations formed the first truly global health institution: the World Health Organization (WHO). In 1958, under the aegis of the WHO and in line with a long-standing focus on communi­ cable diseases that cross borders, leaders in global health initiated the effort that led to what some see as the greatest success in international health: the eradication of smallpox. Naysayers were surprised when the smallpox eradication campaign, which engaged public health officials throughout the world, proved successful in 1979 despite Cold War tensions. Even as attention to and resources for health problems in poor coun­ tries grow, the lack of coordination among global health institutions remains an issue. The global response to the COVID-19 pandemic revealed both strengths and fundamental flaws in the current state of global health governance. The WHO remains underfunded despite the ever-growing need to engage a wider and more complex range of health issues. This may be what some have called “the golden age of global health,” but leaders of major global health organizations must work together to design an effective architecture that will make the most of opportunities to link new resources for and commitments to global health equity with the emerging understanding of disease bur­ den and the unmet need to create robust and resilient national health systems. To this end, new and old players in global health must invest heavily in discovery (relevant basic science), development of new tools (preventive, diagnostic, and therapeutic), and modes of delivery that *Deceased. At the International Conference on Primary Health Care in AlmaAta (in what is now Kazakhstan) in 1978, public health officials from around the world agreed on a commitment to “Health for All by the Year 2000,” a goal to be achieved by providing universal access to primary health care worldwide. Critics argued that the attainment of this goal by the proposed date was impossible. In the ensuing years, a strategy for the provision of selective primary health care emerged. This strategy included four inexpensive interventions collectively known as GOBI: growth monitoring, oral rehydration, breast-feeding, and immunizations for diphtheria, whooping cough, tetanus, polio, tuberculosis, and measles. GOBI later was expanded to GOBI-FFF,

Global Medicine PART 17 which also included female education, food, and family planning. Some public health figures saw GOBI-FFF as an interim strategy to achieve “health for all,” but others criticized it as a retreat from the bolder com­ mitments of Alma-Ata. In 1982, UNICEF, led by James Grant, helped usher in a period of sustained and coordinated efforts to reduce childhood mortality using a similar set of interventions among other measures. Over the ensuing two decades, it is estimated that 25 million children’s lives were saved in what is often called “The Child Survival Revolution.” The influence of the WHO waned during the 1980s. In the early 1990s, many observers argued that, with its vastly superior financial resources and its close—if unequal—relationships with the govern­ ments of poor countries, the World Bank had eclipsed the WHO as the most important multilateral institution working in global health. One of the stated goals of the World Bank was to help poor countries identify “cost-effective” interventions worthy of public funding and international support. At the same time, international financial institu­ tions encouraged many of those nations to reduce public expenditures in health and education in order to stimulate economic growth as part of (later discredited) policies, generally referred to as “structural adjust­ ment,” that imposed restrictions on social sector government spending as a condition for access to credit and assistance through the World Bank, the International Monetary Fund, and regional development banks. There was a resurgence of many diseases—including malaria, trypanosomiasis, and schistosomiasis—in Africa. Tuberculosis, an eminently curable disease, remained the world’s leading infectious killer of adults. Half a million women per year died in childbirth during the last decade of the twentieth century, and few of the world’s largest philanthropic or funding institutions focused on global health equity. HIV/AIDS, first described in the medical literature in 1981, precipi­ tated a change. In the United States, the advent of this newly described infectious killer marked the culmination of a series of events that dashed previous hopes of “closing the book” on infectious diseases. In Africa, which would emerge as the global epicenter of the pandemic, HIV disease strained tuberculosis control programs, and malaria continued to claim as many lives as ever: at the dawn of the twentyfirst century, these three diseases alone killed nearly 6 million people each year. New research, new policies, and new funding mechanisms were called for. The past two decades have seen the rise of important multilateral global health financing institutions such as the Global Fund to Fight AIDS, Tuberculosis, and Malaria; bilateral efforts such as the U.S. President’s Emergency Plan for AIDS Relief (PEPFAR); and private philanthropic organizations such as the Bill & Melinda Gates Foundation. With its 194 member states and 150 country offices, the WHO remains important in matters relating to the cross-border spread of infectious diseases and other health threats. In the aftermath of the epidemic of severe acute respiratory syndrome in 2003, the WHO’s International Health Regulations—which provide a legal foundation for that organization’s direct investigation into a wide range of global health problems, including pandemic influenza, in any member state— were strengthened and brought into force in May 2007.

3844 will ensure the equitable provision of health products and services to all who need them. The adoption of the Sustainable Development Goals (SDGs) in 2015 by the United Nations serves as an example of effective cooperation. The SDGs articulate 17 overarching goals across several domains to be achieved by 2030. Goal 3 specifically relates to global health and contains 13 distinct targets to be met, including reducing maternal and child mortality; ending the epidemics of HIV, tuberculosis, and malaria; and reducing the burden of NCDs. Included in the SDGs is a commitment to achieve universal health coverage (UHC), providing universal access to high-quality essential health services at an affordable cost worldwide. Championed by the WHO, the World Bank, and many civil society organizations, Goal 3 will measure coverage of 16 essential health services and assess the financial burden of health spending by households in every country. PART 17 Global Medicine THE ECONOMICS OF GLOBAL HEALTH Political and economic concerns have often guided global health inter­ ventions. As mentioned, early efforts to control yellow fever were tied to the completion of the Panama Canal. However, the precise nature of the link between economics and health remains a matter for debate. Some economists and demographers argue that improving the health status of populations must begin with economic development; others maintain that addressing ill health is the starting point for development in poor countries. In either case, there is increasing consensus that investments in health care delivery and the control of communicable diseases lead to increased productivity. The question is where to find the necessary resources to start the predicted “virtuous cycle.” During the past two decades, spending on health in poor countries has increased dramatically. According to a study from the Institute for Health Metrics and Evaluation (IHME) at the University of Washington, before the COVID-19 pandemic, total development assistance for health (DAH) worldwide (essentially a measure of “health aid”) grew to $38.9 billion in 2018—up from $5.6 billion in 1990—and seemed to reach a plateau. However, the global response to COVID-19 saw the largest yearly increases in DAH ever recorded. Between 2020 and 2021, DAH grew by 86%. It is estimated that in 2021 DAH reached $64.7 billion. In 2021, the leading contributors included the United States, the United Kingdom, Germany, and private foundations. MORTALITY AND THE GLOBAL

BURDEN OF DISEASE Refining metrics is an important task for global health: only relatively recently have there been solid assessments of the global burden of disease. The first study to look seriously at this issue, conducted in 1990, laid the foundation for the first report on Disease Control Pri­ orities in Developing Countries and for the World Bank’s 1993 World Development Report Investing in Health. Those efforts represented a major advance in the understanding of health status in developing countries. Investing in Health has been especially influential: it famil­ iarized a broad audience with cost-effectiveness analysis for specific health interventions and with the notion of disability-adjusted life years (DALYs). The DALY, which has become a standard measure of the impact of a specific health condition on a population, combines absolute years of life lost and years lost due to disability for incident cases of a condition. (See Fig. 485-1 and Table 485-1 for an analysis of the global disease burden by DALYs.) In 2012, the IHME and partner institutions began publishing results from the Global Burden of Diseases, Injuries, and Risk Factors (GBD) study. The GBD study is the most comprehensive effort to date to pro­ duce longitudinal, globally ambitious, and comparable estimates of the burden of diseases, injuries, and risk factors. This report reflects the expansion of the available data on health in the poorest countries and of the capacity to quantify the impact of specific conditions on a popu­ lation. It measures current levels and recent trends for major diseases, injuries, and risk factors worldwide. Since its original publication, the GBD study team has revised and improved the health-state severity weight system, collated published data, and used household surveys to enhance the breadth and accuracy of disease burden data. Updated

reports were released in 2013, 2015, 2017, and 2019. The report now includes fact sheets that examine 386 diseases and injuries in depth. As analytic methods and data quality improve, important trends can be identified in a comparison of global disease burden estimates from 1990 to 2019. ■ ■GLOBAL MORTALITY Although the COVID-19 pandemic has led to significant excess deaths, it is instructive to look at the last GBD study’s data as a comprehensive baseline of disease burden before the pandemic. In 2019, before the COVID-19 pandemic, of the 56.5 million deaths worldwide, 17% (9.6 million) were due to communicable diseases, maternal and neonatal conditions, and nutritional deficiencies—a marked decrease compared with figures for 1990, when these conditions accounted for 32% of global mortality. Among the fraction of all deaths related to commu­ nicable diseases, maternal and neonatal conditions, and nutritional deficiencies, 78% occurred in Sub-Saharan Africa and southern Asia. While the proportion of deaths due to these conditions has decreased significantly in the past decade, there has been a dramatic rise in the number of deaths from NCDs. The leading cause of death worldwide in 2019 was ischemic heart disease, accounting for 9.1 million deaths (16% of total deaths). In high-income countries, ischemic heart disease accounted for 16% of total deaths, and in low-income countries, it accounted for 16%. It is noteworthy that ischemic heart disease was responsible for just 5% of total deaths in Sub-Saharan Africa (Table 485-2). In second place—causing 11% of global mortality—was stroke, which accounted for 8% of deaths in high-income countries, 6% in lowincome countries, and 5% in Sub-Saharan Africa. Although chronic obstructive pulmonary disease (COPD) was the third leading cause of death globally and was the fifth leading cause in high-income coun­ tries (accounting for 5% of all deaths), this condition did not figure among the top 15 causes in Sub-Saharan Africa. Among the 10 leading causes of death in Sub-Saharan Africa, five were infectious diseases, with HIV/AIDS, lower respiratory infections, diarrheal diseases, and malaria ranking as dominant contributors to disease burden. In highincome countries, however, only 1 infectious disease—lower respira­ tory infection—ranked among the top 10 causes of death. The number of deaths among children under 5 years dropped from 16.4 million in 1970 to 11.8 million in 1990 and to 5.0 million in 2019—a decrease that far surpassed predictions. Of childhood deaths in 2021, 2.3 million (46%) occurred in the neonatal period. Just under one-third of deaths among children under 5 years old occurred in southern Asia and slightly more than one-half in Sub-Saharan Africa, but only ~1% occurred in high-income countries. The global burden of death due to HIV/AIDS and malaria was on an upward slope until 2004, but significant progress has been made since then. Global deaths from AIDS fell from 2.0 million in 2006 to 630,000 in 2022, while malaria deaths dropped from 1.2 million to 608,000 over the same period. Despite these improvements, malaria and HIV/AIDS continue to be major burdens in particular regions, with global impli­ cations. Although it has only a minor impact on mortality outside SubSaharan Africa and Southeast Asia, malaria is the fifth leading cause of death of children under 5 years of age worldwide. HIV infection ranked 30th in global DALYs in 1990 but was the 11th leading cause of disease burden in 2019, with Sub-Saharan Africa bearing the vast majority of this burden (Fig. 485-1). The world’s population is living longer: global life expectancy has increased significantly over the past 50 years from 58.8 years in 1970 to 73.5 years in 2019. This demographic change, accompanied by the fact that the prevalence of NCDs increases with age, is dramatically shifting the burden of disease toward NCDs, which have surpassed communi­ cable, maternal, nutritional, and neonatal causes. By 2019, 74% of total deaths at all ages and 63% of all DALYs were due to NCDs. Increas­ ingly, the global burden of disease comprises conditions and injuries that cause disability rather than death. Worldwide, although both life expectancy and years of life lived in good health have risen, years of life lived with disability also have increased. Globally, the total burden of disability increased by 50% between 1950 and 2019. Despite the higher prevalence of diseases

Global Both sexes, all ages, DALYs 1990 Rank 2019 Rank

1. Neonatal disorders

2. Lower respiratory infections

3. Diarrheal diseases

4. Ischemic heart disease

5. Stroke

6. Congenital defects

7. Tuberculosis

8. Road injuries

9. Measles

10. Malaria

11. COPD

12. Protein-energy malnutrition

13. Low back pain

14. Self-harm

15. Cirrhosis

16. Meningitis

17. Drowning

18. Headache disorders

19. Depressive disorders

20. Diabetes

21. Lung cancer

22. Falls

23. Age-related hearing loss

24. Chronic kidney disease

25. HIV/AIDS

26. Other musculoskeletal Communicable, maternal, neonatal, and nutritional diseases Noncommunicable diseases Injuries FIGURE 485-1  Global disability-adjusted life-year (DALY) ranks for the top causes of disease burden in 1990 and 2019. COPD, chronic obstructive pulmonary disease. (From the Institute for Health Metrics and Evaluation [IHME]. GBD Compare. Seattle, WA: IHME, University of Washington, 2023. Available at http://vizhub.healthdata.org/ gbd-compare. Accessed Dec 15, 2023.) common in older populations (e.g., dementia and musculoskeletal disease) in developed and high-income countries, best estimates from 2019 reveal that disability resulting from cardiovascular diseases, chronic respiratory diseases, and the long-term impact of communi­ cable diseases was greater in low- and middle-income countries. In most developing countries, people lived shorter lives and experienced disability and poor health for a greater proportion of their lives. ■ ■HEALTH AND WEALTH Clear disparities in burden of disease (both communicable and noncom­ municable) across country income levels are strong indicators that pov­ erty and health are inherently linked. Numerous studies have documented the link between poverty and health within nations as well as across them. Poverty remains one of the most important root causes of poor health worldwide, and the global burden of poverty continues to be high. Among the 8 billion persons alive in 2023, 9% (700 million) lived on less than $2.15 per day—a standard measurement of extreme poverty— and half of these individuals lived in Sub-Saharan Africa. While children make up 31% of the overall global population, they account for 50% of persons living in poverty. The extreme poverty rate declined steadily between 1990 and 2019. Before the COVID-19 pandemic, compared

27. Neonatal disorders

28. Ischemic heart disease

29. Stroke

30. Lower respiratory infections

31. Diarrheal diseases Global Issues in Medicine CHAPTER 485

32. COPD

33. Road injuries

34. Diabetes

35. Low back pain

36. Congenital defects

37. HIV/AIDS

38. Tuberculosis

39. Depressive disorders

40. Headache disorders

41. Malaria

42. Cirrhosis

43. Lung cancer

44. Chronic kidney disease

45. Other musculoskeletal

46. Age-related hearing loss

47. Falls

48. Self-harm

49. Meningitis

50. Protein-energy malnutrition

51. Drowning

52. Measles with 1990, there were more than 1 billion fewer people living in poverty despite growth in the global population of more than 2 billion during that time. The COVID-19 pandemic led to significant increases in pov­ erty, especially in low- and middle- income countries. The poorest bore the brunt of the economic shocks of COVID-19. The global poorest lost twice as much income as the richest between 2020 and 2022. ■ ■RISK FACTORS FOR DISEASE BURDEN The GBD study found that the three leading risk factors for global dis­ ease burden in 2019 were (in order of frequency) high systolic blood pressure, smoking, and high fasting plasma glucose—a substantial change from 1990, when childhood malnutrition was ranked first. Although its prevalence has declined, maternal and childhood malnu­ trition remain the leading risk factors for death among children < 5 years of age. In an era that has seen obesity become a major health concern in many developed countries, the persistence of undernutrition is cause for consternation. In its rural reaches, no health care initiative, however generously funded, will be effective or comprehensive without address­ ing undernutrition. In an analysis that examined how specific diseases and injuries are affected by environmental risk, the WHO estimates that 24% of all

TABLE 485-1  Leading Causes of Burden of Disease (DALYs), 2019 DALYS (MILLIONS) PERCENTAGE OF TOTAL DALYs DISEASE OR INJURY World 2540.0

1. Neonatal disorders 185.9 7.3
2. Ischemic heart disease 182.0 7.2
3. Stroke 143.2 5.7
4. Lower respiratory infection 97.2 3.8
5. Diarrheal diseases 80.9 3.2
6. COPD 74.4 2.9 PART 17 Global Medicine
7. Road injuries 72.9 2.9
8. Diabetes 70.9 2.8
9. Low back pain 63.7 2.5
10. Congenital defects 52.8 2.1 Low-Income Countriesa
11. Neonatal disorders 44.4 17.4
12. Lower respiratory infection 24.5 7.6
13. Malaria 23.3 7.2
14. Diarrheal disease 23.2 7.2
15. HIV/AIDS 14.5 4.5
16. Congenital defects 12.8 4.0
17. Tuberculosis 12.2 3.8
18. Stroke 8.6 2.7
19. Road injuries 6.2 2.3
20. Ischemic heart disease 7.4 2.3 High-Income Countriesa
21. Ischemic heart disease 26.8 7.6
22. Low back pain 17.7 4.9
23. Stroke 15.8 4.4
24. Lung cancer 13.7 3.9
25. Diabetes 13.3 3.7
26. COPD 12.0 3.4
27. Falls 9.7 2.7
28. Alzheimer’s disease 9.2 2.6
29. Other musculoskeletal 9.1 2.6
30. Depressive disorders 8.6 2.4 Sub-Saharan Africa
31. Neonatal disorders 70.5 13.8
32. Malaria 43.2 8.5
33. Diarrheal diseases 42.0 8.2
34. Lower respiratory infection 41.1 8.0
35. HIV/AIDS 35.6 7.0
36. Congenital defects 18.1 3.6
37. Tuberculosis 17.6 3.4
38. Road injuries 11.1 2.2
39. Stroke 10.8 2.1
40. Meningitis 10.4 2.0 aThe World Bank classifies high-income countries as those whose gross national income (GNI) per capita is ≥$14,005. Low- and middle-income countries are categorized as low income (GNI per capita, <$1,145), lower-middle income (GNI per capita, $1,146–$4,515), and upper-middle income (GNI per capita, $4,516–$14,005) (https://datahelpdesk.worldbank.org/knowledgebase/articles/906519). Abbreviations: COPD, chronic obstructive pulmonary disease; DALYs, disabilityadjusted life-years. Source: Institute for Health Metrics and Evaluation, University of Washington (2023). Data available at https://vizhub.healthdata.org/gbd-compare/. Accessed

