The Human Microbiome

3695CHAPTER 471

1950

100

200

300

400 Crohn’s

disease

Multiple

sclerosis

Asthma

Measles

Mumps

Tuberculosis

Hepatitis A

Rheumatic

fever

Type 1

diabetes

0

50

100

Incidence of immune disorders (%)

Incidence of infectious diseases (%)

A 1950 1960 1970 1980 1990 2000 B 1960 1970 1980 1990 2000

FIGURE 471-5 There was an inverse relationship between the incidence of select infectious diseases and the

incidence of autoimmune disorders during the latter half of the twentieth century. A. Relative incidence of prototypical

infectious diseases from 1950 to 2000. B. Relative incidence of select autoimmune disorders from 1950 to 2000. (From

JF Bach: The effect of infections on susceptibility to autoimmune and allergic diseases. N Engl J Med 347:911, 2002.

Copyright © 2002, Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society.)

exposures are required to prevent subsequent disease and that the

“westernization” of society has led to a decrease in such exposures. This

concept is now being applied beyond atopic diseases to other inflammatory and autoimmune diseases and is thought to reflect processes

that occur in later life as well.

■ RELATIONSHIP BETWEEN THE MICROBIOTA AND

SPECIFIC DISEASE STATES

The ideas inherent in the hygiene hypothesis—in sum, that microbial

exposure can affect long-term health outcomes—laid the theoretical foundation for translational microbiome studies. While most

of the studies described earlier sought to describe how the microbiota responds to specific and often transient influences (e.g., a

course of antibiotics, dietary interventions, travel), a multitude of

studies have characterized the microbiota in patients with various

diseases in the hope that a better understanding of the nature of

disease-specific microbial communities will provide insight into disease pathogenesis and potentially uncover novel treatment modalities.

Remarkably, virtually all of these studies have demonstrated differences

between the microbiotas of healthy controls and patients, irrespective

of the specific disease process examined. Although it is difficult to

generalize across all studies, a couple of general themes have emerged.

First, disease states are typically associated with microbiotas that are

less diverse than those of healthy individuals. This loss of diversity

can be measured either as a decrease in the number of species (alpha

diversity; often measured as the number of operational taxonomic units

or amplicon sequence variants, which are the bioinformatic equivalent

of species) or as a reduction in the microbial relatedness of the species

present (beta diversity). Often, both alpha and beta diversity decrease

in the setting of disease. Second, states of inflammation—regardless of

site or underlying disease process—are often associated with a relative

increase in the abundance of the bacterial family Enterobacteriaceae

and a decrease in the abundance of Lachnospiraceae.

Dissecting Correlation and Causality Given that most of these

investigations have been designed as case-control studies, it is difficult

to determine whether microbiologic findings are the cause or the effect

of the disease. Even studies that examine treatment-naïve patients at

the time of initial diagnosis are still confounded by this “chicken or

egg” issue. Moreover, prospective, longitudinal clinical studies—still

rare in the microbiome field—may simply yield correlations between

the microbiome and subclinical disease rather than necessarily proving causality. Experiments in animals—specifically, studies using

gnotobiotic mice (germ-free mice that have been colonized with

specified microbial communities)—have been critical in this regard

as they allow investigation of specific differences in microbial components while controlling for the host’s genetics, diet, and housing

conditions. Moreover, human microbes

can be transplanted into gnotobiotic mice

to permit in-depth mechanistic studies of

how these microbial communities affect

disease pathogenesis. This marriage of

human samples and animal experiments

has facilitated the identification of causal

roles played by some microbes in disease

pathogenesis; these findings provide a

critical proof of concept for the interplay

of the microbiota with human health.

However, the vast majority of microbiome studies are still at the level of correlation. The next several sections describe

the clinical and animal data for many

different disease processes. Given the

voluminous and rapidly changing nature

of this field, it is impossible to cover

all of the disease associations known

to date; rather, the following discussion

represents a combination of the leading exemplars of microbiome data and

nascent areas of significant clinical interest. In all cases, the hope is that

further study of the role of the microbiota will provide novel diagnostics, new therapeutic modalities, and/or additional insight into disease

pathogenesis.

Gastrointestinal Diseases Given that the intestines harbor the

largest number and greatest diversity of organisms in the body, much

work has focused on how the microbiota impacts gastrointestinal

diseases. Even though the luminal surface area of the gastrointestinal

tract is 30–40 square meters (~90% of which is contained within the

small intestine) and features marked anatomic and functional differences that result in many discrete macro- and micro-ecosystems, stool

is often used as a surrogate for the intestinal microbiota given the

relative ease of collecting samples. A few studies that have compared

the microbial profile in stool with the mucosa-adherent organisms

present in biopsy samples have demonstrated that stool is, in fact, a

reasonable proxy for biopsy samples; however, the relative microbial

“noise” present in stool can sometimes overwhelm the “signal,” making

biopsy samples more informative for some scientific questions. The key

issue is to ensure that the biopsy samples evaluated represent relatively

similar intestinal regions, as there are significant differences between

the organisms present in the crypt and the tip of the villus and between

microbes found in the ascending versus the descending colon.

OBESITY Obesity is a worsening epidemic throughout the world, and

multiple studies have linked the composition of the intestinal microbiota

to the development of obesity in animal models and in humans. Indeed,

many of the initial translational microbiome studies performed in mice

at the beginning of the twenty-first century focused on obesity. These

early studies suggested that the ratio of the relative abundance of Bacteroidetes to Firmicutes was lower in obese mice than in control animals.

Moreover, a causal relationship between the microbiota and obesity

was established by the finding that gnotobiotic mice colonized with the

microbiota from obese individuals had more rapid and more extensive

weight gain than gnotobiotic mice colonized with the microbiota from

lean individuals. Biologically, it is posited on the basis of metagenomic

surveys that the obesity-associated microbiome has an increased capacity to harvest energy from the diet. Notably, the relationship between the

Bacteroidetes/Firmicutes ratio and obesity did not hold in initial human

studies; however, the finding that this ratio increased in obese patients

who lost weight while on a fat- or carbohydrate-restricted diet suggested

some generalizability between mice and humans. Beyond this ratio of

major bacterial phyla, obesity was linked to a microbiome with a lower

alpha diversity. Over the past ~15 years, numerous human studies

examining the relationship between the microbiome and obesity have

been completed, all with mixed results. A recent meta-analysis of 10

studies including nearly 3000 individuals revealed an apparent lack of

relationship between the Bacteroidetes/Firmicutes ratio and obesity,

3696 PART 16 Genes, the Environment, and Disease

though there is ~2% lower diversity associated with obesity that is

statistically significant but of unclear biologic significance. This finding

highlights a problem common to microbiome studies: i.e., there is no

sense as to what magnitude of change is biologically meaningful. Ultimately, although murine studies have indicated a causal link between

the microbiota and obesity, the human data are less convincing, and

their significance may be limited because the studies primarily examined only high-level taxonomic information rather than also assessing

transcriptional or metabolic differences.

