3708 PART 17 Global Medicine

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 80% as the country—despite its relatively low gross national income

(Fig. 472-3)—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.

■ TUBERCULOSIS

Chapter 178 provides a concise overview of the pathophysiology and

treatment of tuberculosis. In 2017, an estimated 1.2 million people

died from Mycobacterium tuberculosis infection; this figure made

tuberculosis the leading single infectious killer of adults globally. The

disease is closely linked to HIV infection in much of the world: of

the ~10 million estimated new cases of tuberculosis in 2017, 920,000

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 tuberculosis,

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 smear-positive 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 identified. 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

exclusively extrapulmonary tuberculosis are missed by smear microscopy, as are most cases of active disease in children. Second, passive

case-finding 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 infections. 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 2017, 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 tuberculosis over the preceding decade. Gene probes 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 558,000 cases

of MDR-TB were thought to occur in 2017. Approximately 9% 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 management of drug-resistant HIV infection and even drug-resistant malaria,

100

90

United Nations 2020 target

Burundi

Niger

Central

African Rep.

Somalia

Madagascar

Malawi

Rwanda Zimbabwe

Angola

Sudan

Mauritius

Eswatini Namibia

Botswana

Kenya

Gabon

Lesotho

Cameroon

South Africa

80

70

60

50

40

% Estimated ART coverage, 2017

30

20

10

0

100 1000

GDP per capita, 2017, in current US$ (log)

10,000

FIGURE 472-3 Antiretroviral therapy (ART) coverage (percentage of people living with HIV who received ART) in sub-Saharan Africa, 2017. (Source: World Bank; data

available through data.worldbank.org.)

3709 Global Issues in Medicine CHAPTER 472

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 a

number of 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

species are not reliably treated with a single drug.

Second, charging fees for AIDS prevention and care poses insurmountable problems for people 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 countries 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 investments increase, the price of AIDS care continues to

decrease. The use of generic medications means that ART can now

cost <$0.25 per day.

Third, the effective scale-up of pilot projects requires strengthening 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, is incorrectly invoked as a primary reason for failure to treat AIDS in poor countries and must still 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. Specifically, 45% of WHO member states report not achieving

that target. In contrast, the United States and Cuba report 2.59 and 8.19

doctors per 1000 population, respectively. Similarly, ~50% of WHO

member states report having fewer than three nurses and midwives

per 1000 population. Sub-Saharan Africa bears >24% 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 70%

of the national health workforce is concentrated in urban areas, where

just 38% 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. Funding 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 communities. 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 deployment of “wrap-around services”: food supplements for the

hungry, help with transportation to clinics, child care, 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 an effective vaccine—but also to most other neglected

diseases of poverty.

■ MALARIA

Chapter 224 reviews the etiology, pathogenesis, and clinical treatment

of malaria, the world’s sixth-ranking infectious killer. In 2017, there

were 219 million cases of malaria, and the disease killed 435,000

people; 60% of these deaths occurred among children <5 years old.

The poor disproportionately experience the burden of malaria: almost

85% of estimated malaria deaths occur in just 20 countries, and mortality rates are highest in sub-Saharan Africa. Nigeria, the Democratic

Republic of the Congo, Tanzania, Angola, Mozambique, and Niger

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

2016, U.S. $4.3 billion was spent on malaria worldwide, an 8.5% per

year increase since 2000. 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. In light of this enormous cost, it is

little wonder that an important review by the economists Sachs and

Malaney concludes that “where malaria prospers most, human societies have prospered least.”

Microeconomic analyses focusing on direct and indirect costs

estimate that malaria may consume >10% of a household’s annual

income. A recent study in rural Mozambique, where malaria is the

leading cause of care-seeking, concluded that the median household

cost associated with uncomplicated malaria represents 10−21% of a

family’s monthly expenditure, while a severe case may exceed the mean

monthly expenditure per capita by more than three times, thereby continuing the cycle of poverty and disease.

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 sub-Saharan African countries. In 2008, the RBM partnership

launched the Global Malaria Action Plan (GMAP). This strategy

integrates prevention and care and calls for the avoidance of singledose regimens and an awareness of existing drug resistance; the use of

insecticide-treated 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.

Between 2000 and 2015, the global malaria mortality rate was

reduced by an estimated 62%, a figure equating to some 6.8 million

deaths averted. Again, the experience in Rwanda is instructive: from

2005 to 2012, malaria incidence decreased by 86% and deaths dropped

by 76% for the same reasons mentioned earlier in recounting that

nation’s successes in battling HIV. An eight-fold resurgence in cases

3710 PART 17 Global Medicine

there between 2012 and 2016 has been linked to increased access

to health care (and therefore diagnosis), inadequately treated ITNs,

mosquito resistance to insecticides, climate change, and transborder

movement of people.

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 diarrhea, 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, diagnosis, and treatment, we may yet achieve the goal of a world largely

free of malaria.

■ EBOLA

Chapter 210 provides an overview of the epidemiology, pathogenesis,

and clinical manifestations of Ebola virus and Marburg virus infections. 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 country before the Ebola epidemic, or roughly one physician

per 100,000 people. 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 therapies 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

Democratic Republic of the Congo (DRC) and soon became the

world’s second largest on record. In June 2020, when it was declared

over, it had sickened ~3500 people and killed two-thirds of them.

Containment 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 significant 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 aspirational clinical protocols. Nevertheless, the overall case-fatality rate

in DRC reveals that these welcome medical innovations did not reach

everyone in need of them.

■ COVID-19

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 people experiencing homelessness 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. 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

infection, 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, 73% of all deaths worldwide in 2017 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 ~15 million people and exceeding the total number of deaths

due to AIDS, tuberculosis, and malaria combined. By 2030, NCDs

will account for 55 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 noncommunicable 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.