December 15, 2023. deaths and 28% of deaths among children <5 years of age in 2019 were due to modifiable environmental factors: some 17 million children die every year from causes related to unhealthy environments, including the nearly 500,000 deaths stemming from a lack of access to clean water

TABLE 485-2  Leading Causes of Death Worldwide, 2019 DEATHS (MILLIONS) PERCENTAGE OF TOTAL DEATHS DISEASE OR INJURY World 56.5

1. Ischemic heart disease 9.1 16.1
2. Stroke 6.6 11.7
3. COPD 3.3 5.8
4. Lower respiratory infection 2.5 4.4
5. Lung cancer 2.0 3.6
6. Neonatal disorders 1.9 3.3
7. Alzheimer’s disease 1.6 2.9
8. Diabetes 1.6 2.7
9. Diarrheal diseases 1.5 2.7
10. Cirrhosis 1.5 2.6 Low-Income Countriesa
11. Neonatal disorders 0.5 9.7
12. Lower respiratory infection 0.4 8.3
13. Diarrheal diseases 0.3 6.8
14. Stroke 0.3 6.5
15. Ischemic heart disease 0.3 6.2
16. Malaria 0.3 6.1
17. Tuberculosis 0.3 5.5
18. HIV/AIDS 0.2 5.0
19. Congenital defects 0.1 2.8
20. COPD 0.1 2.5 High-Income Countriesa
21. Ischemic heart disease 1.8 16.4
22. Stroke 0.9 8.4
23. Lung cancer 0.7 6.4
24. Alzheimer’s disease 0.7 6.3
25. COPD 0.5 4.9
26. Lower respiratory infection 0.4 4.1
27. Colorectal cancer 0.4 3.8
28. Chronic kidney disease 0.3 3.0
29. Diabetes 0.3 2.3
30. Pancreatic cancer 0.2 2.1 Sub-Saharan Africa
31. Neonatal disorders 0.7 9.9
32. Lower respiratory infection 0.7 8.9
33. HIV/AIDS 0.6 8.4
34. Malaria 0.6 7.8
35. Diarrheal diseases 0.6 7.8
36. Stroke 0.4 5.3
37. Tuberculosis 0.4 5.1
38. Ischemic heart disease 0.4 5.0
39. Congenital defects 0.2 2.5
40. Cirrhosis 0.2 2.5 aThe World Bank classifies high-income countries as those whose gross national income (GNI) per capita is ≥$14,005. Low- and middle-income countries are categorized as low income (GNI per capita, <$1,145), lower-middle income (GNI per capita, $1,146–$4,515), and upper-middle income (GNI per capita, $4,516–$14,005) (https://datahelpdesk.worldbank.org/knowledgebase/articles/906519). Abbreviation: COPD, chronic obstructive pulmonary disease. Source: Institute for Health Metrics and Evaluation, University of Washington (2023). Data available at https://vizhub.healthdata.org/gbd-compare/. Accessed December 15, 2023. and sanitation. Many of these modifiable factors lead to child and adult deaths from infectious pathologies; others lead to deaths from malig­ nancies. Risk factors such as indoor air pollution due to use of solid fuels account for 25% of DALYs due to lower respiratory infections

globally. Various forms of unintentional injury and malaria top the list of health problems to which environmental factors contribute. The third edition of Disease Control Priorities (DCP3), published as a set of serial volumes based on content area, provides evidencebased recommendations and cost-effectiveness analyses for numerous interventions, with attention to strategies for strengthening health systems. Cost-effectiveness analyses that compare relatively equivalent interventions in order to facilitate sound decisions under constraint are necessary; however, these analyses, as the DCP3 authors acknowledge, are unreliable when based on an incomplete knowledge of cost and evolving evidence of effectiveness. As both resources and objectives for global health initiatives grew, cost-effectiveness analyses (particularly those based on older evidence) sometimes steered policy makers and public health experts toward low-cost but ultimately ineffective inter­ ventions or away from higher-priced but effective ones. Thus, we use the term global health equity to emphasize the need to ensure equitable access to high-value health interventions. To illustrate these points, it is instructive to look to HIV/AIDS, which in the course of the last four decades has become one of the world’s leading infectious causes of adult death. ■ ■HIV INFECTION/AIDS Chapter 208 provides an overview of the global HIV epidemic today. Approximately 39 million people worldwide were living with HIV infection in 2022, and it was the underlying cause of death for 630,000 people that year. Approximately 67% of all people living with HIV live in Sub-Saharan Africa. Here the discussion will be limited to HIV/ AIDS in the developing world. Lessons learned from tackling HIV/ AIDS in low-resource settings are highly relevant to discussions of other chronic diseases, including NCDs, for which effective therapies have been developed. In the United States, after the mid-1990s, ART transformed HIV infection from an inescapably fatal disease into a manageable chronic illness. Across high-income countries, improved ART has dramatically prolonged life expectancy for people living with HIV infection, which now approaches that of the general population. This success rate exceeds that obtained with almost any treatment for adulthood cancer or for complications of coronary artery disease. In developing countries, treatment has been offered broadly only since 2003. Before 2003, many arguments were raised to justify not mov­ ing forward rapidly with ART programs for people living with HIV/ AIDS in resource-limited settings. The standard litany included the price of therapy compared with the poverty of patients, the complexity of the intervention, the lack of infrastructure for laboratory monitoring, and the lack of trained health care providers. Narrow cost-effectiveness arguments that created false dichotomies—prevention or treatment rather than their synergistic integration—too often went unchal­ lenged by policy makers, public health experts, and health economists. As a cumulative result of these delays in the face of health disparities both old and new, there were mil­ lions of premature deaths. Disparities in access to HIV treatment did give rise to widespread moral indignation and a new type of health activism. In several middle-income countries, including Brazil, public programs have helped bridge the global access gap. Other innovative projects pioneered by interna­ tional nongovernmental organizations (NGOs) in diverse settings such as Haiti and Rwanda have established that a simple approach to ART based on intensive community engagement and social and economic support for patients and their community-based health workers can achieve remarkable results (Fig. 485-2). During the past decade, the availability of ART has increased sharply in the low- and middle-income coun­ tries that have borne the greatest burden of the HIV/AIDS pandemic. In 2000, few people living with HIV/AIDS in these nations had access to ART, whereas by 2022, 76% of people living with HIV infection were receiving ART. In light of these dramatic gains, coverage targets have grown

more ambitious; for example, in 2014, UNAIDS set the 90-90-90 tar­ gets, which aimed to have 90% of people living with HIV know their status, 90% of those with HIV treated with ART, and 90% of those on treatment achieving viral load suppression by 2020. Five countries met these ambitious goals: Botswana, Eswatini, Rwanda, the United Republic of Tanzania, and Zimbabwe. These goals were updated to “95-95-95” targets for 2030, and by 2023, these same five countries had already achieved them.

This scale-up was made possible by several developments: a stagger­ ing drop in the cost of generically manufactured ART, the development of a standardized approach to treatment, substantial investments by funders, and the political commitment of governments to afford ART as a public good. Civil-society AIDS activists spurred many of these efforts. Global Issues in Medicine CHAPTER 485 Starting in the early 2000s, a combination of factors, including work by the Clinton HIV/AIDS Initiative (now known as the Clinton Health Access Initiative) and Médecins Sans Frontières, led to the availability of generic ART medications. While first-line ART cost

$10,000 per patient per year in 2000, first-line regimens in low- and middle-income countries are now available for <$45 per year. At the same time, fixed-dose combinations made multidrug regimens easier to administer. Also, around this time, the WHO began advocating a public health approach to the treatment of people with AIDS in low-resource settings; this approach promised—thanks to dropping viremia—to lower transmission rates and, if universally available, to end almost all mother-to-child transmission. Derived from models of care pioneered by the NGO Partners In Health and other groups, this approach proposed the use of standard first-line treatment regimens based on a simple five-drug formulary, with a more complex (and more expensive) set of second-line options in reserve. Clinical protocols were standardized, and intensive training packages for health professionals and community health workers were developed and implemented in many countries. Early rollout efforts were supported by new funding from the Global Fund and PEPFAR. In 2003, lack of access to ART was declared a global public health emergency by the WHO and UNAIDS, and those two agencies launched the 3 by 5 Initiative, setting an ambi­ tious target: to have 3 million people in developing countries on treat­ ment by the end of 2005. Many countries set corresponding national targets and have worked to integrate ART into their national AIDS programs and health systems and to harness the synergies between HIV/AIDS treatment and prevention activities. External funding to FIGURE 485-2  An HIV and tuberculosis (TB)–co-infected patient in Rwanda before (left) and after (right) 6 months of treatment.

3848 fight HIV/AIDS in low- and middle-income countries increased dra­ matically during this period and beyond, rising from $332 million in 1996 to $9.9 billion in 2021. The integration of prevention and care led to a sharp drop in transmission—a 96% decline according to one review of the impact of ART rollout in heavily burdened countries in Africa and the Caribbean. Further lessons with implications for policy and action have come from efforts now under way among lower-income countries. Rwanda provides an example: since 2000, mortality from HIV disease has fallen by 85% as the country—despite its relatively low gross national income—has provided almost universal access to ART. The reasons for this success include strong national leadership, evidence-based policy, cross-sector collaboration, community-based care, and a deliberate focus on a health-systems approach that embeds HIV/AIDS treatment and prevention in the primary health care service delivery platform. As we will discuss later in this chapter, these principles can be applied to other conditions, including NCDs. PART 17 Global Medicine ■ ■TUBERCULOSIS Chapter 183 provides a concise overview of the pathophysiology and treatment of tuberculosis. In 2022, an estimated 1.3 million people died from Mycobacterium tuberculosis infection; this figure made tuber­ culosis the second leading single infectious killer after COVID-19 of adults globally. The disease is closely linked to HIV infection in much of the world: of the 10.6 million estimated new cases of tuberculosis in 2022, 890,000 occurred among people living with HIV. A much more substantial proportion of the resurgence of tuberculosis registered in southern Africa is attributed to HIV co-infection. Even before the advent of HIV, however, it was estimated that fewer than one-half of all cases of tuberculosis in developing countries were ever diagnosed. Primarily because of the common failure to diagnose and treat tuber­ culosis, international authorities devised a single strategy to reduce the burden of disease. In the early 1990s, the World Bank, the WHO, and other international bodies promoted the DOTS strategy (directly observed therapy using short-course isoniazid- and rifampin-based regimens) as highly cost-effective. Passive case-finding of smearpositive patients was central to the strategy, as was an uninterrupted drug supply. DOTS was clearly effective for most uncomplicated cases of drugsusceptible tuberculosis, but several shortcomings were soon identi­ fied. First, the diagnosis of tuberculosis based solely on sputum smear microscopy—a method dating from the late nineteenth century—is not sensitive. Many cases of pulmonary tuberculosis and all cases of exclu­ sively extrapulmonary tuberculosis are missed by smear microscopy, as are most cases of active disease in children. Second, passive case-find­ ing relies on the availability of health care services, which is uneven in the settings where tuberculosis is most prevalent. Third, patients with multidrug-resistant tuberculosis (MDR-TB) are by definition infected with strains of M. tuberculosis resistant to isoniazid and rifampin; thus, exclusive reliance on these drugs is unwarranted in settings in which drug resistance is an established problem. The crisis of antibiotic resistance registered in U.S. hospitals is not confined to the industrialized world or to common bacterial infec­ tions. While the great majority of patients sick with and dying from tuberculosis are afflicted with strains susceptible to all first-line drugs, a substantial minority of patients with tuberculosis in some settings are infected with strains of M. tuberculosis resistant to at least one first-line antituberculosis drug. Globally in 2021, an estimated 4% of all patients with new M. tuberculosis infections and 18% of all previously treated patients were infected with rifampin-resistant or MDR strains; most of these cases resulted from primary transmission. It was clear that poor infection control in hospitals and clinics in the face of delays in the initiation of effective therapy led to explosive and lethal epidemics due to these strains. To improve DOTS-based responses to MDR-TB, global health authorities adopted DOTS-Plus, which adds the diagnostics and drugs necessary to manage drug-resistant disease. Even as DOTSPlus was being piloted in resource-constrained settings, however, new strains of extensively drug-resistant (XDR) M. tuberculosis (resistant to isoniazid and rifampin, any fluoroquinolone, and at least one injectable

second-line drug) had already threatened the success of tuberculosis control programs in beleaguered South Africa, for example, where high rates of HIV infection had led to a doubling in the incidence of tuber­ culosis over the preceding decade. Genetic fingerprinting of cultures of infected sputum and tissues suggest that patients may be infected by more than one strain. Despite the poor capacity for detection of MDR- and XDR-TB in most resource-limited settings, an estimated 450,000 cases of MDR-TB were thought to have occurred in 2021. Approxi­ mately 8% of these cases were caused by XDR strains. ■ ■TUBERCULOSIS AND AIDS AS CHRONIC DISEASES: LESSONS LEARNED Strategies effective against MDR-TB have implications for the manage­ ment of drug-resistant HIV infection and even drug-resistant malaria, which, through repeated infections and a lack of effective therapy, has become a chronic disease in parts of Africa (see “Malaria,” below). As new therapies, whether for tuberculosis or for hepatitis C infection, become available, many of the problems encountered in the past will recur. Indeed, examining AIDS and tuberculosis as chronic diseases— instead of simply communicable ones—makes it possible to draw several conclusions, many of them pertinent to global health equity in general. First, the chronic infections discussed here are best treated with multidrug regimens to which the infecting strains are susceptible. This is true of chronic infections due to many bacteria, fungi, parasites, or viruses; even acute infections such as those caused by Plasmodium spe­ cies are not reliably treated with a single drug. Second, charging fees for AIDS prevention and care poses insur­ mountable problems for persons living in poverty, many of whom are unable to pay even modest amounts for services or medications. Like efforts to battle airborne tuberculosis, such services might best be seen as a public good promoting public health. Initially, a subsidy approach will require sustained donor contributions, but many African coun­ tries have set targets for increased national investments in health—a pledge that could render ambitious programs sustainable in the long run, as the Rwanda experience suggests. Meanwhile, as local invest­ ments increase, the price of AIDS care continues to decrease. The use of generic medications means that ART can now cost <$0.13 per day. Third, the effective scale-up of pilot projects requires strengthen­ ing and sometimes rebuilding of health care systems, including those charged with delivering primary care. In the past, the lack of health care infrastructure has been cited as a barrier to providing ART in the world’s poorest regions; however, AIDS resources, which are at last considerable, may be marshaled to rebuild public health systems in Sub-Saharan Africa and other HIV-burdened regions—precisely the settings in which tuberculosis is resurgent. Failure to pursue such a health-systems approach after civil wars ended in Sierra Leone and Liberia accounts for much of their extreme vulnerability to Ebola a decade later. Fourth, the lack of trained health care personnel, most notably doctors and nurses, still must be addressed. The WHO recommends a minimum of 1 physician per 1000 persons, but many countries, especially in Sub-Saharan Africa, fall far short of that target. Specifi­ cally, ~45% of WHO member states report not achieving that target. In Sub-Saharan Africa, there were 0.3 physicians per 1000 people. In contrast, the United States and Cuba report 2.5 and 8.4 doctors per 1000 population, respectively. Similarly, ~50% of WHO member states report having fewer than 3 nurses and midwives per 1000 population. Sub-Saharan Africa bears >20% of the global burden of disease but has access to only 3% of the world’s health workers. Further inequalities in health care staffing exist within countries. Rural–urban disparities in health care personnel mirror disparities of both wealth and health. For instance, in Sierra Leone, an estimated 75% of the national health workforce is concentrated in urban areas, where just 44% of the population lives. Even community health workers trained to provide first-line services to rural populations often transfer to urban districts. In what is termed the “brain drain,” many physicians and nurses emigrate from their home countries to pursue opportunities abroad, leaving behind health systems that are understaffed and ill-equipped to deal with either emergencies like Ebola or the usual burden of disease.