The rise in obesity has elicited a plethora of ideas about the type of

diet that might be most successful in leading to sustained weight loss.

It has become clear that the same dietary ingredient can have highly

diverse effects on blood glucose measurements in different people and

that this effect is mediated largely by the microbiome. These observations suggest that the “optimal” diet needs to be individualized in

the context of the person’s microbiome, which itself may continue to

change over the course of the diet. An intriguing parallel question is

whether the microbiota may also influence dietary preferences; such

an influence would suggest important feedback loops between the

microbiome and diet.

MALNUTRITION Representing the other end of the metabolic spectrum from obesity, malnutrition is also linked to an altered microbiome. Analysis of Malawian twin pairs (≤3 years of age) who were

discordant for kwashiorkor—a severe form of malnutrition—revealed

that kwashiorkor is associated with a microbiologically “immature”

fecal microbiota that resembles that of a chronologically younger child.

Transplantation of the fecal microbiota from these discordant twins

into gnotobiotic mice that were fed a diet similar in composition to

a typical Malawian diet established that the kwashiorkor-associated

microbiome is causally related to poor weight gain. Subsequent studies

demonstrated these same general trends in malnourished Bangladeshi children. Investigators were able to identify five bacterial species (Faecalibacterium prausnitzii, Ruminococcus gnavus, Clostridium

nexile, Clostridium symbiosum, and Dorea formicigenerans) that—

when administered together as a “cocktail” to mice colonized with a

kwashiorkor-associated microbiome—were able to prevent growth

impairments. Moreover, children with moderate acute malnutrition

fed therapeutic food purposefully designed for its ability to alter the

microbiota in defined manners have altered serum biomarkers consistent with improved growth. These results demonstrate that rationally

designed modulation of the microbiota may lead to improved health

outcomes.

INFLAMMATORY BOWEL DISEASE Ulcerative colitis and Crohn’s disease, the two predominant forms of inflammatory bowel disease (IBD),

are chronic gastrointestinal inflammatory conditions that differ in their

locations and patterns of inflammation (Chap. 326). The following

observations have led to the suggestion that IBD is the result of an

immune response to a dysbiotic microbiota in a genetically susceptible

individual: genes account for only ~20% of susceptibility to IBD (and

many of the relevant genes are related to host–microbe interactions),

antibiotic treatment reduces the clinical severity of disease, and relapses

of Crohn’s disease are prevented by diversion of the fecal stream. While

the microbiota clearly is not the only driver of disease, it is considered

to be an important element. Accordingly, numerous animal and clinical

studies have been designed to tease out the nature of the relationship

between the microbiota and IBD.

Most of these studies have focused on comparing the microbiome’s

composition in IBD patients with that in healthy controls, concentrating on microbial diversity and specific bacterial taxa that are associated

with health or disease. Unfortunately, few, if any, results have been

universally obtained, probably because of differences in study design,

inclusion criteria, and methodology (e.g., the use of stool, rectal swabs,

or biopsy samples; the choice of sequencing primers; the analysis

pipeline). Even with these differences among studies, patients with

IBD have been shown typically to have reduced alpha and beta diversity in their fecal microbiotas. Moreover, Clostridium clusters IV and

XIVa, which are polyphyletic and encompass several different bacterial

families, are generally reduced in patients with IBD. F. prausnitzii is a

notable example from Clostridium cluster IV that is often underrepresented in the stool of patients who have Crohn’s disease, with more

mixed results in biopsy samples. The bacterial family Lachnospiraceae,

which is largely contained in Clostridium cluster XIVa, and other

butyrate-producing organisms are also reduced in the stool of patients

with IBD. Some of these species produce butyrate by using acetate

generated by other members of the microbiome, and some of these acetate-producing species are similarly reduced (e.g., Ruminococcus albus).

These complex interactions and dependencies among bacterial species

pose unique challenges to definitive ascertainment of the cause–effect

relationships between microbes and disease. Even before researchers

were able to assess the entire microbiome at once, they often noted that

patients with Crohn’s disease had a higher representation of adherent

invasive E. coli in the ileal mucosa, an observation consistent with the

increased abundance of Enterobacteriaceae seen in more recent microbiome studies. Beyond bacteria, burgeoning evidence supports a role

for Caudovirales bacteriophages in IBD pathogenesis, though these

findings may merely reflect the underlying dysbiosis related to the loss

of bacterial diversity in IBD. Moreover, some data suggest that IBD

is also associated with fungal dysbiosis; several studies have demonstrated an increased ratio of Basidiomycota to Ascomycota. It is still

unclear whether any of these microbial associations reflect the cause of

IBD or merely serve as biomarkers of disease.

Studies of antibiotic-treated mice and gnotobiotic mice colonized

with IBD-associated microbiotas have been useful in confirming that

the microbiota affects colitis severity. Several bacterial species have

been identified as either promoting colitis in mice (e.g., Klebsiella

pneumoniae, Prevotella copri) or protecting against it (e.g., Bacteroides

fragilis, Clostridium species); however, these organisms do not always

correlate with the taxa identified as differentially abundant across

multiple clinical studies. In contrast, IgA-coated commensal organisms

isolated from patients with IBD promote more severe colitis in mice

than either IgA-uncoated bacteria from patients with IBD or IgAcoated bacteria from healthy controls. These data suggest that functional categorization of the microbiota based on immune recognition

(e.g., IgA coating) may be a useful approach for identifying pathogenic

organisms.

Cardiovascular Disease Inflammation helps drive the pathogenesis of atherosclerosis, and it has long been postulated that microbes

are involved in the atherosclerotic process. Early work demonstrated

that patients with cardiovascular disease have higher titers of antibody

to Chlamydia pneumoniae than control patients, that C. pneumoniae is

present within atherosclerotic lesions, and that C. pneumoniae can both

initiate and exacerbate atherosclerotic lesions in animal models. This

type of analysis has been extended to other bacteria, such as Porphyromonas gingivalis, with the idea that multiple different bacteria may

play some role in the pathogenesis of atherosclerosis.