3711 Global Issues in Medicine CHAPTER 472

Some of these insults result from rapid changes in diet and labor

conditions; others are of a less recent vintage. The burden of cardiovascular 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 disabilities due to NCDs in developing countries have led to calls for preventive 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 primarily of elderly populations in middle- and high-income countries has

contributed to the neglect of these diseases by global health institutions, 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 assistance 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 463 million in 2019—1 in 11 adults—to 700 million by 2045.

Already, a significant proportion of diabetic patients live in developing countries where, because those affected are far more frequently

between ages 40 and 59, the complications of micro- and macrovascular 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 estimates that diabetes accounted for

1.4 million deaths in 2017; 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 run. In

contrast, persistently elevated blood pressure above 180/110 mmHg

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 centers, 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 2.5% of all hospitalizations, and is

estimated to account for a substantial proportion of medical admissions in hospitals in low-income countries as well. In high-income

countries, coronary 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 cardiotropic 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. Nonischemic 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 tuberculosis 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 >1.3 million

new cases each year. Among the 834,000 cases of pediatric RHD, 38%

occur in sub-Saharan Africa. A meta-analysis of data on heart failure in

sub-Saharan 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 >285,000 deaths per year—almost all occurring

in developing countries. A survey of the global burden of RHD from

1990 through 2015 found that the highest age-standardized death rates

occurred in Oceania, South Asia, and sub-Saharan Africa, with 1.5%

of Oceania’s population and 1% of the populations in South Asia and

sub-Saharan Africa living with the disease in 2015. 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 established

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 partnerships

can speed the further development of regional centers of excellence

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 2017. By 2030,

annual mortality from cancer is expected to increase to >13 million

deaths—with developing countries experiencing a sharper increase

than developed 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, hepatitis B virus, and Helicobacter pylori, are responsible

for up to 25% of cancer cases in low- and middle-income countries.

Infectious causes of cancer will continue to have a much larger impact

3712 PART 17 Global Medicine

in developing countries. Environmental and dietary factors, such as

indoor air pollution 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 and oral cancers. In contrast to decreasing

tobacco use in many developed countries, the number of smokers is

growing in developing 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 quality 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. 472-4). 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.

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. If trends

continue, tobacco-related deaths will increase to 8 million per year by

2030, with 80% of those deaths 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 2017, ~792 million people worldwide lived with a mental health

disorder, including >548 million people suffering from depression

and anxiety disorders. One in four patients visiting a health service

has at least one mental, neurologic, or behavioral disorder, but most

of these disorders are neither diagnosed nor treated. Almost 800,000

people die by suicide every year, and major depression is the fifth 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.

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; 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 antiseizure medications, even

though all had been prescribed these drugs. Moreover, many patients

in this study had no detectable blood levels of these agents. The same

barriers that prevent the poor from having reliable access to insulin or

ART prevent them from benefiting from antidepressant, antipsychotic,

A B

FIGURE 472-4 An 11-year-old Rwandan patient with embryonal rhabdomyosarcoma before (left) and after (right) 48 weeks of chemotherapy plus surgery. Eleven years

later, she is healthy with no evidence of disease.

3713Emerging and Reemerging Infectious Diseases CHAPTER 473

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 A SCIENCE OF

IMPLEMENTATION

There is a long way to go before evidence-based internal medicine

is applied effectively among the world’s poor. Public health strategies

draw largely on quantitative methods—epidemiology, biostatistics,

and economics. Clinical practice, including the practice of internal

medicine, draws on a rapidly expanding knowledge base and remains

focused on individual patient care; clinical interventions are rarely

population-based. 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 problems 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 a nascent 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 “know-do” 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

effectively 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 work 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 are developing training programs

for physicians with an interest in global health. In medical schools

across the United States and in other wealthy countries, interest in

global health has exploded. One study has shown that >25% of medical

students take part in at least one global health experience prior to graduation. Half a century or even a decade ago, such high levels of interest

would have been unimaginable.

At least half of the world’s population lacks reliable access to essential

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 antibiotics and

other essential medicines, deaths from malaria that would have been

prevented by ITNs and access to therapy, and deaths from waterborne

illnesses. Other excess mortality is attributable to the inadequacy of

efforts to develop new preventive, diagnostic, and therapeutic tools.

The development of 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 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 the

most important goal of global health.

■ FURTHER READING

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 2017 Causes of Death Collaborators: Global, regional, and

national age-sex-specific mortality for 282 causes of death in 195

countries and territories, 1980–2017: A systematic analysis for the

Global Burden of Disease Study 2017. Lancet 392:1736, 2018.

GBD 2017 Disease and Injury Incidence and Prevalence Collaborators: Global, regional, and national incidence, prevalence,

and years lived with disability for 354 diseases and injuries for 195

countries and territories, 1990–2017: A systematic analysis for the

Global Burden of Disease Study 2017. Lancet 392:1789, 2018.

Global Burden of Disease Health Financing Collaborator

Network: Past, present, and future of global health financing: A

review of development assistance, government, out-of-pocket, and

other private spending on health for 195 countries, 1995–2050. Lancet

393:2233, 2019.

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.

THE CONCEPT OF EMERGING

INFECTIOUS DISEASES

Pathogenic organisms have been a constant companion of humans,

their livestock, and their cultivated plants throughout evolution.

Over the centuries, new organisms emerged as ecology changed or

as humans crossed ecologic barriers such as deserts, mountains, and

oceans. Throughout history, there have been severe epidemics of infectious diseases, with devastating consequences to human populations

over vast geographic regions. From the Plague of Justinian in Europe

in the sixth century, to the Black Death in the fourteenth century,

to the five cholera pandemics of the nineteenth century, to the 1918

Spanish influenza pandemic, to the ongoing HIV/AIDS pandemic,

to the SARS-CoV-2 (COVID-19) pandemic, the death toll in human

populations has been enormous. The concept of emerging infectious

diseases arose in the 1970s and 1980s with the recognition of several

“new” diseases, such as legionellosis, HIV infection, Lyme disease, and

toxic shock syndrome and was later expanded to include reemerging

infectious diseases—that is, infectious diseases such as tuberculosis

that reappeared after having been controlled. In 1991, the Institute of

Medicine (IOM), now the National Academy of Medicine, convened a

multidisciplinary committee to elucidate emerging microbial threats

to health, with particular reference to the United States. In its report,

473 Emerging and Reemerging

Infectious Diseases

George W. Rutherford, Jaime Sepúlveda

3714 PART 17 Global Medicine

the committee defined an emerging infectious disease as a disease

“of infectious origin whose incidence in humans has either increased

within the past two decades or threatens to increase in the near future.”