One reason doctors and nurses leave Sub-Saharan Africa and other low-income areas is that they lack the tools to practice there. Fund­ ing for “vertical” (disease-specific) programs can be used not only to strengthen health systems but also to recruit and train physicians and nurses to underserved regions where they, in turn, can help to train and then work with community health workers in supervising care for patients with AIDS and many other diseases within their communi­ ties. Such training should be undertaken even where physicians are abundant, since close community-based supervision represents the highest standard of care for chronic disease, whether in developing or developed countries. The United States, which has a dearth of health care providers in many of its poor and rural communities, has much to learn from Rwanda in this regard. Fifth, the many barriers to adequate health care and patient adherence that are raised by extreme poverty can be removed only with the deploy­ ment of “wrap-around services”: food supplements for the hungry, help with transportation to clinics, childcare, and housing. Extreme poverty makes it difficult for many patients to comply with therapy for chronic diseases, whether communicable or not. Experience shows, however, that these many barriers can be more readily surmounted than the extreme poverty itself to which chronic disease and acute infection contribute substantially. Indeed, poverty in its many dimensions is far and away the greatest obstacle to the scale-up of treatment and prevention services. Finally, there is a need for a renewed basic-science commitment to the discovery and development of vaccines; more reliable, less expensive diagnostic tools; and new classes of therapeutic agents. This need applies not only to HIV, tuberculosis, and malaria—against none of which there is a highly effective vaccine—but also to most other neglected diseases of poverty. ■ ■MALARIA Chapter 231 reviews the etiology, pathogenesis, and clinical treat­ ment of malaria, the world’s fifth-ranking infectious killer. In 2022, there were 249 million cases of malaria, and the disease killed 608,000 people; 77% of these deaths occurred among children <5 years old. The poor disproportionately experience the burden of malaria. SubSaharan Africa was home to about 94% of all malaria cases and 95% of all deaths. Just 4 countries—Nigeria, the Democratic Republic of the Congo, Uganda, and Mozambique—account for more than half of total malaria deaths globally. Malaria’s human cost has been enormous, with the highest toll among children—especially African children—living in poverty. In 2022, $4.3 billion was spent on malaria worldwide, but the WHO target is more than twice that sum. Macroeconomic analyses estimate that malaria may reduce the per capita gross national product of a disease-endemic country by 50% relative to that of a non–malaria-endemic country. The causes of this drag include impaired cognitive development of children, decreased schooling, decreased savings, decreased foreign investment, and restriction of worker mobility. Microeconomic analyses focusing on direct and indirect costs estimate that malaria may consume >10% of a household’s annual income in malaria endemic regions. In part because of differences in vector distribution and climate, resource-rich countries offer few blueprints for malaria control and treatment that are applicable in tropical (and resource-poor) settings. In 2001, African heads of state endorsed the WHO Roll Back Malaria (RBM) campaign, which prescribes strategies appropriate for SubSaharan African countries. In 2008, the RBM partnership launched the Global Malaria Action Plan (GMAP). This strategy integrates pre­ vention and care and calls for the avoidance of single-dose regimens and an awareness of existing drug resistance; the use of insecticidetreated bed nets (ITNs); indoor residual spraying; artemisinin-based combination therapy (ACT); intermittent preventive treatment during pregnancy; prompt diagnosis; and other vector control measures such as larviciding and environmental management. Over the past two decades, these efforts have dramatically reduced the global burden of malaria resulting in the prevention of 1.7 billion cases and saving 10.6 million lives. Meeting the challenge of malaria control will continue to require careful study of appropriate preventive and therapeutic strategies in the

context of an increasingly sophisticated molecular understanding of pathogen, vector, and host. However, an appreciation of the economic and social devastation wrought by malaria—like that inflicted by diar­ rhea, AIDS, and tuberculosis—on the most vulnerable populations should heighten the level of commitment to critical analysis of ways to implement proven strategies for prevention and treatment. Funding from the Global Fund, the Gates Foundation, the World Bank’s International Development Association, and the U.S. President’s Malaria Initiative, along with leadership from public health authorities, is critical to sustain the benefits of prevention and treatment. Building on the growing momentum of the last decade with adequate financial support, innovative strategies, and effective tools for prevention, diag­ nosis, and treatment, we may yet achieve the goal of a world largely free of malaria. Global Issues in Medicine CHAPTER 485 ■ ■EBOLA Chapter 216 provides an overview of the epidemiology, pathogenesis, and clinical manifestations of Ebola virus and Marburg virus infec­ tions. The 2013–2016 outbreak of Ebola virus disease in West Africa was the largest documented Ebola epidemic to date, with >28,000 recorded cases and 11,000 recorded deaths. Prior to the outbreak, the health systems of the three most affected countries—Liberia, Guinea, and Sierra Leone—were among the world’s weakest. Histories of extractive colonial and postcolonial commerce, the conditional aid policies of international financial institutions, recent civil conflict, and underresourced health ministries left this part of West Africa bereft of the means to deliver modern medicine and promote public health. In 2013, Sierra Leone had the world’s highest maternal mortality ratio, with 1180 deaths per 100,000 live births. According to one estimate, Liberia had just 51 physicians working in the entire coun­ try before the Ebola epidemic, or roughly one physician per 100,000 persons. Clinics and hospitals were scarce across the region, especially in rural areas, and routinely lacked drugs, supplies, electricity, running water, laboratories, and personal protective equipment for the prevention of nosocomial infection. Such deficits were not surprising given these countries’ meager public and private expenditures on health. The unprecedented scale of the West African Ebola epidemic was largely a symptom of these chronically weak health systems. As a result, clinicians, patients’ families, and other caregivers—tasked with nursing the sick and interring the dead but lacking the means to do so safely— faced disproportionately high risks of Ebola infection. Health facilities with poor infection control and unsafe burials served as amplifiers of transmission. The quest to contain Ebola in West Africa was one of the largest global public health efforts at that time, but it was far from ambitious clinically. As in previous Ebola outbreaks, preventing new infections was often prioritized over improving survival among those already infected, leading to substandard care for most West African patients and high case-fatality rates—by WHO estimates, ~70%. However, in settings in which quality supportive and critical care could be provided, clinical outcomes among Ebola-infected patients affirmed that Ebola virus disease is treatable, even in the absence of specific antiviral thera­ pies and experimental drugs. As with efforts to combat AIDS and tuberculosis, the global response to Ebola reveals the unintended consequences of pitting preventive strategies against therapeutic ones—and the pull of debates about scarcity. Misguided (and often contradictory) public health messaging, distrust of disease-control and social mobilization teams, punitive containment measures, and the unavailability of safe Ebola treatment units capable of delivering effective clinical care deterred individuals from presenting to health facilities, reporting symptomatic patients and their contacts, and cooperating with epidemic response activities. The resulting epidemic of mistrust facilitated the further spread of new infections by impeding surveillance, timely diagnosis, contact tracing, and patient isolation. In August 2018, a new Ebola outbreak was detected in eastern Dem­ ocratic Republic of the Congo (DRC) and soon became the world’s sec­ ond largest on record. In June 2020, when it was declared over, it had sickened ~3500 persons and killed two-thirds of them. Containment

3850 was complicated by armed conflict in the affected region, which had long experienced strife, impoverishment, and colonial and postcolonial extraction, feeding a well-founded suspicion of foreign intervention. Despite these challenges, responders benefitted from the arrival of new tools to prevent, diagnose, and treat Ebola. A new vaccine was extensively deployed using a ring vaccination strategy. There was sig­ nificant progress in the quality of supportive care provided to patients in DRC, with more routine monitoring, improved access to clinical laboratory services, better staffing of treatment centers, and more aspi­ rational clinical protocols. Nevertheless, the overall case-fatality rate in DRC reveals that these welcome medical innovations did not reach everyone in need of them. PART 17 Global Medicine ■ ■COVID-19 Chapter 205 provides an overview of the epidemiology, pathogenesis, and clinical manifestations of COVID-19 infection. As we near the end of the fourth year of the pandemic, there have been more than 7 million confirmed deaths due to COVID-19 infection and 780 million con­ firmed cases. Reasonable estimates suggest that the true total of deaths is likely ~18 million. During this period, COVID-19 was among the top five causes of death worldwide. In the early months of the COVID-19 pandemic, many health systems in high-income countries were strained to treat the surge of patients afflicted by it. The pandemic revealed deep structural deficiencies in our collective global ability to recognize and contain such “novel” pathogens. Although SARS-CoV-2 is “novel” in relation to our human immune systems, its rapid march across the globe followed the familiar pattern of many pandemic pathogens before it, such as HIV, tuberculosis, and cholera. It has particularly high attack rates among vulnerable populations, such as those experiencing home­ lessness and nursing home residents, and in poor communities where insufficient housing, food insecurity, and marginal employment in low-paid service jobs have resulted in inability to safely social distance and quarantine. The United States suffered during the early parts of this pandemic from underinvestment in public health systems that can provide surveillance testing at scale and perform robust contact tracing. On the global level, profound inequities occurred in access to vaccines and therapeutics. The COVID-19 Vaccines Global Access (COVAX) initiative had broad global support and ambitious goals but was unable to meet its targets. This was due, in part, to lack of access to sufficient vaccine doses as a result of excess procurement by high-income coun­ tries for their own use. COVAX successfully delivered 2 billion doses of vaccine and is thought to have averted 2.7 million deaths. We share a deep hope that this pandemic may catalyze a broader recognition about the effects of poverty on health, about the need to achieve universal access to health care for all the world’s people, and about the urgency of strengthening global public health systems. ■ ■“NONCOMMUNICABLE” CHRONIC DISEASES Although the burden of communicable diseases—especially HIV infec­ tion, tuberculosis, and malaria—still accounts for the majority of deaths in resource-poor regions within Sub-Saharan Africa and in the poorest reaches of several first-world cities, 74% of all deaths worldwide in 2022 were attributed to NCDs. Although we use this term to describe cardiovascular diseases, cancers, diabetes, and chronic lung diseases, this usage masks important distinctions. For instance, two significant NCDs in low-income countries, rheumatic heart disease (RHD) and cervical cancer, represent the chronic sequelae of infections with group A Streptococcus and human papillomavirus, respectively, and it is in these countries that the burden of disease due to NCDs is rising most rapidly. A little more than three-quarters of deaths attributable to NCDs occur in low- and middle-income countries, which also account for 85% of all early NCD-related deaths—a figure representing ~17 million persons and exceeding the total number of deaths due to AIDS, tuberculosis, and malaria combined. By 2030, NCDs will account for 52 million deaths annually worldwide if no additional action is taken. The recent increase in resources for and attention to communicable diseases is both welcome and long overdue, but developing countries are already carrying a “double burden” of communicable and noncom­ municable diseases.

Diabetes, Cardiovascular Disease, and Cancer: A Global Perspective  In contrast to tuberculosis, HIV infection, and malaria—diseases caused by single pathogens that damage multiple organs—cardiovascular diseases reflect injury to a single organ system downstream of a variety of insults, both infectious and noninfectious. Some of these insults result from rapid changes in diet and labor conditions; others are of a less recent vintage. The burden of cardio­ vascular disease in low-income countries represents one consequence of decades of neglect of health systems. Furthermore, cardiovascular research and investment have long focused on the ischemic conditions that are increasingly common in high- and middle-income countries. Predictions of an imminent rise in the share of deaths and disabili­ ties due to NCDs in developing countries have led to calls for preven­ tive policies to improve diet, increase exercise, and restrict tobacco use, along with the prescription of multidrug regimens for persons at highlevel vascular risk. Although this agenda could do much to prevent pandemic NCDs, it will do little to help persons with established heart disease stemming from nonatherogenic pathologies. The misperception of cardiovascular diseases as a problem primar­ ily of elderly populations in middle- and high-income countries has contributed to the neglect of these diseases by global health institu­ tions, including regionally focused ones. Even in Eastern Europe and Central Asia, where the collapse of the Soviet Union was followed by a catastrophic surge in cardiovascular disease deaths (mortality rates from ischemic heart disease nearly doubled between 1991 and 1994 in Russia, for example), the modest flow of overseas development assis­ tance to the health sector during these troubled years focused on the communicable causes that accounted for <1 in 20 excess deaths during that period. DIABETES  The International Diabetes Federation reports that the number of diabetic adult patients in the world is expected to increase from 537 million in 2022—~1 in 11 adults—to 783 million by 2045. Already, a significant proportion of patients with diabetes, 3 in 4 adults with the condition, live in developing countries where, because those affected are often younger, the complications of micro- and macrovas­ cular disease take a far greater toll. Globally, these complications are a major cause of disability and reduced quality of life: a high fasting plasma glucose level ranks third among risks for disability and global mortality. The GBD 2017 study estimates that diabetes accounted for 1.6 million deaths in 2019; 84% of these deaths occurred in low- and middle-income countries. CARDIOVASCULAR DISEASE  Because systemic investigation of the causes of stroke and heart failure in Sub-Saharan Africa has begun only recently, little is known about the impact of elevated blood pressure in this portion of the continent. Modestly elevated blood pressure in the absence of tobacco use in populations with low rates of obesity may confer little risk of adverse events in the short term. In contrast, persis­ tently elevated blood pressure goes largely undetected, untreated, and uncontrolled in this part of the world. In the cohort of men assessed in the Framingham Heart Study, the prevalence of blood pressures above 210/120 mmHg—severe hypertension—declined from 1.8% in the 1950s to 0.1% by the 1960s with the introduction of effective antihypertensive agents. Although debate continues about appropriate screening strategies and treatment thresholds, Africa’s rural health cen­ ters, run largely by nurses, must quickly gain access to antihypertensive medications. The epidemiology of heart failure also reflects inequalities in risk factor prevalence and in access to therapy. The reported burden of this condition has remained unchanged since the 1950s, but the causes of heart failure and the age of the people affected vary across the globe. Heart failure as a consequence of pericardial, myocardial, endocardial, or valvular injury is a leading cause of hospitalization in the United States and Europe, representing ~3% of all hospitalizations, and is estimated to account for a substantial proportion of medical admissions in hos­ pitals in low-income countries as well. In high-income countries, coro­ nary artery disease and hypertension among the elderly account for most cases of heart failure. Among the world’s poorest 1 billion people, however, heart failure reflects poverty-driven exposure of children and

young adults to rheumatogenic strains of streptococci and cardiotro­ pic microorganisms (e.g., HIV, Trypanosoma cruzi, enteroviruses, M. tuberculosis), untreated high blood pressure, and nutrient deficiencies. The mechanisms underlying other causes of heart failure common in these populations—such as idiopathic dilated cardiomyopathy, peripartum cardiomyopathy, and endomyocardial fibrosis—remain unclear. In stark contrast to the extraordinary lengths to which clinicians in wealthy countries will go to treat ischemic cardiomyopathy among elderly patients, little attention has been paid to young patients with nonischemic cardiomyopathies in resource-poor settings. Nonisch­ emic cardiomyopathies, such as those due to hypertension, RHD, and chronic lung disease, account for >90% of cases of cardiac failure in Sub-Saharan Africa and include poorly understood entities such as peripartum cardiomyopathy (which has an incidence in rural Haiti of 1 per 300 live births) and HIV-associated cardiomyopathy. Lessons learned in the scale-up of chronic care for HIV infection and tubercu­ losis may be illustrative as progress is made in establishing the means to deliver heart-failure medications to these patients. Some of the lessons learned from the chronic infections discussed above are, of course, relevant to cardiovascular disease, especially those classified as NCDs but caused by infectious pathogens. Integration of prevention and care remains as important today as in 1960 when Paul Dudley White and his colleagues found little evidence of myocardial infarction in the region near the Albert Schweitzer Hospital in Lambaréné, Gabon, but reported that “the high prevalence of mitral stenosis is astonishing.” They termed it a duty to integrate prevention with penicillin prophylaxis and care, including medical management and surgery, when indicated. “The same responsibility,” they agreed, “exists for those with correctable congenital cardiovascular defects.” RHD affects almost 40 million people worldwide, with ~2.8 million new cases each year. A meta-analysis of data on heart failure in SubSaharan Africa found that RHD was the third most common cause of heart failure in the region. This disease, which may cause endocarditis or stroke, leads to >300,000 deaths per year—almost all occurring in developing countries. Results from 14 low- and middle-income countries included in the Global Rheumatic Heart Disease Registry showed that mortality was significantly higher among patients living in low-income countries and among the less educated. Recent studies in Rwanda and Ethiopia have confirmed a high prevalence of RHD among schoolchildren, including those that are asymptomatic. In part because the prevention of RHD has not advanced since the disease’s disappearance in wealthy countries, no part of Sub-Saharan Africa has eradicated RHD despite examples of success in Costa Rica, Cuba, and some Caribbean nations. Strategies to eliminate RHD may depend on active case-finding, with confirmation by echocardiography, among high-risk groups as well as on efforts to expand access to surgical interventions among children with advanced valvular damage. Partnerships between estab­ lished surgical programs and areas with limited or nonexistent facilities may help expand the capacity to provide lifesaving interventions to patients who otherwise would die early and painfully. Such partner­ ships can speed the further development of regional centers of excel­ lence equipped to provide consistent, accessible, high-quality services to those now without them. CANCER  Low- and middle-income countries accounted for ~70% of the 10 million deaths due to cancer worldwide in 2020. By 2040, annual mortality from cancer is expected to increase to >16 million deaths— with developing countries experiencing a sharper increase than devel­ oped nations. “Western” lifestyle changes may be responsible for the increased incidence of cancers of the breast, colon, and prostate among populations in low- and middle-income countries, but historic realities, sociocultural and behavioral factors, genetics, and poverty itself already have a profound impact on cancer-related mortality and morbidity rates. Cancer-causing infections, such as human papillomavirus, hepa­ titis B virus, and Helicobacter pylori, are responsible for up to 50% of cancer cases in some countries in Sub-Saharan Africa. Infectious causes of cancer will continue to have a much larger impact in developing