More recent studies have demonstrated clinical correlations between

serum levels of trimethylamine N-oxide (TMAO) and atherosclerotic

heart disease. Given that red meat, eggs, and dairy products are important sources of carnitine and choline (both precursors of TMAO), it is

not surprising that levels of TMAO are higher in omnivores than in

vegans. Animal studies have confirmed that transfer of the gut microbiota from atherosclerosis-susceptible strains of mice to atherosclerosisresistant animals leads to increased serum levels of TMAO and a

dietary choline-dependent increase in atherosclerotic plaques; this

observation confirms the role of the gut microbiota in the generation

of TMAO and atherosclerosis. Moreover, treatment of atherosclerosissusceptible strains of mice with a structural analogue of choline that

inhibits the first enzymatic step in TMAO formation leads to decreased

circulating TMAO levels and, more importantly, restrains macrophage

foam-cell formation and atherosclerotic lesion development. In a

study of >4000 patients, plasma TMAO levels were also predictive

of incident thrombosis risk (myocardial infarction, stroke). Gnotobiotic animals were used to demonstrate that this risk was dependent

on the microbiota; although eight bacterial taxa were identified as

being associated with both plasma TMAO levels and thrombotic risk,

organisms with choline-utilization genes that represent the first step

The Human Microbiome

3697CHAPTER 471

of TMAO production were not more abundant in animals at greater

risk for thrombosis. This discrepancy highlights the complexity of the

microbiota and suggests that other aspects of the overall dynamics of

the microbial community may be in play.

Oncology Recent studies exploring the link between the microbiota

and cancer have demonstrated that specific members of the microbiota

can affect treatment efficacy in both a positive and a negative manner.

For example, therapy with antibody to programmed cell death ligand

1 (anti-PD-L1) has proven highly effective for a number of different

cancers (Chap. 73); however, a significant proportion of patients do not

respond even when their tumors have high PD-L1 expression levels, a

prerequisite for this type of checkpoint blockade inhibition. Three groups

have independently performed clinical studies—sometimes coupled

with gnotobiotic mouse experiments to verify causal relationships—to

demonstrate that specific bacteria can potentiate checkpoint blockade

inhibition in melanoma, non-small-cell lung cancer, and renal cell

carcinoma. Intriguingly, these groups identified different bacteria

(Bifidobacterium, Faecalibacterium, and Akkermansia species) as being

associated with the anticancer effects, even when the same oncologic

process was being studied. The biologic factors driving these differences are not yet clear but may relate to differences in adjunctive therapies, geography, and/or other as-of-yet unidentified factors. Although

these seemingly disparate findings raise concern about the generalizability of microbiome studies, it may be that identifying relevant bacterial species—as opposed to their bioactive molecules—does not offer

sufficient granularity for comparison across studies.

In a separate set of studies, the efficacy of therapy with antibody

to cytotoxic T lymphocyte–associated antigen 4 (anti-CTLA-4) was

associated with T-cell responses specific for either Bacteroides thetaiotaomicron or B. fragilis. In particular, administration of B. fragilis to

germ-free or antibiotic-treated mice restored the normally absent

anticancer response to anti-CTLA-4 therapy. While these examples

demonstrate potentiation of anticancer therapies by the microbiota,

other therapies can be antagonized. Some cancers, such as pancreatic

ductal adenocarcinoma, contain intratumoral bacteria, particularly

Gammaproteobacteria, that can metabolize the chemotherapeutic

agent gemcitabine and thereby contribute to the drug resistance of

these tumors. Overall, these examples highlight the microbiota’s critical impact—both direct and indirect—on the efficacy of drugs. Many

other notable examples have been described (e.g., involving cyclophosphamide, digoxin, levodopa, and sulfasalazine), and many more likely

remain to be discovered.

The application of microbiome science to hematopoietic stem cell

transplantation (HSCT) is an area of expanding interest, particularly

given the significant morbidity and mortality related to graft-versus-host

disease (GVHD). In light of studies in the 1970s showing that germ-free

mice developed less frequent and less severe gut GVHD than wild-type

mice, clinicians began to use antibiotics to decontaminate the gut of

patients undergoing HSCT. This decontamination approach yielded

mixed results, probably because of differences in the antibiotic regimens

used. The natural history of patients undergoing allogeneic HSCT

includes a substantial loss of diversity in the fecal microbiota, intestinal

domination (≥30% abundance in the fecal microbiota) by Enterococcus species and other pathogens, and increased mortality. Moreover,

a retrospective analysis of ~850 patients undergoing allogeneic HSCT

revealed that receipt of imipenem-cilastatin or piperacillin-tazobactam

for neutropenic fever was associated with increased GVHD-related

mortality at 5 years; this observation suggested that specific bacteria

may help protect against GVHD-related mortality. More detailed analyses revealed an association between the abundance of Blautia species

and protection against GVHD and mortality, though this correlation is

still being examined with regard to its causal relationship. Despite significant interest in examining these microbial relationships with HSCT,

little has yet been studied in the context of solid organ transplantation,

which likely represents the next frontier of transplantation-related

microbiome investigation.

Autoimmune Diseases The dramatic rise in the incidence of

many autoimmune diseases over the past few decades has been far

more rapid than can be explained simply by genetic factors (Fig. 471-5).

It is increasingly thought that environmental triggers, including the

microbiome, are partially responsible for the development of these

autoimmune diseases.

TYPE 1 DIABETES Type 1 diabetes (T1D) is an autoimmune disorder

characterized by T cell–mediated destruction of insulin-producing

pancreatic islets (Chap. 403). There is a clear genetic predisposition for

the disease: ~70% of patients with T1D have human leukocyte antigen

(HLA) risk alleles. However, only 3–7% of children with these risk

alleles actually develop disease, an observation that suggests a role for

other environmental factors. Studying a prospective, densely sampled,

longitudinal cohort of at-risk, HLA-matched children from Finland

and Estonia, investigators detailed changes in the microbiota prior to

development of disease. Although only 4 of the 33 children studied

developed T1D within the time frame of the study, a marked decrease

of ~25% in alpha diversity occurred after seroconversion but before

disease diagnosis. The low number of cases in this study unfortunately

precluded identification of any specific disease-associated taxa. A

follow-up study compared the microbiomes of a larger cohort of these

high-risk northern European children with those of low-risk Russian

children who lived in geographic proximity. Bacteroides species were

more abundant in the high-risk group than in the low-risk group, particularly at early ages. This difference was postulated to be associated

with an altered structure of the bacterial lipopolysaccharide to which

children were exposed at a young age. It was further suggested that

Bacteroides-derived lipopolysaccharide was not able to provide the

immunogenic stimulus necessary to prevent T1D. These two studies

offer attractive—though logistically complicated—options for future

clinical investigations aimed at exploring the role of the microbiome.