In the year following the publication of the committee’s report, large

outbreaks of Escherichia coli O157:H7 infection, cryptosporidiosis,

and hantavirus pulmonary syndrome spurred the development of a

national plan to recognize and interdict emerging and reemerging

infectious disease threats by the Centers for Disease Control and Prevention (CDC). Since then, the list of emerging and reemerging viral,

bacterial, fungal, and parasitic diseases has grown to include multiple

infections and syndromes. Examples of emerging and reemerging

infectious diseases, as of 2020, are shown in Table 473-1.

The reasons for the emergence of previously unrecognized diseases

and the reemergence of diseases that have previously been largely

under control are legion. At its core, however, emergence has to do

with genetic changes in disease agents or changes in ecology, including

human behavior. The IOM committee listed six primary reasons for

disease emergence or reemergence: human demographics and behavior, technology and industry, economic development and land use,

international travel and commerce, microbial adaptation and change,

and breakdown of public health measures. A disease can emerge or

TABLE 473-1 Examples of Emerging and Reemerging Infectious

Diseases

VIRAL AND PRION

BACTERIAL AND

RICKETTSIAL

FUNGAL AND

PARASITIC

Chikungunya virus infection

Congo-Crimean

hemorrhagic fevera

Variant Creutzfeldt-Jakob

disease

Dengue

Ebola virus, Marburg virus

infectiona

Enterovirus D68 infection

Hantavirus (Sin Nombre,

Seoul) infection

Hendra virus, Nipah virus

infection

Hepatitis C

Hepatitis E

HIV-1 and -2 infection

Human herpesvirus 6, 8

infection

Human T-lymphotropic

virus 1 and 2 infection

Influenza A H1N1pdm,

H5N7, H7N7, H7N9

Lassa fevera

Lyssavirus infection

Middle East respiratory

syndrome (MERS)a

Monkeypox

Nipah virus infectiona

Rift Valley fever virus

infectiona

Severe acute respiratory

syndrome (SARS)a,b

SARS-CoV-2 (COVID-19)c

West Nile virus infection

Whitewater Arroyo virus

infection

Yellow fever

Zika

Anaplasmosis

Anthrax

Carbapenem-resistant

Enterobacterales

Lyme disease

Vibrio cholerae O139

infection

Diphtheria

Ehrlichiosis

Escherichia coli O157:H7

infection

E. coli O154:H4 infection

Legionella pneumophila

infection

Plague

Vancomycin-resistant

Staphylococcus aureus

infection

Streptococcal toxic

shock syndrome

Tuberculosis

Candida auris infection

Coccidioidomycosis

Cryptosporidium

parvum infection

Cyclospora

cayetanensis infection

Drug-resistant malaria

a

Designated by the World Health Organization in 2015 as the highest-priority

diseases for research and development. b

Caused by SARS coronavirus (SARS-CoV). c

Caused by SARS coronavirus type 2 (SARS-CoV-2).

reemerge for one or more of these reasons. For example, the worldwide spread of severe acute respiratory syndrome (SARS) began as a

species crossover, most likely involving transmission of a previously

unknown coronavirus of horseshoe bats to Himalayan palm civets that

were subsequently captured and transported to live-animal (i.e., “wet”)

markets in Guangzhou, China, for human consumption. The SARS

coronavirus was then transmitted to humans—most likely by restaurant workers—and from them to medical personnel and eventually

to individuals around the world. This spread had nothing to do with

migratory patterns of bats or civets but was, instead, a consequence of

human travel. The cities most affected by SARS—Hong Kong, Beijing,

and Toronto—became involved because of rapid human movement

via international passenger aircraft. While likely more complex than

originally thought, the emergence of SARS-CoV-2 in Wuhan, China,

in December 2019 was also thought to involve an intermediate animal

host—the pangolin—that had likely been infected in the wild by a bat

and then brought to a wet market. From Wuhan, the virus was transmitted throughout China, then throughout Asia and the Pacific, and

then to Europe, North and South America, and Africa through human

international air travel, resulting in a pandemic rivaling the 1918–1919

influenza A H1N1 pandemic.

Additional factors can now be included on this list. Either therapeutic or acquired immunosuppression (e.g., as in HIV infection) can

render populations susceptible to infections that have not previously

been recognized, such as that with human herpesvirus 8—the cause of

Kaposi’s sarcoma. Climate change, in particular, can expand the host

range of disease-transmitting vectors. In addition, the weaponization

of pathogenic organisms for biological terrorism or warfare can lead,

at least theoretically, to prolonged chains of human-to-human transmission. One factor is clear: the preponderance of emerging infectious

diseases are zoonotic in origin. The authors of a 2008 review calculated

that 60.3% of all emerging infectious disease events from 1940 to 2004

were zoonotic in origin, and 71.8% of these zoonotic events originated

in wildlife.

In this chapter, we review the recent changing epidemiology of seven

emerging or reemerging infectious viral diseases that exemplify some

of the IOM’s principles for emergence: infections caused by West Nile

virus, dengue virus, Ebola virus, Zika virus, and, most recently, SARSCoV-2, as well as measles and poliomyelitis—two recently resurging

viral diseases that are preventable with existing vaccines but that

resurged in 2020. This list is clearly not exhaustive but highlights a few

prominent instances of the recent emergence of infectious diseases and

their root causes.