countries. Environmental and dietary factors, such as indoor air pol­ lution and high-salt diets, also contribute to increased rates of certain cancers (e.g., lung and gastric cancers). Tobacco use (both smoking and chewing) is the most important source of increased mortality rates from lung, bladder and oral cancers. In contrast to decreasing tobacco use in many developed countries, the number of smokers is growing in devel­ oping countries, especially among women and young persons. For many reasons, outcomes of malignancies are far worse in developing countries than in developed nations. As currently funded, overstretched health systems in poor countries are not capable of early detection; at the time of tissue diagnosis, the majority of patients already have incurable malignancies. Treatment of cancers is available for only a very small number of mostly wealthy citizens in most poor countries, and even when treatment is available, the range and qual­ ity of services are often substandard. Yet this need not be the future. Twenty years ago, MDR-TB and HIV infections were widely deemed untreatable in settings of great poverty. The feasibility of creating innovative programs that reduce technical and financial barriers to the provision of care for treatable malignancies among the world’s poorest populations is now clear (Fig. 485-3). Several middle-income countries, including Mexico, have expanded publicly funded cancer care to reach poorer populations. This commitment of resources has dramatically improved outcomes for cancers, from childhood leukemia to cervical cancer. Global Issues in Medicine CHAPTER 485 Prevention of Noncommunicable Diseases  False dichotomies, including those pitting prevention against care, persist in global health and reflect, in part, outmoded paradigms or a limited understanding of shifts in disease burden and causality as well as the dramatic variations in risk within a single nation. Moreover, such dichotomies or debates are sometimes politicized as a result of vested interests. Although globalization has had many positive effects, one negative effect has been the growth in both developed and developing countries of wellfinanced lobbies that have aggressively promoted unhealthy dietary changes and increased consumption of alcohol and tobacco. The WHO’s 2003 Framework Convention on Tobacco Control represented a major advance, committing all of its signatories to a set of policy measures shown to reduce tobacco consumption. The WHO estimates that 80% of all cases of cardiovascular disease and type 2 diabetes as well as 40% of all cancers can be prevented through healthier diets, increased physical activity, and avoidance of tobacco. These estimates mask large local variations. Although some evidence indicates that population-based measures can have some impact on these behaviors, it is sobering to note that increasing obesity levels have not been reversed in any population. Tobacco avoidance may be the most important and most difficult behavioral modification of all. In the twentieth century, 100 million people worldwide died of tobacco-related diseases; it is projected that >1 billion people will die of these diseases in the twenty-first century, with the vast majority of those deaths in developing countries. Today, ~80% of the world’s 1.1 billion smokers live in low- and middle-income countries. In 2019, tobacco use caused 8.7 million deaths, including deaths due to second-hand smoke. The majority of these deaths occurred in low- and middle-income countries. However, there is well-proven evidence that changes in policy, such as taxes on tobacco and indoor and workplace smoking bans, are effective in decreasing the number of people using tobacco, reducing the amount of tobacco consumed, and preventing young people from starting to use tobacco. ■ ■MENTAL AND NEUROLOGIC HEALTH In 2019, 1 in every 8 people, ~970 million people worldwide, lived with a mental health disorder, including >580 million people suffering from depression and anxiety disorders. One in 4 patients visiting a health service has at least 1 mental, neurologic, or behavioral disorder, but most of these disorders are neither diagnosed nor treated. More than 700,000 people die by suicide every year, and depressive disorders are the second leading cause of years lost to disability in the world today. Most low- and middle-income countries devote <1% of their health expenditures to mental health.

PART 17 Global Medicine A B FIGURE 485-3  An 11-year-old Rwandan patient with embryonal rhabdomyosarcoma before (left) and after (right) 48 weeks of chemotherapy plus surgery. Fifteen years later, she is healthy with no evidence of disease. Increasingly effective therapies exist for many of the major causes of mental disorders. One of the greatest barriers to delivery of such therapies is the paucity of skilled personnel. Most Sub-Saharan African countries have only a handful of psychiatrists, for example, and almost all of them practice in cities and are unavailable within the public sector or to patients living in poverty. Among the few patients who are fortunate enough to see a psychiatrist or neurologist, fewer still are able to adhere to treatment regimens: several surveys of already diagnosed patients ostensibly receiving daily therapy have revealed that, among the poor, multiple barriers prevent patients from taking their medications as prescribed. In one study from Kenya, no patients being seen in an epilepsy clinic had therapeutic blood levels of anti­ seizure medications, even though all had been prescribed these drugs. Moreover, many patients in this study had no detectable blood levels of these agents at all. The same barriers that prevent the poor from having reliable access to insulin or ART prevent them from benefiting from antidepressant, antipsychotic, and antiepileptic agents. To alleviate this problem, some authorities are proposing the training of health workers to provide community-based adherence support, counseling services, and referrals for patients in need of mental health services. One such program instituted in Goa, India, used lay counselors and resulted in a significant reduction in symptoms of common mental disorders among the target population. CONCLUSION: TOWARD GLOBAL

HEALTH EQUITY There is a long way to go before evidence-based internal medicine is applied effectively and equitably among the world’s poor. Public health strategies typically operate on the population level, while clini­ cal practice, including the practice of internal medicine, often remains focused on individual patient care. However, global health equity depends on avoiding the false dichotomies of the past: neither public health nor clinical approaches alone are adequate to address the prob­ lems of global health. The integration of prevention and care, along with adequate funding, has shown that complex infectious diseases such as HIV/AIDS and tuberculosis are not impossible to manage, even though drug resistance and lack of effective health systems have complicated such work. Beyond what is usually termed communicable disease—i.e., in the arena of chronic diseases such as cardiovascular disease and mental illness—global health is still a nascent, but growing, endeavor. Efforts to address any one of these problems in settings of great scarcity need to be integrated into broader efforts to strengthen failing health systems and alleviate the growing personnel crisis within

these systems. Such efforts must include the building of platforms for care delivery that are robust enough to incorporate new preventive, diagnostic, and therapeutic technologies rapidly in response to changes both in the burden of disease and in the needs not met by existing paradigms and systems of care delivery. Academic medical centers have tried to address this gap as new technologies are introduced and assessed through clinical trials, but the reach of these institutions into settings of poverty is limited in rich and poor countries alike. When such centers link their capacities effec­ tively to the public institutions charged with the delivery of health care to the poor, great progress can be made. For these reasons, scholarly work and practice in the field once known as “international health” and now often designated global health equity are changing rapidly. That scholarship and practice is still informed by the tension between clinical practice and population-based interventions, between analysis and action, and between prevention and care. A number of university hospitals have developed training programs for physicians with an interest in global health. These programs pro­ vide training not only in the clinical problems encountered in settings of poverty, but also instruction in public health, health care service delivery, and strategies of health systems strengthening. At least half of the world’s population lacks reliable access to essen­ tial health services; the consequence is millions of preventable deaths each year. An absolute majority of these premature deaths occur in Africa, with the poorer regions of Asia not far behind. They include deaths from vaccine-preventable illness, deaths during childbirth, deaths from infectious diseases that might be cured with access to anti­ biotics and other essential medicines, deaths from malaria that would have been prevented by ITNs and access to therapy, and deaths from waterborne illnesses—in short, from failures of health care delivery. Other excess mortality is attributable to the inadequacy of efforts to develop new preventive, diagnostic, and therapeutic tools. The development of these tools must be followed quickly by their equitable distribution. Those funding the discovery and development of new tools typically neglect the concurrent need for strategies to make them available to the poor. Indeed, some would argue that the biggest challenge facing those who seek to address this outcome gap is the lack of practical means of delivery in the most heavily affected regions. When new preventive and therapeutic tools are developed without concurrent attention to delivery or implementation, one encounters what are sometimes termed “perverse effects”: even as new tools are developed, inequalities of outcome—lower morbidity and mortality rates among those who can afford access, with sustained

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486 Emerging and Re-Emerging Infectious Diseases

high morbidity and mortality among those who cannot—grow in the absence of an equity plan to deliver the tools to those most at risk. Preventing such a future is among the most important goals of global health. ■ ■FURTHER READING Bukhman G et al: The Lancet NCDI Poverty Commission: Bridging a gap in universal health coverage for the poorest billion. Lancet 396:991, 2020. Cancedda C et al: Strengthening health systems while responding to a health crisis: Lessons learned by a nongovernmental organization during the Ebola virus disease epidemic in Sierra Leone. J Infect Dis 214:S153, 2016. Farmer P: Chronic infectious disease and the future of health care delivery. N Engl J Med 369:2424, 2013. Farmer P: Fevers, Feuds, and Diamonds: Ebola and the Ravages of History. New York, Farrar, Straus and Giroux, 2020. GBD 2019 Diseases and Injuries Collaborators: Global Burden of 369 diseases and injuries in 204 countries and territories, 1990–2019: A systematic analysis for the Global Burden of Disease Study 2019. Lancet 396:1204, 2020. GBD 2019 Risk Factors Collaborators: Global Burden of 87 risk factors in 204 countries and territories, 1990–2019: A system­ atic analysis for the Global Burden of Disease Study 2019. Lancet 396:1223, 2020. Institute for Health Metrics and Evaluation: Financing Global Health 2021: Global Health Priorities in a Time of Change. Seattle, Institute for Health Metrics and Evaluation, 2023. Kim JY et al: Redefining global health-care delivery. Lancet 382:1060, 2013. Watkins DA et al: Alma-Ata at 40 years: Reflections from the Lancet Commission on Investing in Health. Lancet 392:1434, 2018. David M. Morens, Anthony S. Fauci

Emerging and

Re-Emerging

Infectious Diseases EMERGING INFECTIOUS DISEASES: DEFINITION AND CLASSIFICATION Pathogenic microorganisms and viruses have existed in the environ­ ment and in numerous animal species for millions of years. Humans have presumably had endemic infectious diseases since the origins of the human species, about 2 million years ago. However, until about 12,000 years ago, humans lived and moved about in small clans and tribal groups, experiencing limited contact with other humans or animals. During this pre-neolithic era, endemic infections were probably limited mostly to skin and gastrointestinal organisms. Even though contact with the environment and with animals undoubtedly led to sporadic infections with non-endemic pathogens, there was little opportunity for these pathogens to become widely spread among humans, i.e., to become epidemic. This situation changed dramatically in the early neolithic age, about 10,000 BCE, in association with domestication of animals for food and for labor, planting and fertilization of crops, storage of water, organized disposal or diversion of sewage, growth of large settled villages and towns, labor specialization, and an enormous increase in human crowd­ ing and animal–human contacts. These new elements of human societal existence were associated with the emergence and human adaptation

of existing enzootic and environmental organisms within populations large enough to sustain human-to-human spread, i.e., to cause emerging epidemics. It is believed that in this period the first significant emerging infectious diseases (EIDs) appeared. The likelihood that numerous pandemic emergences occurred between the onset of the neolithic era and the era of microbial iden­ tification (beginning in the nineteenth century) is suggested by the large number of human pathogens that are today found globally in genetic and phenotypic forms that are identical or highly similar to each other—e.g., skin organisms such as staphylococci (Chap. 152), streptococci (Chap. 153), pneumococci (Chap. 151), and corynebacte­ ria (Chap. 155); enteric pathogens like Escherichia coli (Chap. 166) and salmonellae (Chap. 171); latently infecting neural viruses like herpes­ viruses (Chap. 200); and sexually transmitted agents like human papil­ lomavirus (Chap. 203), gonorrhea (Chap. 161), and syphilis (Chap. 187). In some cases, microbial/virologic phylogenetic data allow rough estimation of the times of pathogen emergences, but even without such data, it is obvious that pandemic spread had to have occurred at some time in the past if we are to explain the global prevalence of many human pathogens today. EIDs and indeed pandemic IDs are thus a very old human phenomenon that we have only recently begun to consider. Emerging and Re-Emerging Infectious Diseases
CHAPTER 486 EIDs have been defined and characterized as shown in Table 486-1. The importance of distinguishing between newly emerging IDs and re-emerging IDs (REIDs) has particular significance for clinicians, who usually are not only among the first to encounter the newly emerging group, but also among those with the greatest expertise in recogniz­ ing and dealing with the second group. It is also of note (Table 486-1) that subcategories of REIDs include accidental release of pathogens by human activities, e.g., vaccine-derived polioviruses or the sudden 1977 pandemic appearance of a long-extinct 1950s-era H1N1 influenza virus, presumably a result of undisclosed vaccine or other virologic research that led to viral “escape.” EMERGING INFECTIOUS DISEASES: THEIR IMPORTANCE EIDs have been among the leading causes of death, disability, and social disruption throughout recorded human history (Table 486-2). For example, it is believed by some historians that at least two of the biblical pharaonic plagues (around the thirteenth century BCE) were EIDs. The regionally pandemic “Plague of Athens” (430–425 BCE) is said to have brought about the end of the “Golden Age” of Greece. TABLE 486-1  Emerging and Re-Emerging Infectious Diseases: Definitions, Categories, and Examples Emerging infectious diseases (EIDs) are those recognized in humans for the first time, e.g., HIV/AIDS, Nipah virus infection, or severe acute respiratory syndrome (SARS) and COVID-19. Re-emerging infectious diseases (REIDs) are those that have infected humans in the past and continue to reappear in new locations (e.g., West Nile virus in the United States and Russia in 1999), reappear in resistant or otherwise phenotypically different forms (e.g., influenza, methicillin-resistant Staphylococcus aureus, drug-resistant falciparum malaria), or reappear after apparent control or elimination (e.g., poliomyelitis in parts of Africa, cholera in Haiti in 2010 and elsewhere in association with natural disasters, wars, and mass migrations) or under unusual circumstances (e.g., deliberately released agents, including the 2001 anthrax bioterrorism attacks). Important subcategories of REIDs include the following: REIDs related to accidental human release—e.g., vaccine-derived polioviruses, epizootic vaccinia virus, and the 1979 Sverdlovsk laboratory explosion releasing anthrax spores REIDs caused by human intent to harm (bioterrorism)—e.g., the 1997 Oregon salad bar poisonings and the 2001 anthrax spore attacks in the United States Established infectious diseases or endemic infectious diseases are those that have been prevalent for a sufficient period of time to allow for a relatively stable and predictable level of morbidity and mortality (e.g., many viral and bacterial respiratory and diarrheal diseases, including respiratory syncytial virus, endemic coronaviruses, noroviruses, pneumococcal disease, drug-susceptible malaria and tuberculosis, and many other tropical diseases such as helminthic and other parasitic diseases, many nosocomial infections).

TABLE 486-2  Selected Emerging Infectious Diseases of Note, 430 BCE to 2024 AD YEAR NAME DEATHS COMMENTS 430 BCE “Plague of Athens” ~100,000 First identified transregional pandemic

Justinian plague (Yersinia pestis) 30–50 million Pandemic; killed half of then-known world population 1340s “Black Death” (Yersinia pestis) ~50 million Pandemic; killed at least one-quarter of the known world population

Syphilis (Treponema pallidum)

50,000 Pandemic brought to Europe from the Americas c. 1500 Tuberculosis High millions Ancient disease; became pandemic in Middle Ages

Hueyzahuatl (Variola major) 3.5 million Pandemic brought to New World by Europeans 1793–1798 “The American plague” ~25,000 Yellow fever terrorized colonial America

Second cholera pandemic (Paris) 18,402 Spread from India to Europe/Western Hemisphere PART 17 Global Medicine

“Spanish” influenza ~50 million Led to additional pandemics in 1957, 1968, 2009 1976–2020 Ebola More than 15,000 deaths First recognized in 1976; 29 regional epidemics to 2020

Acute hemorrhagic conjunctivitis Rare deaths First recognized in 1969; pandemic in 1981

HIV/AIDS

40 million First recognized in 1981; ongoing pandemic

SARS

Near-pandemic

H1N1 “swine flu” 284,000 Fifth influenza pandemic in less than 100 years

Chikungunya Uncommon but high morbidity Pandemic, mosquito-borne

Zika ~1000?* Pandemic, mosquito-borne *Zika mortality has not been fully established. Most deaths are fetal or related to outcomes of severe congenital infections. Source: Reproduced with permission from DM Morens, AS Fauci: Emerging pandemic diseases: How we got to COVID-19. Cell 182:1077, 2020. Both the Justinian plague (544 AD) and the Black Death pandemics of bubonic/pneumonic plague of 1347–1349 AD (Chap. 176) depopu­ lated large segments of Europe and surrounding regions. The cholera (Chap. 173) pandemic of 1831–1832 killed large numbers of Europeans and ushered in the first modern studies to characterize disease and death in modern epidemiologic terms. The past century has featured three of the most highly fatal pan­ demics the world has ever experienced: the 1918 H1N1 influenza (Chap. 206) pandemic, thought to have been the deadliest pandemic in human history; the human immunodeficiency virus (HIV)/acquired immune deficiency syndrome (AIDS) pandemic (Chap. 208), which so far has killed more than 40 million people; and the COVID-19 pandemic (Chap. 205), which is now (2024) in its fifth year, having killed more than 7 million people so far, and by some estimates as West Nile virus Ebola virus Cryptosporidiosis Enterovirus D68 Heartland virus Powassan virus Antimicrobialresistant threats