The first approach—longitudinally following individuals who are at

high risk for a given disease—may provide insight into host–microbe

relationships by mapping temporal changes in the microbiome with

disease onset. An important caveat with this type of study, though, is

that the associations identified may reflect preclinical disease rather

than specifically indicating causality for any observed changes. The

second approach illustrates how careful selection of study participants

may offer an opportunity to uncover more meaningful associations

that can subsequently be experimentally verified.

RHEUMATOID ARTHRITIS Similar to many other autoimmune diseases, rheumatoid arthritis (RA) is a multifactorial disease that comes

to clinical attention after an environmental factor triggers symptoms

in an individual with preexisting autoantibodies. Multiple lines of

evidence support the notion that RA pathogenesis is reliant on the

microbiota, including the findings that germ-free mice do not develop

symptoms in several RA models and that antibiotic treatment of mice

mitigates against RA development. Several taxa (e.g., Bacteroides species, Lactobacillus bifidus, and segmented filamentous bacteria) have

been implicated in promoting RA in murine models, and analysis of

the fecal microbiota of patients with newly diagnosed RA has indicated

that P. copri is a biomarker of disease. That this association with P. copri

does not exist for chronic, treated RA or for psoriatic arthritis suggests

some specificity for new-onset RA. A major limitation of this approach

is that the identified association is shown to be a biomarker of disease

(and, in this case, potentially of response to treatment), but no added

insight is gained into a possible causal relationship between P. copri and

RA. In fact, many of the patients with new-onset RA had no Prevotella

detected, and several of the healthy controls had significant levels of

Prevotella. The lack of a strict concordance between the presence (or

absence) of a specific taxon and a given disease state argues against a

possible causal role.

MULTIPLE SCLEROSIS Epidemiologic studies of twin pairs and at-risk

individuals moving between high- and low-risk geographic areas

indicate that genetics plays a minor component in multiple sclerosis

(MS) susceptibility relative to environmental factors. For example, in

monozygotic twin pairs in which one sibling has MS, the other sibling

also develops MS in only ~30% of cases. Although MS is a disease of

the central nervous system (CNS), there is growing evidence of a link

between MS and the microbiota, specifically that of the gut. Germ-free

3698 PART 16 Genes, the Environment, and Disease

animals and antibiotic-treated animals display reduced disease incidence and severity in an MS model. Similarly, some clinical studies

suggest improved disease outcomes in patients with MS who have been

treated with minocycline, while patients treated with long-term penicillin appear to have an increased disease risk. Although several studies

have compared the fecal microbiotas of healthy controls to those of

patients with MS, these studies have all been relatively small and have

yielded few results (if any) that are common throughout. Although

work relating the microbiome to MS is ongoing, it has opened the

door to exploring this link with other neurologic diseases. Already,

there are animal data demonstrating links between the microbiota

and both Parkinson’s disease and autism, and there are clinical data

assessing fecal microbiomes in relation to a variety of neurologic conditions. It is not quite clear how the gut microbiota is communicating

with the CNS—i.e., whether communication takes place via bacterial

metabolites that travel in the bloodstream and cross the blood-brain

barrier, via migration of whole organisms into the CNS, or via feedback

through the vagus nerve. Emerging data suggest that a subset of enteroendocrine cells in the intestinal epithelium is synaptically connected

to the CNS, which may provide another means for the gut microbiota

to impact neurologic function. Although our understanding of this

brain-gut axis is still in its infancy, research in this area has elicited

tremendous excitement as a tractable approach to potential treatments

for these challenging diseases.

Atopic Diseases The incidence and prevalence of allergic diseases

continue to steadily increase, as do more severe clinical presentations.

Life-threatening food allergies are now such a public health issue that

nut-free classrooms are the norm in many cities. The development of

allergic diseases often follows a stereotyped progression that begins

with atopic dermatitis (AD) and continues, in order, with food allergy,

asthma, and allergic rhinitis. The microbiome has been linked to all of

these conditions and has the potential to modulate effects anywhere

along this spectrum.

ATOPIC DERMATITIS The skin is the largest organ in the body, and

its different anatomic sites (e.g., antecubital fossa, volar forearm, alar

crease) represent distinct ecologic niches and harbor unique microbial

communities. Moreover, given that the skin serves as a critical interface between the body and the external environment (e.g., microbes),

it must be able to respond to unwanted microbes with an adequate

immune response. AD is an inflammatory skin disorder involving

immune dysfunction and a dysbiotic skin microbiota that is typically

marked by greater abundances of Staphylococcus aureus and a lesser

degree of bacterial diversity. Effective treatment of AD does not require

complete elimination of S. aureus but is associated with restoration of

the normal level of diversity. It is likely that this increase in bacterial

diversity reestablishes normal immune homeostasis in the skin; specific

members of the skin microbiota have been shown to induce protective

skin-restricted immune responses. Coagulase-negative staphylococci

(CoNS; primarily S. epidermidis and S. hominis) obtained from lesional

and nonlesional skin of patients with AD were functionally screened

and compared to CoNS from healthy controls; AD-lesional CoNS

were much less often able to produce antimicrobial peptides (lantibiotics) directed against S. aureus. To demonstrate that these lantibioticproducing CoNS were biologically relevant, they were incorporated

into a lotion and applied to the arms of patients with AD. Surprisingly,

a single application of the probiotic-laced lotion led to a decrease in

the abundance of S. aureus recovered; no such decrease was observed

when lantibiotic-negative strains were used. The authors of this study

did not specifically comment on the clinical improvement of the AD

lesions. Nevertheless, this is one of a limited number of studies that is

beginning to extend microbiome-related findings into clinical trials.