EXAMPLES OF EMERGING

INFECTIOUS DISEASES

■ WEST NILE VIRUS

West Nile virus (WNV) is a flavivirus that was originally discovered

in Uganda in 1937 and emerged as a cause of neurologic disease in

humans and equines. WNV exists in nature in an enzootic cycle that

involves certain birds and mosquitoes, particularly those of the genera

Culex and Aedes. Humans, horses, and other vertebrates are incidental

hosts and, except through blood transfusion, are unlikely to transmit

WNV because levels of viremia are insufficiently high to infect mosquitoes. When originally described, WNV was believed to cause a

mild febrile illness, but subsequent experience showed that it caused

neuroinvasive disease in some cases. Cases of neuroinvasive disease

were described first in an outbreak among elderly patients in Israel and

subsequently in humans and horses in the Mediterranean basin, India,

and South Africa. By the 1990s, outbreaks had been reported from

Romania, Russia, and Central Asia; these outbreaks were probably a

result of seasonal bird migrations from endemic Mediterranean countries, with introduction of infected mosquitoes and the establishment

of infection in local bird species.

An explosive outbreak of WNV infection began in the United States in

the summer of 1999 and initially involved infection of birds of the family

Corvidae (e.g., American crows and blue jays) that were susceptible to

neuroinvasive disease. The first human cases appeared in New York City

3715Emerging and Reemerging Infectious Diseases CHAPTER 473

that same summer. Thereafter, sufficient numbers of birds more resistant

to neuroinvasive disease and mosquitoes of the genus Culex became

infected, and an enzootic cycle was established in North America. Over

the next 3 years, WNV spread across the continental United States,

Canada, and Mexico and became an important cause of human and

equine neurologic disease. The WNV clade causing the North American

outbreak was the same (clade 1a) as that causing disease in the Middle

East, Europe, North Africa, and parts of Asia.

In 2019, 971 cases of WNV infection in humans, including 633 cases

of neuroinvasive disease, were reported in the United States; these figures are certainly gross underestimates of the actual number of cases.

There were 60 deaths, almost all from neuroinvasive disease and almost

all among the elderly. An additional 90 cases were reported in horses

from 25 states despite the availability of a reasonably protective equine

vaccine. Human cases were reported from 40 states; only Hawaii has

been consistently free of the disease. Infected mosquito pools were

even more widespread; Maine, Minnesota, Vermont, and West Virginia

were the only states in the continental United States to be free of all

WNV activity. Thus, from an initial introduction into New York City,

WNV has successfully established itself across North America and

infected an estimated 2.6–6.1 million people in the United States (1.1%

of the population).

Why did this happen? First, microorganisms and larger organisms,

such as plants and animals, have been exchanged between the Old and

New Worlds since the initial voyages of exploration in the fifteenth

and sixteenth centuries. However, it is the advent of modern highspeed transportation that allows vectors, such as mosquitoes, to move

between continents in hours or days as opposed to months or years.

In the most likely scenario for the introduction of WNV into North

America, a single viremic mosquito was accidentally transported from

an area endemic for clade 1a WNV to New York City in the cargo hold

of an airplane in 1999. The original strain associated with the 1999 outbreak (NY99) had caused outbreaks in Tunisia and Israel in 1997 and

1998, respectively; this information suggests that one of those countries

was the source. The imported strain in turn infected corvids, which in

turn infected more competent mosquitoes, establishing an enzootic life

cycle in North America that involved at least three Culex species and

multiple species of birds. This scenario represents a successful invasion

of WNV into a new ecologic niche.

The likelihood that WNV will gradually disappear from North

America is low. The virus has many avian hosts and more than one

mosquito vector; it has undergone at least one successful mutation in

the North American outbreak, thereby becoming infectious to Culex

piperans and Culex tarsalis—mosquitoes with a broad range in the

western United States. Moreover, the occurrence of outbreaks in 19

consecutive years in North America suggests that WNV has been

successfully introduced onto the continent and will remain endemic

for years to come.

■ DENGUE VIRUS

Dengue is the most important of the human arboviral infections,

with almost half of the world’s population at risk. Occurring in the

range of Aedes aegypti mosquitoes, dengue virus infection imposes a

heavy burden of morbidity and mortality worldwide, with as many

as 50–200 million infections, 500,000 severe cases, and 20,000 deaths

annually. Dengue virus is a flavivirus and exists in four serotypes

(DENV1–4) that circulate independently of one another; immunity

to one serotype does not confer immunity to the others.

Dengue is transmitted primarily by Ae. aegypti and secondarily by

Ae. albopictus. The original life cycle of dengue virus was most likely

similar to that of yellow fever virus, consisting of sylvatic transmission

from mosquitoes to nonhuman primates and back to mosquitoes; over

the past few centuries, the virus has adapted to an urban and periurban mosquito–human–mosquito cycle as well. Dengue and its more

severe manifestations, dengue hemorrhagic fever and dengue shock

syndrome, were first described in outbreaks in Japan in 1943 and

Hawaii in 1945. However, clinically similar diseases had been reported

during the previous two centuries in a geographic band extending from

India south to Queensland, Australia, and east through Polynesia; in

addition, there had been occasional outbreaks in areas as disparate as

Greece, Panama, and southern Texas.

The ecology of dengue changed dramatically in the second half of

the twentieth century. This change was led by the successful invasion

of the global tropics by Ae. aegypti after World War II, coincident with

the postwar dispersion of troops and materiel. From its ancestral roots

in Southeast Asia, all four dengue serotypes have now spread globally.