• CRE
• C. difficile
• MRSA - N. gonorrhoeae H3N2v influenza Cyclosporiasis E. coli O157:H7 Hepatitis C vCJD Lyme disease Measles Listeriosis Adenovirus 14 Human mpox Acute flaccid myelitis Bourbon virus 2009 H1N1 influenza Anthrax bioterrorism Hantavirus pulmonary syndrome Dengue Chikungunya Zika virus Yellow fever Human African trypanosomiasis Cholera Plague February 2020 Newly emerging Re-emerging/resurging “Deliberately emerging” FIGURE 486-1  Selected newly emerging, re-emerging, and human-caused emergences over recent decades. (Reproduced with permission from DM Morens, AS Fauci: Emerging pandemic diseases: How we got to COVID-19. Cell 182:1077, 2020.)

many as 20 million. In addition to the highly fatal and the potentially fatal pandemics of the past century, recent decades featured a seeming Pandora’s box of EIDS (Fig. 486-1), including novel pathogenic agents, re-emerging agents, and agents that are known but have re-emerged in entirely new forms, e.g., dengue hemorrhagic fever (Chap. 215), Zika, and numerous antibiotic-resistant bacteria (Chap. 150). It appears that we have entered a new era in which emergences and re-emergences of IDs are increasing in frequency and impact. RESPONSE OF THE MEDICAL COMMUNITY TO INFECTIOUS DISEASES Acceptance of the concept of infection—almost complete before 1890—quickly led to treatments such as antitoxins and immune plasmas, soon thereafter to non-vaccinia immunogens, by the 1930s to powerful Diphtheria Drug-resistant malaria Akhmeta virus MERS-CoV E. coli O104:H4 Rift Valley fever Typhoid fever SFTSV bunyavirus E. coli O157:H7 PNA syndrome H5N6 influenza Coronavirus disease 2019 (COVID-19) H10N8 influenza H7N9 influenza Lassa fever HIV H5N1 influenza SARS Nipah virus Hendra virus Nipah virus Enterovirus 71 Human mpox Ebola virus Zika virus Marburg virus MDR/XDR tuberculosis

antibiotics, and, by the 1950s, to antivirals. Ironically, however, these successes, which many considered miraculous, also led to significant overconfidence. By the 1960s, experts were predicting that infectious diseases would be conquered. In 1981 the U.S. Centers for Disease Control and Prevention was reorganized to pivot away from IDs and toward chronic and lifestyle-associated diseases that caused the great­ est U.S. mortality and years of productive life lost (YPLL). Then, before the year was out, the world was shocked by the appearance of the AIDS pandemic, caused by a previously unknown body fluid–transmitted virus: HIV. Although the AIDS pandemic was an enormous challenge, the biomedical research community, together with the pharmaceutical industry, eventually responded, most importantly by developing effec­ tive combination antiretroviral therapies, as well as risk-reduction pro­ grams such as needle exchanges and education in safe sexual practices. A 1992 report of the Institute of Medicine (IOM; now the National Academy of Medicine) drew attention to the enormous problem of emerging infections, coined the term and characterized the scope of EIDs, defined the variables associated with emergences, and made farreaching recommendations for preparedness, response, research, train­ ing, and medical and public health practice. Today, clinicians, scientists, public health officials, and government leaders work together within a global infrastructure of EID awareness, in which preparedness and response capacity have been increasingly successful. Such successes include stopping SARS from becoming globally pandemic and then eradicating its virus as a human pathogen; turning AIDS from an inevitably fatal disease to one associated with a normal lifespan for most patients who take antiviral medication; establishing the United States President’s Emergency Plan for AIDS Relief (PEPFAR) program to bring life-saving AIDS treatment to the poorest corners of the world; and success in controlling the 2014–2016 regional Ebola (Chap. 216) pandemic in West Africa, without a vaccine or proven treatment, using standard public health measures alone. This modern global EID control infrastructure includes not only vigorous detection of and response to EIDs, including international health regulations and EID oversight by the World Health Organiza­ tion (WHO), but also controlling and even eradicating existing dis­ eases. Apart from SARS, mentioned above, in 1980 smallpox (Chap. 201) was declared eradicated, a feat considered by some to be the most sig­ nificant accomplishment in medical history, given the millions killed by the virus over many thousands of years. In 2011, the veterinary disease rinderpest was declared eradicated as well. A number of other important IDs now appear to be either close to eradication—e.g., polio­ myelitis (Chap. 210), dracunculiasis (Chap. 240)—or significantly controlled globally with eradication at least on the horizon—e.g., mea­ sles (Chap. 211), rubella (Chap. 212), yaws (Chap. 183). All aspects of ID control, including controlling and trying to eradicate old emerging and still-re-emerging IDs, as well as preventing and controlling the emergences of new ones, work toward the same goal of reducing the impact of IDs on global human morbidity and mortality. MECHANISMS OF EMERGENCE Pathogens that newly emerge into humans are acquired via several dif­ ferent mechanisms. Some emerging pathogens are dead-end infections, i.e., they are not usually transmitted onward to other humans, and thus are not likely to become epidemic. Common examples of such infec­ tions are those arising from environmental “point-source exposures,” in which many humans are exposed to a pathogen in one place over a very narrow window of time, e.g., coccidioidomycosis (Chap. 219) and histoplasmosis (Chap. 218) outbreaks associated with excavations, norovirus (Chap. 209) outbreaks aboard cruise ships (due to sewagecontaminated water), or bacterial/bacterial toxin contamination of foods in restaurants or at picnic or banquet events. Such point-source emergences tend to be sporadic, unpredictable, and of very short dura­ tion, the causative organisms being from the environment and usually well known and easily diagnosed, e.g., norovirus outbreaks identified by epidemiologic and clinical characteristics, or easily tested for, e.g., bacterial culture of enteric pathogens. They are typically short out­ breaks of high morbidity but low mortality.

A second category of disease emergence, animal-to-human host switching, is of relevance to both newly emerging and re-emerging dis­ eases and accounts for virtually all novel pandemics (e.g., the influenza pandemic of 1918, HIV/AIDS) and many re-emerging IDs as well (e.g., human mpox, human Rift Valley fever). In the past two decades there has been much theoretical and microbiologic and virologic research on how such zoonotic emergences occur. Current concepts are briefly summarized. Most animal and human pathogens, and especially viruses infecting mammals, are specifically adapted to a narrow host group, such as a single host species—e.g., the many New World hanta­ viruses, which tend to have been finely adapted to single rodent species over thousands of years. Such pathogens may have a limited ability to infect closely related species, and they are not normally highly trans­ missible between members of new host species they do infect. Measles, for example, is a human-adapted virus which can infect some primate species, but despite its extraordinary contagiousness for humans, it is not naturally transmitted between primates. How then do pathogen emergences into new host species, and most importantly into humans, occur? Emerging and Re-Emerging Infectious Diseases
CHAPTER 486 This is an extraordinarily difficult question to answer, since emer­ gences tend to occur in a “black box,” out of sight of scientists and epi­ demiologists, and indeed typically in remote locales. But it is theorized that such emergences result from uncommon constellations of other­ wise low-risk molecular genomic and ecologic events (Chaps. 125 and 126), which include pathogens (particularly viruses) with high mutation rates, such as many RNA viruses; intense or unusual human–animal contact; and chance. A theoretical model (Fig. 486-2) posits that a virus well adapted to its primary host is likely to be non-adapted or at least far less adapted to other potential hosts, even closely related ones. But since viruses have high mutation rates, there will always be some virions that have mutated to become less well adapted to their own hosts and, by chance, some of these may “accidentally” have acquired an ability to adapt to a new host. Presumably, very few of these mutated viruses come into contact with potential new hosts before they are “purged,” but if one or more virions is (1) is not significantly de-adapted to its normal host, (2) is, at the same time, capable of adapting to a new host, and (3) is able to cross a “fitness valley” of de-adaptation to the old host and neo-adaptation to the new host, a host switch may occur (Fig. 486-2). This model attempts to explain why major emergences are relatively uncommon (e.g., despite countless billions of viral muta­ tions occurring daily, looking back over the past 500 years, there has only been about one new recognized influenza pandemic every 30 or so years). It might be said, teleologically, that pathogens are constantly “trying” to emerge, but almost always failing to do so. A third category of disease emergence relates to mutations that occur in pathogens that are already human adapted, the best-known example being development of antibiotic resistance in a bacterial species previously susceptible to particular antibiotics. Although antibiotic-resistant pathogens live in the soil and other natural envi­ ronments and have done so since before human-developed antibiotics existed, bacteria are also capable of horizontally transmitting to other bacteria DNA-containing resistance genes, and these may be selected for in Darwinian fashion, e.g., by medical and hospital environments in which antibiotics are administered (Chap. 147). An analogous prin­ ciple even applies to viruses. Particularly as viruses gain access to larger human populations via crowding and human movement, mutation may lead to a fitness advantage, e.g., to a more transmissible phenotype that may escape natural and vaccine-induced immunity, and may even be associated with increased pathogenicity, as may have happened with the SARS-CoV-2 delta variant in 2022. A similar phenomenon was seen beginning in 2014 with the re-emergence of enterovirus D68 (EV-D68) to cause global epidemics of acute flaccid myelitis. VARIABLES ASSOCIATED WITH

DISEASE EMERGENCE Whatever the mechanisms of pathogen emergence may be, it has become clear that the determinants of emergence—i.e., variables that provide opportunities for pathogens in disturbed ecosystems to emerge, typically beginning with the host switch of an animal pathogen

Steep Fitness Valley Shallow Fitness Valley Fitness Fitness Donor Species Recipient Species Donor Species Recipient Species PART 17 Global Medicine Mutation frequency Mutation frequency A B Chance Transmission of Multiple Advantageous Mutations Progressive Adaptation in the Recipient Species Donor Species Recipient Species C D FIGURE 486-2  A theoretical model of how animal-to-human pathogen host-switching might occur, in this case the pathogen being a virus. The light-colored viruses represent those adapted to the transmitting host, and the darkcolored viruses represent those mutating in the direction of the host to which the virus is adapting. A and B compare two different situations in which there is a deep virus–host fitness valley (A) or a shallow fitness valley (B), the valleys representing the degree of challenges that mutable viruses need to overcome to be able to infect new host species. To be able to cross the steep fitness valley, a virus that is at peak adaptation to host 1 must mutate significantly in the direction of de-adaptation to be able to infect host 2, an event that is more likely if the virus has a high natural rate of mutations. In B, a narrow fitness valley is more easily crossed, resulting in a host switch. The phylogenetic trees in C and D show the adaptational mutations that necessarily occur for a virus that has crossed a steep fitness valley (shown in A) as it adapts to the new host (C). In D, a virus that has crossed a narrow fitness valley (as shown in B) does not “need to” adapt to the new host as significantly (C) to be able to initiate and sustain transmission between hosts of the new species. (Reproduced with permission from DM Morens, AS Fauci: Emerging pandemic diseases: How we got to COVID-19. Cell 182:1077, 2020.) within a geographically identified global “hot spot”—are largely related to humans and human activities (Fig. 486-3). Most of the important variables associated with pathogen emergence are either activities of the human host—demographics and behavior including crowding, human movement, sexual practices, and occupation (Fig. 486-3, upper right)—or variables that reflect human degradation of the environment— poverty and social ills, wars, displacements, land use practices, and inadequate public health infrastructure (Fig. 486-3, lower right). Even though HIV clades probably emerged separately and independently more than a century ago, AIDS did not become pandemic until signifi­ cant viral transmission could be sustained within a modern humandominated global environment, once composed of remote villages but more recently replaced by urban environments, transnational travel and commercial sex work, meeting places for men who have sex with men, IV drug use, and blood product transfusions. The emergence of hyperendemic dengue and dengue hemorrhagic fever after World War II was associated with urban crowding and domestic water storage. The United States epidemic of hepatitis C (Chaps. 350 and 352), which began in the 1960s, was associated with blood product transfusions and injection drug use. The emergence of hantavirus pulmonary syn­ drome was associated with construction of human-made peridomestic outbuildings and unfinished basements that housed infected reservoir

rodents during the winter. The emergence of Nipah virus (Chap. 204) in Malaysia in 1998 was associated with both deforesta­ tion and intensive pig farming practices. The 2003 United States mpox outbreak was associated with unregulated importation of rodent pets from enzootic areas. Emer­ gence in China of both H5N1 and H7N9 poultry influenza A (“bird flu”) was associ­ ated with crowded live animal markets, and it stopped quickly when these markets were shut down. The 2010 cholera epidemic in Haiti followed a devastating earthquake associated with human displacement, loss of access to safe water, inadequate medi­ cal and social support, and the arrival of aid from foreign locales that inadvertently imported cholera organisms. It should be noted that emergence vari­ ables are not always identical between the newly emerging and re-emerging IDs. Reemergences of known pathogens are more likely to result from societal failures to cre­ ate and sustain safe human environments, and to disruption of balanced ecosystems in the natural world. Emergences of new pathogens such as pandemic influenza, on the other hand, are sometimes unique and highly improbable events. It is noteworthy that for diseases like influenza, in which transmission is facilitated by crowding and human movement, the intervals between pandemics are about the same today as they were 500 years ago, despite an eightfold increase in the global population and the advent of modern rapid global travel. This suggests that influenza pandemics are rare stochastic events unrelated to the size of the population that spreads them, even though population growth spreads them more widely and more quickly than they once did. EXAMPLES OF CHALLENGES OF DISEASE EMERGENCE AND HOW THEY ARE BEING MET The complexities of potential control of pathogen emergence and re-mergence are noteworthy: each emergent disease presents a differ­ ent challenge, as briefly summarized below for three selected patho­ gens of global importance. ■ ■INFLUENZA A The reservoir of influenza A viruses is the global pool of wild waterfowl and shorebirds. All human, other mammalian, and poultry-associated influenza viruses are derived from this pool. The 1918 pandemic influenza H1N1 “founder” virus either was derived directly from a waterfowl or had a brief period in another mammalian host before becoming pandemic. Humans immediately transmitted it to domestic pigs in 1918; descendants of those human and pig viruses still exist in whole or in part, having devolved into separate and increasingly diver­ gent lineages over the past century. The three influenza pandemics that have occurred since 1918 were all caused by genetic descendants of the 1918 virus, having been naturally modified by genetic changes of sev­ eral types. Such mutations make control and prevention difficult. The viruses have multiple mutational mechanisms to circumvent human immunity, including (1) genetic “drift” (point mutations); (2) “shift” (importation of different avian hemagglutinins with or without impor­ tation of neuraminidases); (3) intrasubtype reassortments (importation

• Cell tropism • Alternative and co-receptors • ADE and related phenomena • Genetic/inherent susceptibility • Immune protection • Genetic diversity • Genetic evolution and change • Variable infectivity • Immunodominant antigens • Co-pathogenesis ENVIRONMENT AGENT FIGURE 486-3  Infectious agents, hosts, and the environment: determinants of disease emergence, re-emergence and persistence. Factors most closely associated with re-emergences are highlighted, including accidental and purposeful human release of infectious pathogens. (Reproduced with permission from DM Morens, AS Fauci: Emerging pandemic diseases: How we got to COVID-19. Cell 182:1077, 2020.) of whole human hemagglutinin or neuraminidase subtype variants), and (4) glycosylation of external protein sites that can alter viral struc­ ture and function. With a broad repertoire of mutational possibilities, a human-adapted virus may repeatedly escape population immunity elicited by natural infection and vaccination, as has been the case with the 1968 pandemic H3N2 virus, which is still causing infections and death, and escaping vaccine immunity, 56 years after its appearance. During this interval it has also periodically, and for unknown reasons, increased in pathogenicity. Influenza control is further confounded by the fact that influenza A is a nonsystemic virus that replicates on a one-cell-deep layer of respiratory epithelium, without fully encountering the human systemic immune system. Because influenza has a very short incubation period, there is too little time for the virus to fully elicit memory immune cells, the virus only encountering the less specific innate immune system, as well as IgA and IgM antibodies secreted across the epithelium from the systemic circulation (only fully effective in high concentration). It also has an advantage in replicating only in an immune environ­ ment of the upper respiratory tract that tolerates multiple continuous antigenic exposures, including brief viral infections, without massive immune responses that could be harmful to the host. Thus, influenza vaccines are at best incompletely effective and protect for only a matter of months. This will be an important challenge in attempts to develop universal influenza vaccines. It is also noteworthy that pandemic and postpandemic influenza viruses are increasingly better adapted to the modern world. Before 1889, the predominant travel mechanism of influenza spread was by coach, globalization of spread taking as much as a year or more, or failing to occur at all. Until the 1700s, the Americas and Europe did not even appear to have been on the same influenza pandemic cycles. (Although the earliest genetically sequenced influenza viruses date to 1918, scholars have for several centuries presumptively identified influenza pandemics on the basis of characteristic clinical-pathologic signs and symptoms, epidemiologic patterns, and route and rapid­ ity of global spread). In the 1889 pandemic, presumed influenza was spread from East Asia to Europe by rail. The 1918 and 1957 pandemics were spread predominantly by ship, and the 1968 and 2009 pandem­ ics predominantly by air. Influenza spread is ideally suited to human movement and crowding. Furthermore, high rates of presymptomatic and subsymptomatic infection allow the virus to be transmitted by