ASTHMA Asthma is characterized by the clinical triad of airflow

obstruction, bronchial hyperresponsiveness, and inflammation in the

lower respiratory tract. Although the long-standing dogma was that

the lungs are sterile, there is now convincing evidence for a constant

ebb and flow of bacteria within the lower airways. In healthy states, the

mucociliary escalator continually eliminates these bacteria soon after

they land in the airways; in disease states (e.g., cystic fibrosis, chronic

obstructive pulmonary disease), these bacteria establish long-term

colonization of the airways and influence disease pathogenesis. In

asthma specifically, both fecal and airway microbes have been linked

to clinical outcomes.

Early studies of the microbiome’s influence on asthma used

culture-based methods to assess the hypopharyngeal microbiota of

asymptomatic 1-month-old infants. Intriguingly, in one study, early-life

colonization with S. pneumoniae, Haemophilus influenzae, Moraxella

catarrhalis, or a combination of these organisms—but not S. aureus—

was significantly associated with persistent wheeze and asthma at

5 years of age. Eosinophilia and total IgE levels at 4 years of age were

also increased in children who were neonatally colonized with these

organisms. Although this study examined a fairly focused set of bacteria, it laid the experimental groundwork indicating that early-life

microbial exposures influence subsequent development of asthma.

A later longitudinal investigation of the fecal microbiota in a generalpopulation birth cohort of >300 children demonstrated that lower

abundances of the genera Lachnospira, Veillonella, Faecalibacterium,

and Rothia at 3 months of age were associated with an increased risk

for development of asthma. The fact that these bacterial changes were

no longer apparent when the children were 1 year of age is consistent

with the notion that microbial exposures early in life are important to

disease pathogenesis later in life. Transplantation of stool samples from

3-month-old children at risk for asthma into gnotobiotic mice resulted

in significant airway inflammation in a murine model of asthma; preand postnatal exposure of mice to a four-species cocktail (F. prausnitzii,

Veillonella parvula, Rothia mucilaginosa, and Lachnospira multipara)

inhibited airway inflammation, with a marked reduction in neutrophil

numbers in bronchoalveolar lavage fluid. These data suggest that earlylife modulation of the microbiome may be an effective strategy to help

prevent asthma, though the specific logistics (e.g., strains, dose, timing

of exposure, patient selection) remain to be clarified.

Infectious Diseases The increased susceptibility of antibiotictreated mice to infection with a wide range of enteric pathogens was

initially observed in the 1950s and led soon thereafter to the concept

of colonization resistance, which holds that the normal intestinal microbiota plays a critical role in preventing colonization—and therefore

disease production—by invading pathogens. Seminal work in the

1970s demonstrated that this protection is largely reliant on anaerobic

gram-positive organisms, and the subsequent half-century has been

spent trying to identify the specific microbes involved. Although much

of the work relating the microbiota to infection has focused on enteric

pathogens, the intestinal microbiota has also been clearly linked to

bacterial pneumonia in mouse models, and changes in the microbial

composition of the gut have been causally related to changes in the

severity of disease. Although this gut-lung axis clearly exists in animals,

its relevance in humans is still unclear. Several groups are beginning to

study the human lung microbiome in the context of pneumonia and

tuberculosis. Moreover, the relationships between the microbiota and

both systemic infections (e.g., HIV infection, sepsis) and the response

to vaccination are starting to be explored.

ENTERIC INFECTIONS Clostridium difficile infection (CDI) represents

a growing worldwide epidemic and is the leading cause of antibioticassociated diarrhea (Chap. 134). Roughly 15–30% of patients who are

successfully treated for CDI end up with recurrent disease. The strong

association between antibiotic exposure and CDI initially raised the

idea that the microbiota is inextricably linked to acquisition of disease,

presumably because of the loss of colonization resistance. Consistent

with the epidemiologic data, characterization of the fecal microbiota of patients with CDI revealed that it is a markedly less diverse,

dysbiotic community. Fecal microbiota transplantation (FMT)—the

“transplantation” of stool from a healthy individual into patients with

disease—was successfully used in the 1950s to treat four patients with

severe CDI and has recently been demonstrated in numerous studies

to be an effective therapy for recurrent CDI, with clinical cure in

85–90% of patients (as detailed below). Thus, FMT for recurrent CDI

has become the “poster child” for the idea that microbiome-based

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3699CHAPTER 471

therapies may transform the management of many diseases previously

considered to be refractory to medical therapy. Although FMT is

agnostic as to the underlying mechanism of protection, work is ongoing to identify specific microbes and host pathways that can protect

against CDI. Studying mice with differential susceptibilities to CDI

due to antibiotic-induced changes in their microbiota, investigators

identified a cocktail of four bacteria (Clostridium scindens, Barnesiella

intestihominis, Pseudoflavonifractor capillosus, and Blautia hansenii)

that conferred protection against CDI in a mouse model. Intriguingly,

treatment of mice with just C. scindens offered significant, though not

complete, protection in a bile acid–dependent manner. Clinical data

from patients who underwent HSCT also associated C. scindens with

protection from CDI, an observation that suggests the possibility of

translating these findings from mice to humans. This study provides

another example of the identification of relevant bacterial factors

through examination of microbial differences in populations that differ

in disease risk.

Microbiome-related changes associated with Vibrio cholerae infection include a striking loss of diversity (largely due to V. cholerae

becoming the dominant member of the microbiota) and an altered

composition that rapidly follows the onset of disease. These changes,

which occur in a reproducible and stereotypical manner, are reversible

with treatment of the disease. This recovery phase involves a microbial succession that is similar to the assembly and maturation of the

microbiota of healthy infants. In addition to V. cholerae, streptococcal

and fusobacterial species bloom during the early phases of diarrhea,

and the relative abundances of Bacteroides, Prevotella, Ruminococcus/

Blautia, and Faecalibacterium species increase during the resolution

phase and mark the return to a healthy adult microbiota. Analysis of

these microbial changes occurring in patients with cholera and in healthy

children led to the selection of 14 bacteria that were transplanted into

gnotobiotic mice, which were then challenged with V. cholerae. Bioinformatic analysis of specific taxa changing during cholera determined

that Ruminococcus obeum restrained V. cholerae growth. Subsequently,

this relationship was experimentally confirmed, and the R. obeum

quorum-sensing molecule AI-2 (autoinducer 2) was found to be responsible for restricting V. cholerae colonization via an unclear mechanism.