DENV2 was introduced into West Africa by the 1960s and established both sylvatic enzootic nonhuman primate and urban endemic

human cycles. Travel and commerce facilitated dissemination, probably through both viremic human hosts and infected mosquitoes. In

the Americas in particular, a campaign to eradicate Ae. aegypti, which

is also the principal vector of yellow fever, failed in the mid-1970s, and

both Ae. aegypti and dengue virus, especially DENV2, rapidly reinvaded their prior habitat; thus, dengue reemerged as a major arboviral

disease extending from the southern United States in the north through

northern Argentina in the south. Recent outbreaks have occurred along

the U.S.-Mexico border and in the state of São Paulo in Brazil, where

DENV1, DENV2, and DENV4 are co-circulating.

Dengue’s emergence and spread have been intimately linked to

human activity. In particular, globalization, with the movement of

viremic people and mosquitoes through modern transportation of

both passengers and goods, has been critical to dengue’s success. One

particular adaptation has also facilitated its urban spread: Aedes is able

to breed in standing water associated with human habitation, such as

cisterns, ornamental ponds, puddles, and water trapped in abandoned

tires. This ability of Aedes has allowed dengue to be one of the only

three known arboviruses (the others being yellow fever and Zika) that

are adapted to an urban environment and can replicate entirely in a

mosquito-to-human cycle. Together, these factors have led to widespread dengue transmission in a band extending across the tropics

worldwide, a host range that will likely expand with warmer and wetter

weather due to climate change.

■ EBOLA AND MARBURG VIRUSES

Ebola virus is a filovirus that most likely exists in a sylvatic cycle in bats

in Central and West Africa. Four strains are known to cause human

disease. The first outbreak was described in Zaire in 1976. Since then,

31 outbreaks have been reported across tropical Africa, ranging in size

from tens of cases to tens of thousands of cases in the West African

outbreak of 2013–2016.

The life cycle of Ebola virus in the wild is not fully understood. There

is evidence for sustained transmission in fruit bats, with occasional

nonhuman primate spillover infections. It has been speculated that

humans become infected from contact with infected bats or nonhuman

primates, but, once an index case has occurred, essentially all transmission is from human to human due to contact with blood and other

body fluids. Preparing bodies for burial has been an especially efficient

means of transmission. In addition, health care providers who do not

wear adequate personal protective equipment while caring for Ebola

patients are particularly vulnerable to acquiring infection. In the 2013–

2016 West African epidemic, there was only a single zoonotic introduction, and all subsequent transmission was from human to human.

The principal cause of Ebola outbreaks prior to the West African outbreak was the migration of humans into sylvatic areas, with enzootic

transmission and accidental infection. In West Africa, only a single

case had been recognized in Côte d’Ivoire before the 2013–2016 outbreak in the Republic of Guinea, Liberia, and Sierra Leone. It has been

speculated that cultivation of palm oil attracted fruit bats, who feed

on palm fruit; if so, environmental modification from dense tropical

forests to palm oil plantations may have been a contributory cause.

Other evidence suggests that the index patient—a 2-year-old boy—was

exposed to insectivorous free-tailed bats (Mops condylurus). Whatever

the initial event, the explosive amplification that occurred in these

countries and in the seven countries to which cases were exported

was due to an inadequate medical and public health infrastructure. In

fact, when Ebola virus was imported to countries with more functional

public health systems, such as Nigeria, transmission was extinguished

within three generations.

3716 PART 17 Global Medicine

Other filovirus outbreaks have involved the transport of infected

primates for medical research. The original Marburg virus outbreak,

which occurred in Marburg and Frankfurt, West Germany, and

Belgrade, Yugoslavia, in 1967, was likely caused by the importation

of African vervet monkeys (Cercopithecus aethiops) from Uganda

for medical research. This outbreak resulted in 31 human cases and

7 deaths. In addition, an outbreak among five crab-eating macaques

(Macaca fascicularis) imported from the Philippines and infected

with Reston Ebola virus—a strain nonpathogenic for humans—led to

an epizootic in northern Virginia in 1989, eventually resulting in the

culling of >500 primates. This outbreak had no human cases associated with it, although epidemiologic investigation identified a handful

of asymptomatic primate handlers who were seropositive for Reston

Ebola virus. Since 1989, four additional outbreaks have been recognized in Cynomolgus monkeys imported from the Philippines to the

United States and Italy.

Another reservoir of Ebola virus infection has been identified: the

semen of patients who have survived Ebola infection. The occurrence

of several small clusters of sexually transmitted cases developing up to

284 days after symptom onset indicates prolonged carriage of Ebola

virus in the testes. Moreover, the virus may remain viable over the long

term in the vitreous humor.

Thus, Ebola represents a spillover event to humans and nonhuman

primates from their interaction with certain species of infected and

infectious bats. Contact with either the bats themselves or an infected

nonhuman primate leads to infection of an index patient, which leads

in turn to ongoing transmission from humans to humans. Several

factors clearly contribute to the continued transmission. First, medical

and public health systems are weak in severely affected countries. This

inadequacy was especially apparent in the 2018−2020 outbreak in eastern Democratic Republic of the Congo, where insecurity due to ongoing armed conflict greatly amplified the epidemic. As experience with

Ebola grows and the capacity for surveillance and response improves,

numbers of secondary cases can fall; for example, in five outbreaks

in Uganda stretching from 2000 to 2012, the numbers of secondary

cases and the geographic spread of the outbreaks decreased with each

new introduction. Second, behavioral factors contribute, in particular,

funeral practices that bring mourners into close contact with infectious

blood and tissues during preparation of a body for burial. Third, the

areas in which the initial waves of transmission occur are often remote;

thus, recognition of the outbreak can be delayed, and, as in both the

West African and the current Congolese outbreaks, highly mobile populations can travel to larger cities to seek care.

Two new preventive vaccines, monoclonal antibody therapy, and

portable isolation facilities are now available, and a ring vaccination

strategy has now been successfully employed. The widespread transmission seen both in West Africa and especially in the 2018 outbreak in

eastern Democratic Republic of the Congo were limited where all these

measures were employed rapidly and with sufficient coverage.