• Demographics and behavior – International travel/trade/recreational – Sex – Occupation – Antibiotic misuse HOST Emerging and Re-Emerging Infectious Diseases
CHAPTER 486 • Animal exposures • Environmental degradation • Climate and weather • Economic development/land use • Technology/industry/agriculture • Poverty and social ills • Wars, famines, natural disasters • Lack of public health infrastructure • Lack of political will DISEASE persons who do not know they are infectious or capable of transmitting, thwarting attempts to lower transmission by public health measures. In short, influenza A is an avian virus emerging out of nature. It remains difficult to prevent or to identify in advance an avian influ­ enza virus with pandemic potential. At this point we have limited ability to control constantly mutating viruses once they have become human-adapted. ■ ■SARS AND SARS-CoV2 The sarbecoviruses (SARS-like beta-coronaviruses) are similar to influenza in some respects and different in others. Their natural reser­ voir is not birds but bats, and the main human host receptor for viral infection is the angiotensin-converting enzyme 2 (ACE2) receptor, as opposed to respiratory tract sialic acid receptors for influenza. Because ACE2 receptors on bats, many other mammals, and humans are quite similar, sarbecoviruses can be thought of as potentially preadapted to humans. It is in part for this reason that many experts predict future emergences of these viruses. Similar to influenza, SARS-CoV2 is a respiratory virus that does not produce true viremia, has a short incubation period and incomplete exposure to the systemic immune system, and often causes asymptom­ atic or subsymptomatic infection, bedeviling control with public health measures such as social distancing and isolation. Also similar to influ­ enza, and despite its moderate transmissibility, it can be “superspread” in crowded environments such as restaurants and bars, churches, sports venues, or any crowded place, especially if there is imperfect airflow and humidity. In addition, like influenza, SARS-CoV2 evolves continually (not however by genetic reassortment, but by mutation and recombination), continually escapes population immunity, and is imperfectly prevented by vaccines. As has been the case with influenza, control of emerging SARS-CoV2, and prevention of population spread and large-scale mortality, remains difficult. ■ ■DENGUE A third example of the complexities of emergence and response, in this case re-emergence, is dengue. An Aedes aegypti–borne flavivirus, “dengue virus” is actually four closely related viruses (DEN-1, DEN-2, DEN-3, and DEN-4) that interact with each other serologically and with respect to immunity and pathogenicity. Dengue is believed to have emerged more than 400 years ago, perhaps much earlier, and has

3858 been endemic and hyperendemic around the tropical belt ever since, re-emerging sporadically to cause high morbidity and sometimes high mortality. Emergences now occur repeatedly in the U.S. commonwealths of the Northern Mariana Islands and Puerto Rico, in the U.S. territories of Guam, American Samoa, and the United States Virgin Islands, and in the United States–affiliated Federated States of Micronesia. At one time, large-scale dengue epidemics were common in the continental United States, e.g., a major epidemic in Philadelphia in 1780; in recent years smaller outbreaks have occurred in southern states. Despite the fact that all dengue cases occur within a human-to-mosquito-to-human transmission cycle, without direct human-to-human transmission, den­ gue re-emergences can be so explosive that they mimic the most highly contagious respiratory viruses. During simultaneous 1977 outbreaks of dengue and influenza in Puerto Rico, within-household studies showed greater case-clustering of dengue than of influenza. PART 17 Global Medicine Dengue is highly associated with peridomestic water storage (where vector mosquitoes oviposit), lack of sanitation, crowding, and lack of screens and air conditioning. It would seem a simple matter to control dengue by controlling water storage, but even Singapore—a developed country whose residences have screens, air conditioning, excellent sanitation, and public health mosquito police who constantly patrol residences and public places to examine for breeding sites, assessing fines for even minor breeding site violations—is unable to prevent dengue outbreaks from occurring. A difficult problem seems to be that mosquitoes can oviposit in the tiniest and most inconspicuous bits of water, e.g., the slight (several millimeter) indentations in the bases of porcelain toilets where they are bolted to the floor. Although dengue was historically considered a nuisance disease, shortly after World War II (during which only 4 of more than 90,000 dengue-infected servicemen/service women died) a new and highly fatal clinical form emerged in Southeast Asia and quickly became a significant killer of children. Studied by teams of Thai and American scientists, the new clinical form was classified as dengue hemorrhagic fever (DHF) and, in its most severe form, dengue shock syndrome (DSS), a result of sudden massive extravasation of intravascular fluids into the tissues. But the very same viruses that caused the mild form of dengue were also those that caused DHF and DSS, a puzzle that was unraveled by Halstead and others when it was learned that it was predominantly only with the second of four potential dengue infec­ tions (one with each of the four serotypes) that DHF/DSS occurred. Epidemiologic data were consistent with the belief that cross-reactive antibodies elicited by the first dengue infection, unable to neutralize the second virus, actually potentiate viral entry into cells via antibodydependent enhancement for the acute clinician, dealing with EIDS depends upon ecologic perspectives on infectious disease occurrence. Only in recent years have science and medicine begun to make an impact on severe dengue disease, including training of clinicians and parents, the widespread availability of oral rehydration solutions that reverse shock syndrome, and several recently developed vaccines. But fear remains that vaccines might potentiate more severe disease, and dengue remains among the greatest re-emerging disease problems for more than 3 billion people. The three emerging disease examples noted above exemplify the complexity of disease emergence: the role of demographic and envi­ ronmental variables (live poultry markets in severe human influenza; human-made peridomestic environments in dengue), pathogen inter­ actions (partial immune crosses in influenza and dengue, related to both protection and disease severity, as well as to diagnostic dif­ ficulties), complete or partial immune escape (all three pathogens), immunopathogenesis (1918 influenza and dengue), inherent problems in vaccine prevention (all three diseases), animal reservoir hosts of progenitor viruses (all three diseases), viral evolution via mutations (all three diseases), and many other factors. THE ROLE OF CLINICIANS AND LABORATORIANS IN EID CONTROL Clinicians and laboratorians are on the front lines of EID control and response efforts, and they must continue to play a leading role in global pandemic preparedness and response. It is typically the astute

clinician who first recognizes a new disease, usually because signs and symptoms, or complications, are not typical of similar diseases. For example, in the 1918 influenza pandemic there was never-before-seen pneumonia-associated case-fatality featuring viral infection and bacterial co-pathogenesis, the bacteria being normal oral flora and the pneumonia producing an anatomic pattern, diagnosed clinically or in some cases by x-ray, which was invariably bronchopneumonic. In the 1950s, emergence of dengue hemorrhagic fever was associated with never-before-seen complications, including shock and death, occurring in association with endemic dengue viruses and in epidemiologic patterns that were novel (shock occurring only in infants under one, and in older toddlers and school-aged children, but sparing children between these ages, as well as those in and beyond the older teenage years). In fact, it was the bizarre and unprecedented age-specific mortality patterns of DSS that suggested its pathogenetic mechanisms. That legionellosis (Chap. 164), first identi­ fied in 1976, must have been an unknown emerging disease was learned when clinicians were unable to make a pathogen-specific pneumonia diagnosis and laboratories were unable to isolate a pathogen. A similar profile was seen with SARS, emerging in 2002–2003, when adults with respiratory/constitutional symptoms typical of many respiratory viruses experienced an approximate 10% case-fatality rate. It is not only primary care providers who are in a position to recognize newly emerging diseases. Both emerging acute hemorrhagic conjuncti­ vitis (AHC) in 1969–1970 and emerging human Rift Valley fever (RVF) in 1977 were largely identified by ophthalmologists who observed the unexpected: severe and explosively epidemic conjunctivitis with AHC, and blindness associated with macular infiltrates in RVF. In 1981, it was pathologists who identified Pneumocystis carinii (now jirovecii) pneumonia in autopsies of previously healthy young men, joining epi­ demiologists and clinicians in characterizing a new clinical-pathologic syndrome that was eventually recognized as AIDS. And it was pediatric neurologists who played a major role in identifying emergent enterovirus D68–associated acute flaccid myelitis beginning in about 2014. Even looking back in history to a time before the microbial era, we can identify the same phenomenon: it was a “proto-epidemiologist” who first imag­ ined that cervical cancer was the result of a contagious disease when he showed, in the 1840s, that nuns never suffered from it. Among the skills of medical practitioners related to a key front-line role in dealing with EIDs are the following: (1) abiding curiosity; (2) the ability to sense something out of the ordinary and pursue suspicions, using the medical history, physical examination, and laboratory tests (Chaps. 8 and 505); (3) a sense of the epidemiology of different diseases that allows imagination of how an illness might have been acquired, of the mechanism of acquisition—environmental, respiratory, inocula­ tion (including sexual inoculation), gastrointestinal, occupational, etc. (Fig. 486-3); (4) whether there are family or other case clusters, and whether such clusters represent common-source exposure, zoonotic exposure, or person-to-person transmission; (5) determination of an approximate incubation period and duration of infectivity; (6) a close relationship with the diagnostic laboratory and knowledge of when to seek additional laboratory follow-up; (7) a close relationship with allied practitioners, including specialists, and with disease researchers; (8) a close relationship with public health workers, diligence in promptly reporting reportable diseases and reportable disease syndromes, and awareness of outbreaks that may be occurring in the community; (9) regular reading of the medical literature to stay grounded within and outside of one’s specialty; and (10) skill at communicating with and eliciting trust from patients, which appears to maximize the chance of finding clues that may be easily missed. History tells us that EIDs will certainly continue to appear, includ­ ing some so novel that they cannot even be imagined. An important component of the biomedical and public health enterprise is the ability to recognize, diagnose, and begin to control EIDs at the earliest pos­ sible time, and to limit their spread so that emergences do not evolve into epidemics. This requires coordinated efforts of those in multiple disciplines, communicating with each other rapidly and effectively. It is a part of the significant responsibilities of medical, biomedical, and public health practitioners, who together have the critical skill sets needed to confront the existential threats of EIDs.

03 - 487 Primary Care and Global Health

487 Primary Care and Global Health

■ ■FURTHER READING Fauci AS, Morens DM: The perpetual challenge of infectious diseases. N Engl J Med 366:454, 2012. Harper K: Plagues Upon the Earth: Disease and the Course of Human History. Princeton, Princeton University Press, 2023. Keusch GT et al: Pandemic origins and a One Health approach to preparedness and prevention: Solutions based on SARS-CoV-2 and other RNA viruses. Proc Natl Acad Sci USA 119:e2202871119, 2022. Lederberg J et al: Emerging Infections. Microbial Threats to Health in the United States. Washington, DC, National Academies Press, 1992. Menachery VD et al: SARS-like WIV1-CoV poised for human emer­ gence. Proc Natl Acad Sci USA 113: 3048, 2016. Morens DM, Fauci AS: Emerging pandemic diseases: How we got to COVID-19. Cell 182:1077, 2020. Morens DM, Taubenberger JK: Pandemic influenza: Certain uncer­ tainties. Rev Med Virol 21:262, 2011. Parrish C et al: Cross-species virus transmission and the emergence of new epidemic diseases. Microbiol Molec Biol Rev 72:457, 2008. Wasik BR et al: Onward transmission of viruses: How do viruses emerge to cause epidemics after spillover? Philos Trans R Soc Lond B Biol Sci 374:20190017, 2019. Wegner GI et al: Averting wildlife-borne infectious disease epidem­ ics requires a focus on socio-ecological drivers and a redesign of the global food system. EClinicalMedicine 47:101386, 2022. Tim Evans, Kumanan Rasanathan

Primary Care and

Global Health The twentieth century witnessed the rise of an unprecedented global health divide. Industrialized or high-income countries experienced rapid improvement in standards of living, nutrition, health, and health care (Chap. 485). Meanwhile, in low- and middle-income countries with much less favorable conditions, health and health care progressed much more slowly. The scale of this divide is reflected in the cur­ rent extremes of life expectancy at birth, with Japan at the high end (84 years) and Chad at the low end (54 years). This 30-year shortfall in Chad reflects the daunting range of health challenges faced by low- and middle-income countries. These nations must deal not only with a complex mixture of diseases (both infectious and chronic) and illness-promoting conditions but also, and more fundamentally, with the fragility of the foundations underlying good health (e.g., sufficient food, water, sanitation, and education) and of the systems necessary for universal access to good-quality health care and public health. In the last decades of the twentieth century, the need to bridge this global health divide and establish health equity was increasingly recognized. The Declaration of Alma-Ata in 1978 crystallized a vision of justice in health, regardless of income, gender, ethnicity, or education, and called for “health for all by the year 2000” through primary health care. While progress since the declaration is remarkable, >45 years later and in the aftermath of a global pandemic of COVID-19, much remains to be done to achieve global health equity. This chapter looks first at the nature of the health challenges that underlie the health divide in low- and middle-income countries. It then outlines the values and principles of a primary health care approach, with a focus on primary care services. Next, the chapter reviews the experience of low- and middle-income countries in addressing health challenges through primary care and a primary health care approach. Finally, the chapter identifies how current challenges and global context, in particular, the global pandemic, shape an agenda for the

renewal of primary health care and primary care, allied to the move­ ment to achieve universal health coverage. PRIMARY CARE AND PRIMARY HEALTH CARE The term primary care has been used in many different ways: to describe a level of care or the setting of the health system, a set of treat­ ment and prevention activities carried out by specific personnel, a set of attributes for the way care is delivered, or an approach to organizing health systems that is synonymous with the term primary health care. In 1996, the U.S. Institute of Medicine encompassed many of these different usages, defining primary care as “the provision of integrated, accessible health care services by clinicians who are accountable for addressing a large majority of personal health care needs, developing a sustained partnership with patients, and practicing in the context of family and community.”1 We use this definition of primary care in this chapter. Primary care performs an essential function for health systems, providing the first point of contact when people seek health care, dealing with most problems, and referring patients onward to other services when necessary. As is increasingly evident in countries of all income levels, without strong primary care, health systems cannot function properly or address the health challenges of the communities they serve. Primary Care and Global Health CHAPTER 487 Primary care is only one part of a primary health care approach. The Declaration of Alma-Ata, drafted in 1978 at the International Confer­ ence on Primary Health Care in Alma-Ata (now Almaty in Kazakhstan), identified many features of primary care as being essential to achieving the goal of “health for all by the year 2000.” However, it also identi­ fied the need to work across different sectors, address the social and economic factors that determine health, mobilize the participation of communities in health systems, and ensure the use and development of technology that was appropriate in terms of setting and cost. The decla­ ration drew from the experiences of low- and middle-income countries in trying to improve the health of their people following independence. Commonly, these countries had built hospital-based systems similar to those in high-income countries. This effort had resulted in the development of high-technology services in urban areas while leaving the bulk of the population without access to health care unless they traveled great distances to these urban facilities. Furthermore, much of the population lacked access to basic public health measures. Primary health care efforts aimed to move care closer to where people lived, to ensure their involvement in decisions about their own health care, and to address key aspects of the physical and social environment essential to health, such as water, sanitation, and education. After the Declaration of Alma-Ata, many countries implemented reforms of their health systems based on primary health care. Most progress involved strengthening of primary care services; unexpect­ edly, however, much of this progress was seen in high-income coun­ tries, most of which constructed systems that made primary care available at low or no cost to their entire populations and that delivered the bulk of services in primary care settings. This endeavor also saw the reinforcement of family medicine as a specialty to provide primary care services. Even in the United States (an obvious exception to this trend), it became clear that the populations of states with more primary care physicians and services were healthier than those with fewer such resources. Progress was also made in many low- and middle-income countries. However, the target of “health for all by the year 2000” was missed by a large margin. The reasons were complex but partly entailed a general failure to implement all aspects of the primary health care approach, particularly work across sectors to address social and economic fac­ tors that affect health and provision of sufficient human and other resources in order to make possible the access to primary care attained in high-income countries. Furthermore, despite the consensus in Alma-Ata in 1978, the global health community rapidly became frac­ tured in its commitment to the far-reaching measures called for by the 1Institute of Medicine. Primary Care: America’s Health in a New Era (1996).