These studies highlight the potential for use of microbiome-based

therapies to prevent and/or treat infectious diseases. Moreover, they

suggest that temporal analysis of longitudinal microbiome data may be

an effective strategy for identifying microbes with causal relationships

to disease.

HIV INFECTION The augmentation of HIV pathogenesis by some

viral, bacterial, and parasitic co-infections suggests that a patient’s

underlying microbial environment can influence the severity of HIV

disease. Moreover, it has been hypothesized that the intestinal immune

system plays a significant role in regulating HIV-induced immune

activation; this seems particularly likely since the intestines are an early

site for viral replication and exhibit immune defects before peripheral

CD4+ T-cell counts decrease. Several studies have examined the intestinal microbiotas of HIV-infected individuals. Initial studies performed

in nonhuman primates infected with simian immunodeficiency virus

found no alteration in the bacterial components of the fecal microbiota; however, there were profound changes in the enteric virome.

In contrast, many recent studies exploring this issue in patients have

identified substantial differences in the HIV-associated fecal microbiota that correlate with systemic markers of inflammation. Curiously,

these microbial changes do not necessarily normalize with antiretroviral therapy; this finding suggests that the microbiota may have some

“memory” of the previously high HIV loads and/or that HIV infection

helps reset the “normal” microbiota. This memory-like capacity of the

microbiota has been demonstrated in animal models in the context of

other infections and in response to dieting.

Given that the majority of new HIV transmission events follow heterosexual intercourse, there has been significant interest in examining

the relationship between the vaginal microbiota and HIV acquisition.

A longitudinal study of South African adolescent girls who underwent high-frequency testing for incident HIV infection facilitated

the identification of bacteria that were associated with reduced risk

of HIV acquisition (Lactobacillus species other than L. iners) or with

enhanced risk (Prevotella melaninogenica, Prevotella bivia, Veillonella

montpellierensis, Mycoplasma, and Sneathia sanguinegens). In mice

inoculated intravaginally with Lactobacillus crispatus or P. bivia, the

latter organism induced a greater number of activated CD4+ T cells

in the female genital tract, a result suggesting that the increased risk

of HIV acquisition associated with P. bivia may be secondary to the

increased presence of target cells. In a separate study, the composition

of the vaginal microbiota was shown to modulate the antiviral efficacy

of a tenofovir gel microbicide. Although tenofovir reduced HIV acquisition by 61% in women who had a Lactobacillus-dominant vaginal

microbiota, it reduced HIV acquisition by only 18% in women whose

vaginal microbiota comprised primarily Gardnerella vaginalis and

other anaerobes. This difference in efficacy was due to the ability of

G. vaginalis to metabolize tenofovir faster than the target cells can take

up the drug and convert it into its active form, tenofovir diphosphate.

These findings illustrate how microbial ecology can be an important

consideration in choosing effective treatment regimens.

RESPONSE TO VACCINATION Second only to the provision of clean

water, vaccination has been the most effective public health intervention in the prevention of serious infectious diseases. Its effects are

mediated by antigen-specific antibodies and, in some cases, effector

T-cell responses. Although vaccines are clearly effective on a population scale, the magnitude of the immune response to vaccines can vary

among individuals by tenfold to a hundredfold. Although many factors

(e.g., genetics, maternal antibody levels, prior antigen exposures) can

affect vaccine immunogenicity, the microbiota is now recognized as

another important factor. Analysis of the fecal microbiotas of ~50

Bangladeshi children identified specific taxa that exhibited positive

associations (e.g., Actinomyces, Rothia, and Bifidobacterium species)

and negative associations (e.g., Acinetobacter, Prevotella, and staphylococcal species) with responses to vaccines against polio, tuberculosis (bacille Calmette-Guérin), tetanus, and hepatitis B. A study of

infants from Ghana revealed an inverse relationship between the fecal

abundance of Bacteroidetes and a response to the rotavirus vaccine.

Moreover, the nasal microbiota has been implicated as a factor that

contributes to the IgA response to live, attenuated influenza vaccines.

These correlations based on clinical data have been partially confirmed in animal studies. The best example is the demonstration that

the responses to non-adjuvanted viral subunit vaccines (inactivated

influenza and polio vaccines) are reliant on the microbiota, whereas

the responses to live or adjuvanted vaccines (live attenuated yellow

fever, Tdap/alum, an HIV envelope protein/alum vaccine) are not. A

causal role for the microbiome influencing vaccine-induced immunity

in humans was demonstrated by comparing microneutralization titers

following the inactivated influenza vaccine in individuals treated with

or without antibiotics, although an antibiotic-dependent effect was

only present in subjects who had low levels of preexisting immunity

to influenza. These data suggest that the microbiota may serve as an

adjuvant for certain vaccine types and in naïve populations. Confirmation of these findings in clinical settings may suggest ways to improve

vaccine efficacy in the future.

MECHANISMS OF MICROBIOME-MEDIATED

EFFECTS

As highlighted in the examples above, numerous associations have

been made between the microbiome and various disease states. These

correlations have often been established at broad taxonomic levels,

with little or no insight into causality. Given that most clinical studies

of these relationships have a fairly small sample size (often <100) and

are simultaneously comparing numerous variables (i.e., each of the

bacterial species in the microbiota is effectively a different feature being

compared), many of these studies may not be adequately powered and

therefore may yield false-positive results. Testing of these correlations

in animal models of disease has been critical in demonstrating a causal

relationship between microbes and specific phenotypes. Because

microbiome-wide association studies typically result in a long list of

3700 PART 16 Genes, the Environment, and Disease

bacterial taxa that are correlated with a disease, it has been challenging

to know which organism to test further in mechanistic studies. Moreover, even if a specific bacterial species is identified in these analyses,

there is potentially enough strain-to-strain variation that the “functional” isolate may need to be recovered from the individuals studied;

a publicly available representative of the species may not confer the

same phenotype.

Despite all these difficulties, a handful of specific microbes have

now been linked to disease effects; some examples have been mentioned above. The next layer of challenges relates to identification

of the specific mechanisms that underlie these causal relationships.

Successes along these lines have been more limited, but approaches

are being developed to tackle the issue of defining specific bacterial

factors and metabolites that are responsible for the phenotypic changes.

Complicating factors are that many organisms, particularly those in

the phylum Firmicutes, are not readily genetically tractable and that

many of the phenotypes are not easy to assess with high-throughput

screening.