■ ZIKA VIRUS

Zika virus is a flavivirus that is transmitted by Aedes mosquitoes and

was originally described as an infection of nonhuman primates in

Uganda in 1947. The first human cases were reported in Uganda in

1962 and 1963. Zika was thought to be an illness causing a mild rash

and fever in humans in tropical Africa and southern Asia. The clinical and serologic similarity of Zika virus infection to dengue virus

infection may have caused some outbreaks to be missed. Since 2007,

an Asian lineage of Zika virus has spread from the Western Pacific

(initially, Yap Island) through Polynesia and on to Easter Island, Chile,

where it was documented in 2014. From Polynesia, it also spread

to Brazil, most likely through viremic travelers attending the world

Va’a World Sprint Championships (Polynesian canoe racing) in Rio

de Janeiro in the late summer of 2014. From there, Zika virus spread

hemisphere-wide, following the host range of Ae. aegypti. Forty-eight

countries in the Americas—all except Canada and Chile—reported

autochthonously acquired Zika virus infections during the 2014–2016

outbreak. In the United States, locally acquired cases were diagnosed

in Florida, Texas, Puerto Rico, the U.S. Virgin Islands, and American

Samoa; >35,000 cases were reported from Puerto Rico alone in 2016.

Cases have continued to occur at lower levels, with 102 cases reported

in the United States and its territories in 2019; 73 of these cases were

from Puerto Rico and were most likely acquired autochthonously

rather than imported.

As Zika virus spread through the Americas, a parallel epidemic of

fetal microcephaly appeared; this epidemic was both temporally and

geographically associated with the spread of Zika virus. More than

1.6 million cases of Zika virus infection, including 41,473 cases in

pregnant women and 1950 cases of Zika-associated microcephaly,

were reported from Brazil alone in 2015 and 2016. Data from a large

registry of Zika-exposed pregnancies in the U.S. territories show that

the overall risk of microcephaly following confirmed Zika virus infection is ~5%, ranging from 8% for infection in the first trimester to 4%

for infection in the third trimester. Other fetal complications include

stillbirth, neural tube defects, eye abnormalities, and sensorineural

deafness. Complications in adults occur in about one of every thousand

cases and include Guillain-Barré syndrome, encephalitis, leukopenia,

and thrombocytopenic purpura. Moreover, it is now recognized that

Zika virus can be transmitted sexually and via blood transfusion.

Thus, the introduction of Zika into the Americas represents viral

invasion of a new ecosystem already widely populated by a highly

competent mosquito host with an established urban habitat and an

immunologically inexperienced human population. The invasion by

Zika virus is in many ways similar to the original dengue virus invasion in the Americas in the 1950s and to the introduction of WNV

into North America in 1999. Both the original importation of Zika

virus and its establishment of new foci in the Americas (e.g., Florida

and the Caribbean) were consequences of modern travel. Zika’s spread

has also been linked to climate variations, deforestation, and urban

poverty.

■ SARS-COV-2

SARS-CoV-2 is a coronavirus of the beta-coronavirus lineage

(Chap. 199). It is closely related to SARS-CoV, the causative agent of

SARS, and to the Middle East respiratory syndrome (MERS) virus and

is transmitted primarily through droplet transmission and secondarily

through aerosol or airborne transmission; unlike SARS-CoV infection,

outbreaks of SARS-CoV-2 infection have not been linked to fomite

transmission. The first human cases of the clinical disease caused by

SARS-CoV-2—COVID-19—were reported in December 2019 from

Wuhan, a large city in Hubei Province, China, eventually leading to

an outbreak with >70,000 reported cases in that city. The phylogenetic

origins of SARS-CoV-2 are clear. It is an enzootic infection of bats,

one of several bat-adapted beta-coronavirus infections that have been

recognized. How it crossed into humans is less clear. Originally, as

early cases centered around a wet market in Wuhan, it was thought

that transmission most likely occurred via an infected intermediate

host sold in the market: the pangolin, an animal heavily trafficked for

its scales. However, subsequent investigations have suggested that the

virus may have been in circulation a month or two earlier in China and

sporadically in Western Europe and the United States soon thereafter.

What is clear is that SARS-CoV-2 caused an explosive outbreak in

Wuhan and subsequently spread from China to Iran, Western Europe,

and North America and from those regions to the rest of the world.

This spread has been aided by an utter lack of preexisting immunity

in humans, although it has been speculated that prior infection with

alpha-coronaviruses, which are common causes of upper respiratory

tract infections, may have some modest protective effect. Twenty-one

months later, 218 million cases and >4.5 million deaths have been

reported worldwide; in terms of number of deaths, the most affected

countries are the United States, India and Brazil. SARS-CoV-2 infection and its clinical disease, COVID-19, were the third leading cause of

death in the United States in 2020.

Clinically, SARS-CoV-2 infection causes upper and lower respiratory tract disease. What complicates the control of its transmission

is that ~40% of infected individuals never develop acute symptoms

and one-third of transmission from symptomatic individuals occurs

during the presymptomatic period. While the period of high-level

3717Emerging and Reemerging Infectious Diseases CHAPTER 473

viral shedding and infectiousness is short (on the order of 3–5 days),

patients who develop lower respiratory tract symptoms requiring more

intensive care are likely infectious for up to 2 weeks, necessitating

strong infection control measures, especially for aerosol-generating

procedures.