3860 declaration. Economic recession tempered enthusiasm for primary health care, and momentum shifted to programs concentrating on a few priority measures such as immunization, oral rehydration, breast- feeding, and growth monitoring for child survival. Success with these initiatives supported the continued movement of health development efforts away from the comprehensive approach of primary health care and toward programs that targeted specific public health priorities. This approach was reinforced by the need to address the HIV/AIDS epidemic. By the 1990s, primary health care had fallen out of favor in many global-health policy circles, and low- and middle-income countries were being encouraged to reduce public sector spending on health and to focus on cost-effectiveness analysis to provide a package of health care measures thought to offer the greatest health benefits. PART 17 Global Medicine HEALTH CHALLENGES IN LOW- AND MIDDLE-INCOME COUNTRIES Low- and middle-income countries, defined by a per-capita gross national income of <$12,535 (U.S.) per person per year, account for

85% of the world’s population. Average life expectancy in these coun­ tries lags far behind that in high-income countries: whereas the average life expectancy at birth for a girl in high-income countries is 83 years, it is only 65 years for a girl in low-income countries. This discrepancy has received growing attention over the past 50 years. Initially, the situation in poor countries was characterized primarily in terms of high fertility and high infant, child, and maternal mortality rates, with most deaths and illnesses attributable to infectious or tropical diseases among remote, largely rural populations. With growing adult (and especially elderly) populations and changing lifestyles linked to global forces of urbanization, a new set of health challenges characterized by chronic diseases, environmental overcrowding, and road traffic injuries has emerged rapidly (Fig. 487-1). The majority of tobacco-related deaths globally now occur in low- and middle-income countries, and the

Deaths (millions)

Year/countries grouped by income per capita FIGURE 487-1  Projections of disease burden to 2030 for high-, middle-, and low-income countries (left, center, and right, respectively). TB, tuberculosis. (Reproduced with permission from World Health Organization: The Global Burden of Disease 2004 Update, 2008.)

risk of a child’s dying from a road traffic injury in Africa is more than twice that in Europe. Thus, low- and middle-income countries in the twenty-first century face a full spectrum of health challenges—infectious, chronic, and injury-related—at much higher incidences and preva­ lences than are documented in high-income countries and with many fewer resources to address these challenges. Addressing these challenges, however, does not mean simply waiting for economic growth. Analysis of the association between wealth and health across countries reveals that, for any given level of wealth, there is a substantial variation in life expectancy at birth that has persisted despite overall global progress in life expectancy during the past 40 years (Fig. 487-2). Health status in low- and middle-income countries varies enormously. Nations such as Cuba and Costa Rica have life expectan­ cies and childhood mortality rates similar to or even better than those in high-income countries; in contrast, countries in Sub-Saharan Africa and the former Soviet bloc have at times experienced significant reversals in these health markers, particularly in the 1990s. As Angus Deaton stated in the World Institute for Development Economics Research annual lecture on September 29, 2006, “People in poor countries are sick not primarily because they are poor but because of other social organizational failures, including health delivery, which are not automatically ameliorated by higher income.” This analysis concurs with classic studies of the array of societal factors explaining good health in poor settings such as Cuba and Kerala State in India in the 1980s. Analyses conducted over the past 4 decades indeed show that rapid health improvement is possible in very different contexts. That some countries continue to lag far behind can be understood through a comparison of regional differences in progress in terms of life expec­ tancy over this period (Fig. 487-3). As average levels of health vary across regions and countries, so too do they vary within countries (Fig. 487-4). Indeed, disparities within countries are often greater than those between high-income Intentional injuries Other unintentional injuries Road traffic accidents Other noncommunicable diseases Cancers Cardiovascular disease Maternal, perinatal, and nutritional conditions Other infectious diseases HIV/AIDS, TB, and malaria

Life expectancy at birth (years)

Namibia South Africa

Botswana Swaziland

10,000 15,000 20,000 25,000 30,000 35,000 40,000 GDP per capita, constant 2000 international $ FIGURE 487-2  Gross domestic product (GDP) per capita and life expectancy at birth in 169 countries, 1975 and 2005. Only outlying countries are named. (Reproduced with permission from World Health Organization: Primary Health Care: Now More Than Ever. World Health Report 2008.) and low-income countries. For example, if low- and middle-income countries could reduce their overall childhood mortality rate to that of the richest one-fifth of their populations, global childhood mortality could be decreased by 40%. Disparities in health are mostly a result of social and economic factors such as daily living conditions, access to resources, and ability to participate in life-affecting decisions. In most countries, the health care sector actually tends to exacerbate health inequalities (the “inverse-care law”); because of neglect and discrimination, poor and marginalized communities are much less likely to benefit from public health services than those that are better off. Reforming health systems toward people-centered primary care provides an opportunity to reverse these negative trends. Health services have failed to make their contribution to reducing these pervasive social inequalities by ensuring universal access to existing, scientifically validated, low-cost interventions such as insecticide-treated bed nets for malaria, taxes on cigarettes, short-course chemotherapy for tuberculosis, antibiotic treatment for pneumonia, dietary modification and secondary prevention measures for high blood pressure and high 1970–1975 2000–2005 52.1 66.9 Arab states 60.5 70.4 East Asia and Pacific Latin America and Caribbean 61.1 71.7 50.1 63.2 South Asia 45.8 46.1 Sub-Saharan Africa

68.1 CEE and CIS 71.6 78.8 High-income OECD

Life expectancy (years) FIGURE 487-3  Regional trends in life expectancy. CEE, Central and Eastern Europe; CIS, the Commonwealth of Independent States; OECD, Organization for Economic Cooperation and Development. (Reproduced with permission from World Health Organization: Closing the Gap in a Generation: Health Equity Through Action on the Social Determinants of Health. Commission on Social Determinants of Health Final Report, 2008.)

Primary Care and Global Health CHAPTER 487

Rural Urban

Under 5 mortality rate per 1000

A Haiti Nigeria Pakistan Philippines Rwanda Lowest quintile Quintile 2 Quintile 3 Quintile 4 Highest quintile

Bangladesh

Colombia

Indonesia 2002–2003 Mozambique

B FIGURE 487-4  A. Mortality of children under 5 years old, by place of residence, in five countries. (Reproduced with permission from World Health Organization: Data from the World Health Organization.) B. Full basic immunization coverage (%), by income group. (Reproduced with permission from World Health Organization: Primary Health Care: Now More Than Ever. World Health Report 2008.)

3862 cholesterol levels, and water treatment and oral rehydration therapy for diarrhea. Despite decades of “essential packages” and “basic” health cam­ paigns, the effective implementation of what is already known to work with requisite scale and quality appears (deceptively) to be difficult. Recent analyses have begun to focus on “the how” (as opposed to “the what”) of health care delivery, exploring why health progress is slow and sluggish despite the abundant availability of proven inter­ ventions for health conditions in low- and middle-income countries. Three general categories of reasons are being identified: (1) shortfalls in performance of health systems; (2) stratifying social conditions; and (3) skews in science. PART 17 Global Medicine ■ ■SHORTFALLS IN PERFORMANCE

OF HEALTH SYSTEMS Specific health problems often require the development of specific health interventions (e.g., tuberculosis requires short-course chemotherapy). However, the delivery of different interventions is often facilitated by a common set of resources or functions: money or financing, trained health workers, and facilities with reliable supplies fit for multiple pur­ poses. Unfortunately, health systems in most low- and middle-income countries are largely dysfunctional across these core functions. In the large majority of low- and middle-income countries, the level of public financing for health is woefully insufficient: whereas high-income countries spend, on average, >7% of the gross domestic product on health, middle-income countries spend <3%, and lowincome countries <2%. External financing for health through various donor channels grew rapidly in the first decade of the twenty-first century but has grown more slowly in the second decade to its current level of $37 billion. While these funds for health are significant, they represent <2% of total health expenditures in low- and middle-income countries and therefore are neither a sufficient nor a long-term solution to chronic underfinancing. In Africa, 70% of health expenditures come from domestic sources. The predominant form of health care financing—charging patients at the point of service—is the least efficient and the most inequitable, tipping millions of households into poverty annually. Health workers, who represent another critical resource, are often inadequately trained and supported in their work, especially in locations with the greatest needs. Recent estimates indi­ cate a shortage of >18 million health workers, constituting a crisis that is greatly exacerbated by the migration of health workers from low- and middle-income countries to high-income countries. Sub-Saharan Africa carries 24% of the global disease burden but has only 3% of the health workforce (Fig. 487-5). Critical diagnostics and drugs often do not reach patients in need because of supply-chain failures. Moreover, facilities fail to provide good-quality and safe care: new evidence suggests much higher rates of adverse events among hospitalized patients in low- and middle-income countries than in high-income countries. Weak government planning,

South-East Asia % of global burden of disease Africa

Western Pacific Europe Americas

Eastern Mediterranean

% of global workforce FIGURE 487-5  Global burden of disease and health workforce. (Reproduced with permission from World Health Organization: Working Together for Health, 2006.)

regulatory, monitoring, and evaluation capacities are associated with rampant, unregulated commercialization of health services and cha­ otic fragmentation of these services as donors “push” their respective priority programs. With such fragile foundations, it is not surprising that low-cost, affordable, validated interventions are not reaching those who need them. ■ ■STRATIFYING SOCIAL CONDITIONS Health care delivery systems do not exist in a vacuum but rather are embedded in a complex of social and economic forces that often stratify opportunities for health unfairly. Most worrisome are the pervasive forces of social inequality that serve to marginalize popula­ tions with disproportionately large health needs (e.g., the urban poor; illiterate mothers). Why should a poor slum dweller with no income be expected to come up with the money for a bus fare needed to travel to a clinic to learn the results of a sputum test for tuberculosis? How can a mother living in a remote rural village and caring for an infant with febrile convulsions find the means to get her child to appropriate care? Shaky or nonexistent social security systems, dangerous work environments, isolated communities with little or no infrastructure, and systematic discrimination against racialized minorities are among the myriad forces with which efforts for more equitable health care delivery must contend. ■ ■SKEWS IN SCIENCE While science has yielded enormous breakthroughs in health in highincome countries, with some spillover to low- and middle-income countries, many important health problems continue to affect primar­ ily low- and middle-income countries whose research and develop­ ment investments are deplorably inadequate. The past two decades have seen growing efforts to right this imbalance with research and development investment for new drugs, vaccines, and diagnostics that effectively cater to the specific health needs of populations in low- and middle-income countries. For example, the TB Alliance has revitalized a previously “dry” pipeline for new tuberculosis drugs. In 2019, their new drug (pretomanid) received U.S. Food and Drug Administration approval as part of a triple oral regimen (bedaquiline, pretomanid, and linezolid [BPaL]) that treats extensively drug-resistant tuberculosis faster, better, and cheaper. Nevertheless, the global vaccine inequity witnessed during the COVID-19 pandemic is indicative of the need for further efforts to right the research and development balance globally. As discussed above, the primary constraint on better health in low- and middle-income countries is related less to the availability of health technologies and more to their effective delivery. Underlying these health delivery challenges is a major bias regarding what consti­ tutes legitimate “science” to improve health equity. The lion’s share of health research financing is channeled toward the development of new technologies—drugs, vaccines, and diagnostics; in contrast, virtually no resources are directed toward research on how health care delivery systems can become more reliable and overcome adverse social condi­ tions. The complexity of systems and social context is such that this issue of delivery requires an enormous investment in terms not only of money but also of scientific rigor, with the development of new research methods and measures and the attainment of greater legiti­ macy in the mainstream scientific establishment. These common challenges to low- and middle-income countries partly explain the resurgence of interest in the primary health care approach and the emergence of a global movement toward universal health coverage, now enshrined as one of the Sustainable Develop­ ment Goal targets adopted in Agenda 2030 by all countries at the United Nations in September 2015. In some countries (mostly middleincome), significant progress has been made in expanding coverage by health systems based on primary care and even in improving indicators of population health. More countries are embarking on the creation of primary care services despite the challenges that exist, particularly in low-income countries. Even when these challenges are acknowledged, there are many reasons for optimism that low- and middle-income countries can accelerate progress in building primary care as a key vehicle toward achieving universal health coverage.

PRIMARY HEALTH CARE IN THE

TWENTY-FIRST CENTURY The new millennium has seen a resurgence of interest in primary health care as a means of addressing global health challenges but also of familiar obstacles to its implementation. This interest has been driven by many of the same issues that led to the Declaration of Alma-Ata: rapidly increasing disparities in health between and within countries; spiraling costs of health care at a time when many people lack qual­ ity care; dissatisfaction of communities with the care they are able to access; and failure to address changes in health threats, especially noncommunicable diseases, pandemics, and challenges arising from accelerated climate change. These challenges require a comprehensive approach and strong health systems with effective primary care. Global health development agencies have partially recognized that sustaining gains in public health priorities such as HIV/AIDS and pandemic pre­ paredness requires not only robust health systems but also the tackling of social and economic factors related to disease incidence and progres­ sion. Weak health systems have proved a major obstacle to delivering new technologies, such as COVID-19 vaccines and antiretroviral therapy, to all who need them. We discuss experiences in low- and middle-income countries in relation to primary care in greater detail below. First, we consider the features of primary health care and pri­ mary care as currently understood. ■ ■REVITALIZATION OF PRIMARY HEALTH CARE At the 2019 World Health Assembly (an annual meeting of all coun­ tries to discuss the work of the World Health Organization [WHO]), a resolution was passed reaffirming the principles of the Declaration of Alma-Ata and the need for national health systems to be based on pri­ mary health care. This resolution reframed primary health care as three components: (1) primary care and essential public health functions as the core of integrated health services; (2) empowered people and com­ munities; and (3) multisectoral policy and action. This reframing itself drew on the 2008 WHO World Health Report, which asserted that a primary health care approach was necessary “now more than ever” to address global health priorities, especially in terms of disparities and new health challenges. The 2008 World Health Report highlighted four broad areas for reform (Fig. 487-6). One of these areas—the need to organize health care so that it places the needs of people first—relates to the necessity SERVICE DELIVERY REFORMS UNIVERSAL COVERAGE REFORMS to make health systems people-centered to improve health equity LEADERSHIP REFORMS PUBLIC POLICY REFORMS to make health authorities more reliable to promote and protect the health of communities FIGURE 487-6  The four reforms of primary health care renewal. (Reproduced with permission from World Health Organization: Primary Health Care: Now More Than Ever. World Health Report 2008.)

for strong primary care in health systems and what this requirement entails. The other three areas also relate to primary care. All four areas require action to move health systems in a direction that will improve health, reduce disparities, and increase satisfaction. Universal Coverage Reforms to Improve Health Equity   Despite progress in many countries, most people in the world can receive health care services only if they can pay at the point of service. Disparities in health are caused not only by a lack of access to necessary health services but also by the impact of expenditure on health. More than 100 million people are still being driven into extreme poverty each year by health care costs, with countless others deterred from accessing services at all. Moving toward prepayment financing systems for universal coverage, which ensure access to a comprehensive package of services according to need without precipitating economic ruin, has therefore emerged as a major priority in low- and middleincome countries. Increasing coverage of health services can be consid­ ered in terms of three axes: the proportion of the population covered, the range of services underwritten, and the percentage of costs paid (Fig. 487-7). Moving toward universal health coverage requires ensur­ ing the availability of health care services to all, eliminating barriers to access, and organizing pooled financing mechanisms, such as taxation or insurance, to remove user fees at the point of service. It also requires measures beyond financing, including expansion of health services in poorly served areas, improvement in the quality of services provided to marginalized communities, and increased coverage of other social services that significantly affect health (e.g., education). Primary Care and Global Health CHAPTER 487 Service Delivery Reforms to Make Health Systems PeopleCentered   Health systems have often been organized around the needs of those who provide health care services, such as clinicians and policymakers. The result is a centralization of services or the provi­ sion of vertical programs that target single diseases. The principles of primary health care, including the development of primary care, reori­ ent care around the needs of the people to whom services cater. This “people-centered” approach aims to provide health care that is both more effective and appropriate. The increase in noncommunicable diseases in low- and middleincome countries offers a further stimulus for urgent reform of service delivery to improve chronic disease care. As discussed above, large numbers of people currently fail to receive relatively low-cost interven­ tions that have reduced the incidence of these diseases in high-income countries. Delivery of these interventions requires health systems that can address multiple problems and manage people over a long period within their own communities, yet many low- and middle-income countries are only now starting to adapt and build primary care ser­ vices that can address noncommunicable diseases and communicable diseases requiring chronic care. Even some countries (e.g., Iran) that have had significant success in reducing communicable diseases and improving child survival have been slow to adapt their health systems to rapidly accelerating noncommunicable disease epidemics. Total health expenditure Height: what proportion of the costs is covered? Reduce cost sharing Include other services Public expenditure on health Extend to uninsured Depth: which benefits are covered? Breadth: who is insured? FIGURE 487-7  Three ways of moving toward universal coverage.