■ BACTERIAL FACTORS

B. fragilis polysaccharide A (PSA) is perhaps the best-studied

commensal-derived molecule that has been demonstrated to influence

disease outcomes in mouse models. PSA—one of at least eight capsular polysaccharides expressed by B. fragilis—has a unique zwitterionic

structure that incorporates both a positive and a negative charge within

each repeating unit. Studies in which mice have been treated either with

isogenic strains of B. fragilis that differ in PSA expression or with purified

PSA have shown that PSA confers protection—prophylactically and therapeutically—against experimental colitis and MS. PSA is recognized by

Toll-like receptor 2 on antigen-presenting cells, particularly plasmacytoid dendritic cells, and—in the setting of inflammation—induces

interleukin 10 (IL-10)–producing regulatory T cells (Tregs) that help

restrain inflammation.

B. fragilis is also the source of the only other microbiota-based bacterial factor identified thus far: an immunomodulatory glycosphingolipid that affects the numbers of invariant natural killer T (iNKT) cells.

It is not clear whether these glycosphingolipids activate or inhibit iNKT

cells; results have been discordant, probably because different glycosphingolipid species have been tested. Analysis of a specific purified

glycosphingolipid (Bf717) demonstrated that it inhibits endogenous

iNKT cell agonists in vitro and in vivo. Treatment of neonatal mice

with Bf717 leads to a decreased number of colonic iNKT cells in adulthood and to improved outcomes in a model of colitis.

■ BACTERIAL METABOLITES

The use of mass spectrometry to detect and profile tens of thousands

of different metabolites present in different bodily fluids has offered

the promise of deeper insight into microbially mediated processes that

underlie disease susceptibility. However, the fact that the overwhelming majority of these metabolites are not annotated, coupled with the

sheer volume of data generated, has so far limited the general utility

of these untargeted approaches. Instead, interest in more targeted

approaches has increased, with a current emphasis on examining the

role of short-chain fatty acids (SCFAs) and bile acids.

Short-Chain Fatty Acids Several groups have demonstrated

that SCFAs, the intestinal levels of which are largely determined

by bacterial metabolism, are important for the induction of Tregs,

though there is not agreement on which specific SCFA (propionate,

acetate, or butyrate) is most relevant. Wild-type mice colonized with

bacteria known to induce colonic Tregs have elevated cecal levels of

SCFAs. Colonization with any of three Bacteroides species (B. caccae,

B. massiliensis, and B. thetaiotaomicron) increases levels of acetate and

propionate, whereas colonization with Parabacteroides distasonis or

a mix of 17 human-derived Clostridium species elevates levels of all

three SCFAs. In all of these cases, though, the SCFAs inhibit histone

deacetylase, with a consequent increase in Foxp3 expression. Notably,

microbe-induced SCFA production has not been shown to be critical

for Treg induction by any of these organisms. In contrast, there appears

to be no correlation between SCFA levels and Treg numbers in mice

monocolonized with various Treg-inducing bacterial species. Taken

together, these data suggest important heterogeneity in the mechanisms underlying Treg development and do not rule out the possibility

of other, redundant mechanisms for Treg induction. In addition to

effects on Tregs, SCFAs also promote the epithelial barrier, impact

cell proliferation (directionality depends on the specific cell type and

SCFA), regulate host metabolism, and provide an energy source to

colonocytes.

Bile Acids Bile acids are produced in the liver but then are metabolized by intestinal bacteria to form deconjugated and secondary bile

acids. These microbially produced bile acid profiles act through complex signaling pathways to balance the metabolism of lipids and carbohydrates and to affect immune responses. Therefore, bile acids are now

being investigated as microbial metabolites that are critical to maintaining human health. As mentioned above, C. scindens helps protect

mice against CDI through a bile acid–dependent process. Alterations

in bile acid profiles due to underlying microbial dysbiosis have also

been associated with hepatic and colonic inflammation, hepatic cellular carcinoma, colorectal cancer, and impaired gut motility. Almost all

of these relationships have been documented at the level of correlation

and, at best, reflect a partial change in phenotype in the setting of bile

acid sequestrants (e.g., cholestyramine). Work is ongoing to determine

causal relationships between bacterial metabolism of bile acids and

changes in host physiology, though the most definitive evidence is that

microbe-produced bile acid metabolites influence Treg homeostasis.

Other Bacterial Metabolites Although most work has thus far

focused on SCFAs and bile acids, a few notable examples of other

bacterial metabolites have been implicated in maintaining health.

The microbiota metabolizes tryptophan into various products (e.g.,

kynurenine, indole and its derivatives) that influence immune function,

metabolic diseases, and neuronal function, among other things. Taurine enhances NLRP6 inflammasome–induced colonic IL-18 secretion,

while histamine, spermine, and putrescine suppress IL-18 secretion.

Desaminotyrosine produced by Clostridium orbiscindens confers protection from influenza by inducing type I interferon activity. In both

of these cases, the microbiota was initially shown to influence the phenotype, with either untargeted metabolomics or a more targeted screen

indicating a potential role for the indicated metabolites. Given the

thousands of different bacterial metabolites throughout the body, many

more metabolites will undoubtedly be linked to health and disease.

MOVING MICROBIOME SCIENCE FROM

BENCH TO BEDSIDE

The numerous microbiome–disease associations identified thus far

have generated a great deal of hope that understanding the relevant

microbe–host interactions will open the door to unlimited therapeutic

applications. Microbiome-based therapies offer several potential benefits. Patients often view such treatment as more “natural” than conventional drug therapy and are therefore more likely to comply with it.

Biologically, microbiome-based therapies are more likely to address one

of the root causes of disease (microbial dysbiosis) rather than simply

affecting the downstream sequelae. Finally, a given microbiome-based

therapy may serve as a “polypill” that is effective against several different

diseases stemming from similar microbial changes. Despite tremendous

interest in therapeutically exploiting the microbiome, there have thus

far been few clinical successes along these lines.