The SARS-CoV-2 pandemic resulted from a species crossover from

bats to humans (possibly through an intermediate host). What human

behavior facilitated that crossover is unclear and may have had to do

with population pressure and human intrusion into previously unoccupied semitropical forests where bats roost. What is clear, however, is

that international travel led to transmission across the globe, first to

international ports of entry and then throughout affected countries. In

the United States, for instance, original introductions occurred in Seattle, Los Angeles, San Francisco, and New York City, with explosive subsequent expansion in the New York City region during the first wave

of the pandemic in March and April of 2020. Control of the pandemic

has thus far hinged on social distancing interventions and universal

masking. Countries that have done a better job of implementing those

interventions, such as Australia, New Zealand, Singapore, South Korea,

Taiwan, and Vietnam, have been substantially less impacted than

countries that have not. As of this writing, two mRNA vaccines and an

adenovirus-vectored vaccine have been deployed in the United States,

with approximately 52% of the population fully vaccinated; if they are

accepted by a large proportion of the population, these vaccines may

lead to levels of immunity sufficiently high to achieve herd immunity

and epidemic control. Nowadays, all sorts of conspiracy theories are

circulating in social media around COVID-19 vaccines, as has been

the case with polio and measles vaccines in the past. Moreover, with

disease currently reported in almost every country, it is unlikely that,

even with high levels of vaccination, SARS-CoV-2 will be eliminated.

Possibly, it will become a sporadic disease and part of the differential

diagnosis of severe respiratory viral infection.

■ POLIOVIRUS

Poliovirus is an RNA enterovirus of the family Picornaviridae. It is the

causative pathogen of poliomyelitis, a disease of the central nervous

system. Poliovirus is transmitted through the oral-fecal route. Until

recently, there were three serotypes of wild poliovirus in nature: PV1,

PV2, and PV3. In 1988, all member countries of the World Health

Organization (WHO) committed to eradicating poliomyelitis by the

year 2000. Thanks to massive immunization campaigns, PV2 was

declared eradicated in 2015 and PV3 in 2019. Thus, only wild PV1

still exists and is confined to two countries: Pakistan and Afghanistan.

Poliomyelitis has existed since ancient times. Egyptian steles from

1400 b.c. depict victims of the disease. It probably existed at low

endemicity for centuries, until epidemics occurred first in Europe in

the nineteenth century and later in the United States in the early to

mid-1900s. Although the virus was isolated in 1909, it was not until

1955 that Jonas Salk succeeded in creating an inactivated polio vaccine

(IPV). In 1961, Albert Sabin developed an oral polio vaccine (OPV).

Both vaccines have advantages and disadvantages. OPV is affordable

and easy to administer, provides individual protection, decreases

transmission, and—through fecal viral shedding—induces immunity

in nonvaccinees. The main disadvantages of OPV are that it may rarely

cause paralysis (1 case per 2.4 million doses) and that the vaccine virus

may revert to neuropathogenic form if circulating in places with low

vaccination prevalence (see below). OPV is also less efficacious in

locations with unsanitary conditions because of competition with other

enteroviruses. IPV is both safe and efficacious and is preferred to OPV

in industrialized countries. However, it is more costly to produce and

requires administration by injection. In addition, it does not produce

gut immunity and therefore does not contribute to elimination of

transmission in outbreaks.

As mentioned above, the attenuated virus in OPV can mutate and

regain both the neurovirulence and the transmissibility properties

of wild poliovirus, leading to outbreaks of polio in underimmunized

populations. This mutated virus is known as circulating vaccinederived poliovirus (cVDPV). Unfortunately, the current COVID-19

pandemic crisis led the WHO to suspend polio vaccination in all

critical countries, with the consequence that the number of polio cases

has increased substantially—both those caused by wild poliovirus

strains (137 cases in Pakistan and Afghanistan) and those caused by the

vaccine-derived strain (751 cases in 24 countries by the end of

November 2020).

Twenty years after establishment of the aspirational goal of eradicating polio by 2000, a combination of factors, such as civil war, other

violence, conspiracy theories, verticality of programs, a less-thanperfect vaccine, and now the COVID-19 pandemic, has led to a reconsideration of time lines and strategies.

■ MEASLES VIRUS

The virus causing measles (Chap. 205), a serious exanthematic disease,

is an RNA virus of the paramyxovirus family. Measles virus is the most

contagious human pathogen and is particularly lethal in malnourished

or immunocompromised children. In addition to the measles virus,

the genus Morbillivirus includes two similar animal viruses: canine

distemper virus and rinderpest virus. The latter has been now eradicated, thanks to the immunization of cattle. The measles virus evolved

from rinderpest in cattle, probably between the eleventh and twelfth

centuries in the Middle East. Thus, measles originated as a zoonosis.

Through history, measles has wrought havoc in unexposed populations. Indigenous peoples in the Americas were devastated in the

sixteenth century with the arrival of Europeans. The virus requires a

minimal population size of ~250,000 to remain endemic. With increasing birth cohorts and urbanization, measles was a common cause of

death in children during the past two centuries. Before the vaccine

was introduced in 1963, up to 8 million children died from measles

each year. Even by 1980, with a highly efficacious vaccine in place,

2.6 million people died of this preventable disease.

There are no animal reservoirs for measles, the virus is very stable,

and there is a highly efficacious, safe, and affordable vaccine. Therefore,

measles is the ideal candidate for eradication through mass vaccination. If measles had been targeted for eradication instead of polio in

1988, the disease would have been eliminated some time ago.

Measles virus is airborne and can remain suspended in air for hours

indoors after a cough or sneeze. Measles can be transmitted from

4 days before the rash appears to 4 days afterward. The virus causes

immunosuppression, which can last for months or years after infection.

This immune amnesia renders children more vulnerable to other infectious diseases. It is estimated that an index patient can infect as many as

12–18 unprotected people. This number is known as the reproduction

number or Ro. For comparison, the Ro is ~2 for Ebola virus and ~2.5

for SARS-CoV-2.

According to the WHO, there was a vast global resurgence of measles in the past few years, with the highest number of reported cases in

23 years in 2019. That year, nine countries accounted for three-quarters

of the cases reported: the Central African Republic, the Democratic

Republic of the Congo, Georgia, Kazakhstan, Madagascar, North

Macedonia, Samoa, Tonga, and Ukraine. The outbreak of measles in

the Democratic Republic of the Congo is the largest recorded in any

single country in decades, with >300,000 cases and 6500 deaths. Madagascar, Ukraine, and the Philippines were facing large outbreaks in

2020. The fact is that measles outbreaks are occurring in every region

of the world, including in rich countries, as a consequence of years of

declining vaccination coverage. As some experts say, the problem is not

vaccine failure, but failure to vaccinate.