People-centered care requires a safe, comprehensive, and integrated response to the needs of those presenting to health systems, with treat­ ment at the first point of contact or referral to appropriate services. Because no discrete boundary separates people’s needs for health promotion, curative interventions, and rehabilitation services across different diseases, primary care services must address all present­ ing problems in a unified way. Meeting people’s needs also involves improved communication between patients and their clinicians, who must take the time to understand the impact of the patients’ social context on the problems they develop. This enhanced understanding is made possible by improvements in the continuity of care so that responsibility transcends the limited time people spend in health care facilities. Primary care plays a vital role in navigating people through the health system; when people are referred elsewhere for services, primary care providers must monitor the resulting consultations and perform follow-up. All too often, people do not receive the benefit of complex interventions undertaken in hospitals because they lose con­ tact with the health care system once discharged. Comprehensiveness and continuity of care are best achieved by ensuring that people have an ongoing personal relationship with a care team. PART 17 Global Medicine Public Policy Reforms to Promote and Protect the Health of Communities   Public policies in sectors other than health care are essential to reduce disparities in health and to make progress toward global public health targets. The 2008 final report of the WHO Commission on Social Determinants of Health provided an exhaus­ tive review of the multisectoral policies required to address health inequities at the local, national, and global levels. Advances against major challenges such as HIV/AIDS, tuberculosis, emerging infec­ tions, cardiovascular disease, cancers, and injuries require effective collaboration with sectors such as transport, housing, labor, agricul­ ture, urban planning, trade, and energy. The COVID-19 pandemic has underscored the importance of multisectoral action to protect health; countries that have been most successful in managing the pandemic have been those best able to coordinate across their societies to imple­ ment nonpharmaceutical health measures and build social solidarity. Similarly, while tobacco control provides a striking example of what is possible if different sectors work together toward health goals, the lack of implementation of many evidence-based tobacco control measures in most countries just as clearly illustrates the difficulties encountered in such multisectoral work and the unrealized potential of public poli­ cies to improve health. Leadership Reforms to Make Health Authorities More Reliable   The Declaration of Alma-Ata emphasized the importance of participation by people in their own health care. In fact, participa­ tion is important at all levels of decision-making. Contemporary health challenges require models of leadership that acknowledge the role of government but also the many types of organizations involved in health care delivery. Governments need to engage, guide, negotiate, and regulate among these diverse actors, including but not limited to nongovernmental organizations (NGOs), the private sector, pro­ fessional societies, academia, and patient groups. This difficult task requires concerted investment in leadership and governance capacity, especially if action requires the engagement of different sectors such as local government and education. The complex landscape for leadership at the national level extends to the international level. The increasing transnational character of health as seen by the interdependence of countries with respect to pandemics, climate change, health worker migration, and food security emphasizes the need for more effective global health governance mechanisms. EXPERIENCES WITH PRIMARY CARE IN LOW- AND MIDDLE-INCOME COUNTRIES Aspects of the primary health care approach described above, with an emphasis on primary care services, have been implemented to varying degrees in many low- and middle-income countries over the past halfcentury. As discussed above, some of these experiences inspired and informed the Declaration of Alma-Ata, which itself led many more

countries to attempt to implement primary health care. This section describes the experiences of a selection of low- and middle-income countries in improving primary care services that have enhanced the health of their populations. Before Alma-Ata, few countries had attempted to develop pri­ mary care on a national level. Rather, most focused on expanding primary care services to specific communities (often rural villages), making use of community volunteers to compensate for the absence of facility-based care. In contrast, in the post–World War II period, China invested in primary care on a national scale, and life expectancy doubled within roughly 20 years. The Chinese expansion of primary care services included a massive investment in infrastructure for pub­ lic health (e.g., water and sanitation systems) linked to innovative use of community health workers. These “barefoot doctors” lived in and expanded care to rural villages. They received a basic level of training that enabled them to provide immunizations, maternal care, and basic medical interventions, including the use of antibiotics. Through the work of the barefoot doctors, China brought low-cost universal basic health care coverage to its entire population, most of which had previ­ ously had no access to these services. In 1982, the Rockefeller Foundation convened a conference to review the experiences of China along with those of Costa Rica, Sri Lanka, and the state of Kerala in India. In all of these locations, good health care at low cost appeared to have been achieved. Despite lower levels of economic development and health spending, all of these juris­ dictions, along with Cuba, had health indicators approaching—or in some cases exceeding—those of developed countries. Analysis of these experiences revealed a common emphasis on primary care services, with expansion of care to the entire population free of charge or at low cost, combined with community participation in decision-making about health services and coordinated work in different sectors (espe­ cially education) toward health goals. During the more than three decades since the Rockefeller meeting, some of these countries have built on this progress, while others have experienced setbacks. Recent experiences in developing primary care services show that the same combination of features is necessary for success. For example, Brazil— a large country with a dispersed population—made major strides in increasing the availability of health care from 1980 to 2010. The Brazilian Family Health Program expanded progressively across the country to reach universal coverage. This program provided communities with free access to primary care teams made up of primary care physicians, community health workers, nurses, dentists, obstetricians, and pedia­ tricians. These teams were responsible for the provision of primary care to all people in a specified geographic area—not only those who access health clinics. Moreover, individual community health workers were responsible for a named list of people within the area covered by the primary care team. Solid evidence indicated that the Family Health Program has contributed to impressive gains in population health, particularly in terms of childhood mortality and health inequities (Fig. 487-8). Nevertheless, systemic inequalities, magnified during the COVID-19 crisis, highlight how continued progress is not guaranteed, and efforts to implement and expand a primary health care approach need to adapt to new health and political challenges. Chile has also built on its existing primary care services in the past two decades, aiming to improve the quality of care and the extent of coverage in remote areas, above all for disadvantaged populations. This effort has been made in concert with measures aimed at reducing social inequalities and fostering development, including social welfare benefits for families and disadvantaged groups and increased access to early-childhood educational facilities. As in Brazil, these steps have improved maternal and child health and have reduced health inequi­ ties. In addition to directly enhancing primary care services, Brazil and Chile have instituted measures to increase both the accountability of health providers and the participation of communities in decisionmaking. In Brazil, national and regional health assemblies with high levels of public participation are integral parts of the health policymaking process. Chile has instituted a patient’s charter that explicitly specifies the rights of patients in terms of the range of services to which they are entitled.

3.96 Mean annual change (since 1998)

–2 –2.08 –4 –4.24 –6 –6.82 –6.97 –6.77 –8 –10 0–20 21–50 51–70 71+ PSF coverage (% population covered) FIGURE 487-8  Improvements in childhood mortality following the Family Health Program in Brazil. HDI, Human Development Index; PSF, Program Saúde da Família (Family Health Program). (Source: Ministry of Health, Brazil.) Other countries that have made recent progress with primary health care include Bangladesh, once one of the poorest countries in the world. Since achieving its independence from Pakistan in 1971, Bangladesh has seen a dramatic increase in life expectancy, and child­ hood mortality rates are now lower than those in neighboring nations such as India and Pakistan. The expansion of access to primary care services has played a major role in these achievements. This progress has been spearheaded by a vibrant NGO community that has focused its attention on improving the lives and livelihoods of poor women and their families through innovative and integrated microcredit, educa­ tion, and primary care programs. The above examples, along with others from the past 40 years in countries such as Thailand, Rwanda, Ethiopia, Turkey, Vietnam, and Oman, illustrate how the implementation of a primary health care approach, with a greater emphasis on primary care, has led to bet­ ter access to health care services—a trend that has not been seen in many other low- and middle-income countries. This trend, in turn, has contributed to improvements in population health and reductions in health inequities. However, as these nations have progressed, other countries have shown how previous gains in primary care can easily be eroded. In Sub-Saharan Africa, undermining of primary care services contributed to catastrophic reversals in health outcomes catalyzed by the HIV/AIDS epidemic. Countries such as Botswana and Zimbabwe implemented primary health care strategies in the 1980s, increasing access to care and making impressive gains in child health. Both coun­ tries were severely affected by HIV/AIDS, with pronounced decreases in life expectancy. However, Zimbabwe has also seen political turmoil,

Percentage of total health expenditure

FIGURE 487-9  Changes in source of health expenditure in China over the past 40 years. (Reproduced with permission from World Health Organization: Primary Health Care: Now More Than Ever. World Health Report 2008.)

a decline of health and other social services, and the flight of health personnel, whereas Botswana has maintained primary care services to a greater extent and has managed to organize widespread access to antiretroviral therapy for people living with HIV/AIDS. High HDI Low HDI China provides a particularly striking example of how changes in health policy relevant to the organization of health systems (Fig. 487-9) can have rapid, far-reaching consequences for population health. Even as the 1982 Rockefeller conference was celebrating China’s achievements in primary care, its health system was unraveling. The deci­ sion to open up the economy in the early 1980s led to rapid privatization of the health sector and the breakdown of universal health coverage. As a result, by the end of the 1980s, most people, especially the poorer segments of the population, were paying directly out of pocket for health care, and almost no Chinese had insurance—a dramatic transformation. The “barefoot doctor” schemes collapsed, and the population either turned to care paid for at hospitals or simply became unable to access care. This undermining of access to primary care ser­ vices in the Chinese system and the resulting increase in impoverish­ ment due to illness contributed to the stagnation of progress in health in China at the same time that incomes in that country increased at an unprecedented rate. Reversals in primary care have meant that China now increasingly faces health care issues similar to those faced by India, although the country has more recently implemented measures to restore universal health coverage, with significant success. In both countries, rapid economic growth has been linked to lifestyle changes and noncommunicable disease epidemics. The health care systems of the two nations share two negative features that are common when primary care is weak: a disproportionate focus on specialty services provided in hospitals and unregulated commercialization of health ser­ vices. China and India both saw expansion of private hospital services that cater to middle-class and urban populations who can afford care; at the same time, hundreds of millions of people in rural areas struggled to access basic services. Even in the wealthier groups, a lack of primary care services has been associated with late presentation with illness and with insufficient investment in primary prevention approaches. This neglect of prevention poses a risk of large-scale epidemics of cardio­ vascular disease, which could endanger continued economic growth. In addition, the health systems of both countries now depend for the majority of their funding on out-of-pocket payments by people when they use services. Thus, substantial proportions of the population must sacrifice other essential goods as a result of health expenditure and Primary Care and Global Health CHAPTER 487 –5.64 –8.38 Out-of-pocket expenditure Prepaid private expenditure Social security expenditure Other general government expenditure

3866 may even be driven into poverty by this cost. The commercial nature of health services with inadequate or no regulation has also led to the proliferation of charlatan providers, inappropriate care, and pressure for people to pay for expensive and sometimes unnecessary care. Faced with these problems, China and India have implemented measures to strengthen primary health care. China has increased gov­ ernment funding of health care, has taken steps toward restoring health insurance, and has enacted a target of universal access to primary care services. India has similarly mobilized funding to greatly expand pri­ mary care services in rural areas and in urban settings. Both countries are increasingly using public resources from their growing economies to fund primary care services. PART 17 Global Medicine These encouraging trends are illustrative of new opportunities to implement a primary health care approach and strengthen primary care services in low- and middle-income countries. Linked to goal number 3 of the UN Sustainable Development Goals, Over the past decade, nearly all countries have adopted universal health coverage—the provision of quality health services in a timely manner at affordable cost—and the primary health care approach remains key to achieving this. ■ ■OPPORTUNITIES TO BUILD PRIMARY CARE IN LOW- AND MIDDLE-INCOME COUNTRIES To reach global health targets, health systems must be strengthened. More money is currently being spent on health than ever before. In 2020, global health spending totaled $9 trillion (U.S.)—more than double the amount spent a decade earlier. Although most expendi­ ture occurs in high-income countries, spending in many emerging middle-income countries has rapidly accelerated, as has the allocation of monies for this purpose by both governments in, and donors to, lowincome countries. These twin trends—greater emphasis on building health systems based on primary care and allotment of more money for health care—provide opportunities to address many of the challenges discussed above in low- and middle-income countries. Accelerating progress requires a better understanding of how global health initiatives (GHIs) can more effectively facilitate the development of primary care in low-income countries. Recent reviews including the WHO Maximizing Positive Synergies Collaborative Group and the Wellcome Trust Future of GHIs have assessed the impact on coun­ try health systems of diverse GHIs such as the Global Fund to Fight AIDS, Tuberculosis and Malaria; the Global Alliance for Vaccines and Immunization; the U.S. President’s Emergency Plan for AIDS Relief; and the Global Financing Facility of the World Bank. While evidence of improved access to targeted health services is encouraging, systemic concerns related to increasing domestic resources for health and accel­ erating comprehensive primary care remain. If GHIs implement pro­ grams that work in tandem with other components of national health systems without undermining staffing and procurement of supplies, they have the potential to contribute substantially to the capacity of health systems to provide comprehensive primary care services. In the context of the recent pandemic, GHIs appear even more important. The imperative of vaccinating the world’s population against SARS-CoV-2 led to the creation of the multi-billion-dollar COVAX facility that failed to ensure equitable access to COVID-19 vaccines. After the pandemic, the need to recover essential health ser­ vices, particularly for mothers and children, underlines the importance of GHIs like the Global Financing Facility for every mother and child as catalysts for universal access to life-saving services. The general trend is to coordinate this funding in order to reduce fragmentation of national health systems and to concentrate more on strengthening these systems. Comprehensive primary care in low-income countries must inevitably deal with the rapid emergence of chronic diseases and the growing prominence of injury-related health problems; thus, inter­ national health development assistance must become more responsive to these needs. Beyond funding for health services, other opportunities exist. Increased social participation in health systems can help build pri­ mary care services. In many countries, political pressure from com­ munity advocates for more holistic and accountable care as well as

entrepreneurial initiatives to scale up community-based services through NGOs have accelerated progress in primary care without major increases in funding. Participation of the population in the provision of health care services and in relevant decision-making often drives services to cater to people’s needs as a whole rather than to nar­ row public health priorities. Participation and innovation can help address critical issues related to the health workforce in low- and middle-income countries by estab­ lishing effective people-centered primary care services. Many primary care services do not need to be delivered by a physician or a nurse. Multidisciplinary teams can include paid community workers who have access to a physician if necessary but who can provide a range of health services on their own. In Ethiopia, >38,000 community health workers have been trained and deployed to improve access to primary care services, and there is increasing evidence that this measure is contributing to better health outcomes. In India, >600,000 community health advocates have been recruited as part of expanded rural primary care services. In Niger, the deployment of community health work­ ers to deliver essential child health interventions (as a component of integrated community case management) has had impressive results in reducing childhood mortality and decreasing disparities. After the Declaration of Alma-Ata, experiences with community health work­ ers were mixed, with particular problems regarding levels of training and lack of payment. Current endeavors are not immune from these concerns. However, with access to physician support and the deploy­ ment of teams, some of these concerns may be addressed. Growing evidence from many countries indicates that shifting appropriate tasks to primary care workers who have had shorter, less expensive training than physicians will be essential to address the human resources crisis. Finally, recent improvements in information and communication technologies, particularly mobile phone and Internet systems, have cre­ ated the potential for systematic implementation of e-health, telemedi­ cine, and improved health data initiatives in low- and middle-income countries. These developments raise the tantalizing possibility that health systems in these countries, which have long lagged behind those in high-income countries but are less encumbered by legacy systems that have proved hard to modernize in many settings, could leapfrog their wealthier counterparts in exploiting these technologies. Although the challenges posed by poor or absent infrastructure and investment in many low- and middle-income countries cannot be underestimated and will need to be addressed to make this possibility a reality, the rapid rollout of mobile networks and their use for health and other social services in many low-income countries where access to fixed telephone lines was previously very limited offer great promise in building pri­ mary care services in low- and middle-income countries. To a partial extent, this potential has been demonstrated and even realized in many countries during the COVID-19 pandemic, with greatly increased uptake of the use of telemedicine and clinical support via digital means. CONCLUSION As concern continues to mount about glaring inequities in global health, there is a growing commitment to redress these egregious shortfalls, as exemplified by the central place of equity in the United Nations’ Sustainable Development Goals adopted in 2015, including a specific target on the achievement of universal health coverage in all countries by 2030. This commitment begins first and foremost with a clear vision of the fundamental importance of health in all countries, regardless of income. The values of health and health equity are shared across all borders, and primary health care provides a framework for their effective translation across all contexts. The translation of these fundamental values has its roots in four types of reform that reflect the distinct but interlinked challenges of (re)orienting a society’s resources on the basis of its citizens’ health needs: (1) organizing health care services around the needs of people and communities; (2) harnessing services and sectors beyond health care to promote and protect health more effectively; (3) establishing sustainable and equitable financing mechanisms for universal health coverage; and (4) investing in effective leadership to steward change locally, nationally and across borders. This common primary health

care agenda highlights the striking similarity, despite enormous dif­ ferences in context, in the nature and direction of the reforms that national health systems must undertake to promote greater equity in health. This shared agenda is complemented by the growing reality of global health interconnectedness due, for example, to shared microbial threats, bridging of ethnolinguistic diversity, flows in migrant health workers, and mobilization of global funds to support the neediest populations. Embracing solidarity in global health while strengthening health systems through a primary health care approach is fundamental to sustained progress in global health. The shortfalls in health system performance, stratification of social conditions leading to unfair differences in health, and skews in science that undermine the realization of “Health for All” have never been more glaringly visible than during the COVID-19 pandemic. But they also have never commanded such global political attention at the high­ est level. Out of this crisis, then, is a once-in-a-lifetime opportunity to recast global and national systems to enable the genuine implementa­ tion of the primary health care approach in all countries. ■ ■FURTHER READING Aquino R et al: Impact of the family health program on infant mortal­ ity in Brazilian municipalities. Am J Public Health 99:87, 2009. Commission on Social Determinants of Health: Closing the Gap in a Generation: Health Equity through Action on the Social

Determinants of Health: Commission on Social Determinants of Health Final Report. Geneva, World Health Organization, 2008. Kruk ME et al: The contribution of primary care to health and health systems in low- and middle-income countries: A critical review of major primary care initiatives. Soc Sci Med 70:904, 2010. Li X et al: The primary health-care system in China. Lancet 390:2584, 2017. Macinko J et al: The impact of primary healthcare on population health in low- and middle-income countries. J Ambul Care Manage 32:150, 2009. Rasanathan K, Evans T: Primary health care, the Declaration of Primary Care and Global Health CHAPTER 487 Astana and COVID-19. Bulletin of the World Health Organization 98:801, 2020. Rasanathan K et al: Primary health care and the social determinants of health: Essential and complementary approaches for reducing inequities in health. J Epidemiol Community Health 65:656, 2011. Starfield B et al: Contribution of primary care to health systems and health. Milbank Q 83:457, 2005. Tangcharoensathien V et al: Health systems development in Thailand: A solid platform for successful implementation of universal health coverage. Lancet 391:1205, 2018. Van Lerberghe W et al: Primary Health Care: Now More Than Ever. World Health Report 2008. Geneva, World Health Organization, 2008.