The COVID-19 pandemic has forced many countries to suspend

or postpone vaccination campaigns, including for measles. This tragic

situation will surely contribute to larger measles outbreaks globally.

Another contributing factor is vaccine hesitancy among some groups

of parents (Chap. 3). The false claim that measles vaccination might

be linked to autism fostered a movement against vaccines in general

and measles-containing vaccines in particular. This opposition began

in wealthy countries but is spreading to other regions. During recent

measles outbreaks, antivaccination messages had more online links

than messages favoring vaccination. Understanding the causes behind

decreased vaccination coverage will be critical to the eventual eradication of measles virus.

3718 PART 17 Global Medicine

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. 7). 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

current extremes of life expectancy at birth, with Japan at the high

end (84 years) and Lesotho at the low end (51 years). This 33-year

difference 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, >40 years later and in the

midst 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 movement 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 treatment and prevention activities carried out by specific personnel, a set

of attributes for the way care is delivered, or an approach to organizing

474 Primary Care and Global

Health

Tim Evans, Kumanan Rasanathan

CONTROL OF EMERGING INFECTIOUS

DISEASES

Humans will continue to experience outbreaks of emerging and

reemerging infectious diseases. Emerging diseases will most likely

come from two sources. The first source consists of organisms that

have acquired new genetic materials from other strains of the same

species or from different species altogether. An example is influenza

A virus, in which strains can acquire new genetic material through a

process called reassortment. If the new gene is a hemagglutinin gene,

the resulting reassortant virus will have a new surface hemagglutinin

that is unrecognized immunologically by most human populations.

An interesting case is influenza A H1N1 virus, which emerged in 2009

from the reassortment of H1N1 swine influenza virus with human

seasonal H3N2 influenza virus, North American avian influenza virus,

and Eurasian avian-origin swine influenza viruses. Despite a worldwide pandemic, people born before 1950 were relatively spared because

they had earlier exposure to an H1N1 strain sufficiently similar to provide them with cross-immunity. Another example is E. coli O157:H7,

which acquired a virulence gene from Shigella, probably as the result of

horizontal genetic exchange. The resulting organism and several other

serotypes of E. coli that have acquired the gene constitute the leading

cause of hemolytic-uremic syndrome worldwide. The second source

for emergence of infections consists of existing organisms entering new

ecologic niches and spreading broadly, often through insect vectors,

to immunologically naïve humans—as occurred with WNV and Zika

virus. In a variation on this theme, humans can enter new ecosystems

and become infected with organisms to which they have no immunity.

An organism’s epidemic potential will be determined by whether it is

largely incapable of leaving the human host to continue onward via

human-to-human transmission (e.g., Coccidioides) or can be efficiently

transmitted from human to human (e.g., SARS-CoV-2, HIV, and Ebola

virus).

In its 1994 strategic plan to address emerging infectious disease

threats, the CDC listed four goals: (1) to detect, promptly investigate,

and monitor emerging pathogens, the diseases they cause, and the

factors influencing their emergence; (2) to integrate laboratory science

and epidemiology in order to optimize public health practice; (3) to

enhance communication of public health information about emerging

diseases and ensure prompt implementation of prevention strategies;

and (4) to strengthen local, state, and federal public health infrastructures in order to support surveillance and implement prevention

and control programs. Much of this plan has been implemented. The

concept of “emerging infectious diseases” has been broadly accepted,

and molecular biological methods have improved to the point that, for

example, the SARS coronavirus was completely sequenced in a matter

of days. In addition, there has been an increasing recognition of the

“one health” concept: the nexus among human, livestock, wildlife, and

plant health and the development of surveillance systems to provide

early warnings of emerging and reemerging infections. New vaccines

and new vector-control agents are important promising weapons in the struggle to contain existing diseases; two highly effective

messenger RNA vaccines for SARS-CoV-2 were deployed beginning

in December 2020, Ebola vaccines are being widely employed in the

current outbreak in the Democratic Republic of the Congo, and dengue

vaccine is effective, although only in the United States, its use is limited to children 9–16 years old who have laboratory evidence of prior

dengue infection. Moreover, a new vector-control technique involving

deliberate infection of the Aedes population with Wolbachia, a bacterial

genus that inhibits the transmission of arbovirus from mosquito hosts,

is being evaluated.

The WHO has developed new international health regulations

that are designed, in part, to facilitate the recognition and reporting

of infectious disease threats. However, as evidenced by the current

SARS-CoV-2 pandemic and the 2013–2016 Ebola virus epidemic in

West Africa, additional capacity and new forms of global health governance and response may be required. Clearly, robust, flexible, and

timely responses will be needed to control emerging and reemerging

infections.

■ FURTHER READING

Abede GM: Emerging and re-emerging viral diseases: The case of

coronavirus disease-19 (COVID-19). Int J Virol AIDS 7:067, 2020.

Campbell-Lendrum D et al: Climate change and vector-borne diseases:

What are the implications for public health research and policy?

Philos Trans R Soc Lond B Biol Sci 370:20130552, 2015.

Heymann DL et al: Global health security: The wider lessons from the

west African Ebola virus disease epidemic. Lancet 385:1884, 2015.

Lederberg J et al (eds): Committee on Emerging Microbial Threats to

Health. Emerging Infections. Microbial Threats to Health in the United

States. Washington, DC, National Academy Press, 1992.

Lessler J, Orenstein WA: The many faces of emerging and re-emerging

infectious disease. Epidemiol Rev 41:1, 2019.

Morens DM, Fauci AS: Emerging infectious diseases in 2012: 20 years

after the Institute of Medicine report. mBio 3:e00494, 2012.