The most successful therapeutic application of microbiome science

has been the use of FMT, particularly for CDI. As mentioned earlier,

FMT involves “transplanting” stool from a healthy individual to a diseased patient, with the idea that the “healthy” microbiota will correct

whatever derangement may exist in the ill patient and therefore will

alleviate symptoms. Fundamentally, this notion is agnostic as to the

specific microbial dysbiosis and holds that any healthy microbiota will

be curative. The idea of FMT dates back to at least the fourth century,

when traditional Chinese doctors used a “yellow soup” (fresh human

fecal suspension) to successfully treat food poisoning and severe

The Human Microbiome

3701CHAPTER 471

diarrhea. The continued use of FMT through the centuries for the

treatment of diarrheal illnesses in both humans and animals, along

with the growing appreciation in recent years of the importance of the

microbiota, laid the groundwork for using FMT to treat CDI. Since the

first major prospective trial assessing FMT for recurrent CDI in 2013,

most of the numerous studies of FMT for CDI have demonstrated

remarkable efficacy, with an average clinical cure rate of ~85%. The

donor stool can be fresh or frozen (use of the latter allows biobanking

of samples from a limited number of prescreened donors) and can be

administered via nasogastric tube, nasoduodenal tube, colonoscopy,

enema, or oral capsules; the cure rate is slightly higher with lower-gastrointestinal administration than with upper-gastrointestinal treatment.

The optimal screening, preparation, and concentration of infused

donor stool have not yet been determined, and there have been cases

of antimicrobial-resistant pathogens transmitted by FMT that have led

to mortality. The most common adverse effects of FMT include altered

gastrointestinal motility (with constipation or diarrhea), abdominal

cramps, and bloating, all of which are generally transient and resolve

within 48 h. Although controlled studies of the use of FMT in immunosuppressed patients do not yet exist, meta-analyses of case reports

and case series have found no serious FMT-related adverse events in

>300 immunocompromised patients.

The successful use and the favorable short-term safety profile of

FMT for CDI have led to its expanded application for other indications.

At the end of 2020, >350 trials (listed at ClinicalTrials.gov) were investigating the efficacy of FMT for a range of indications, including CDI,

IBD (ulcerative colitis and Crohn’s disease), obesity, eradication of

multidrug-resistant organisms, anxiety and depression, cirrhosis, and

type 2 diabetes. The few published studies regarding indications other

than CDI have generally included small sample sizes and have offered

mixed results. In contrast to the successes in CDI, the results have been

more varied for patients with IBD, which is perhaps the second-beststudied indication. It is not clear whether these discrepancies are due

to heterogeneity in recipients (e.g., in terms of underlying disease

mechanisms or endogenous microbiotas), the donor material, and/

or the logistical details of FMT administration (e.g., route, frequency,

dose). However, these results demonstrate that—under the right

circumstances—modulation of the microbiota can be an effective

therapy for IBD.

Although FMT offers an important proof of concept that

microbiome-based therapies can be effective, treatment is difficult

to standardize across large populations because of variability among

stool donors and among the endogenous microbiotas of recipients.

In addition, FMT is fraught with safety concerns, and its mechanisms

of action are unclear. FMT likely represents the first generation of

microbiome-based therapies; subsequent generations will include the

use of more refined bacterial cocktails, single strains of bacteria, or

bacterial products and/or metabolites as the therapeutic intervention.

The field of probiotics has a complicated history: many different strains

have been tested against a multitude of diseases. Several meta-analyses

have combined results across bacterial strains and/or disease indications and have generally concluded that the data are not yet convincing

enough to support the use of the tested regimens. It should be noted

that the tested organisms have been chosen mainly on the basis of

their presumed safety profile rather than in light of a plausible biologic

link to disease. The hope is that more focused, mechanistic microbiome studies will identify specific commensal organisms—and their

underlying mechanisms of action—that are involved in disease pathogenesis and that will serve as the basis for the next wave of rationally

chosen probiotics, a few of which are currently in clinical trials. The

main hurdle in this endeavor has been identifying specific microbes

that are causally related to protection from disease.

PERSPECTIVE

The medical view of microbes has changed radically, moving from the

early-twentieth-century notion that we are engaged in a constant struggle with microbes—an “us-versus-them” mentality that focused on the

necessity of eradicating bacteria—to the more recent understanding

that we live in a carefully negotiated state of détente with our commensal organisms. Instead of holding a simple view of microbes as enemies

to be eliminated with antibiotics, scientists are increasingly recognizing

the critical role these organisms play in maintaining human health;

loss of these host–microbe interactions in the increasingly sterile

environment typical of Western civilization may have predisposed to

the increased incidence of autoimmune and inflammatory diseases.

The field of microbiome research has made great strides over the past

decade in cataloguing the normal microbiota and is now on the cusp of

being able to identify clinically actionable microbe–host relationships.

The recent explosion of “–omics” technologies (e.g., metagenomics,

metatranscriptomics, metabolomics) has enabled the generation of

vast amounts of data, but it is not yet clear how best to integrate data

sets in order to gain useful insights into host–microbe relationships.

The use of FMT has demonstrated that modulation of an individual’s

microbiota can effectively treat certain diseases; however, models

with which to predict specifically how a microbiota will change after

modulation—and what potentially untoward effects these changes

might have—are still lacking. Implicit in this limitation is our ignorance about what microbial configuration is optimal and how a given

microbiota should be rationally altered to obtain an ideal outcome.

Despite initial hyperbolic hype and a few false starts, microbiome

research now stands at the forefront of an ability to treat the fundamental basis of many diseases. As the field continues to mature, it will need

to move beyond correlations and address causation. The identification

of causal microbes and their mechanisms of action will create a “microbial toolbox” from which relevant bioactive strains can be chosen on

a per-patient basis to correct specific underlying microbial dysbioses.

In the near future, our knowledge base regarding the microbiome and

its relationship to health and disease will be robust enough that this

information can be applied in making important treatment decisions.

■ FURTHER READING

Goodrich JK et al: Conducting a microbiome study. Cell 158:250,

2014.

Human Microbiome Project Consortium: Structure, function and

diversity of the healthy human microbiome. Nature 486:207, 2012.

Lynch SV, Pederson O: The human intestinal microbiome in health

and disease. N Engl J Med 375:2369, 2016.

Rajilic’-Stojanovic’ M, deVos WM: The first 1000 cultured species

of the human gastrointestinal microbiota. FEMS Microbiol Rev

38:996, 2014.

Schmidt TSB et al: The human gut microbiome: From association to

modulation. Cell 172:1198, 2018.

Stefan KL et al: Commensal microbiota modulation of natural resistance to virus infection. Cell 183:1, 2020.

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Global Medicine PART 17

Global Issues in Medicine

Joseph J. Rhatigan, Paul Farmer

472

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

achieving health equity worldwide, with an emphasis on addressing

transnational 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 investment 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

international bodies that address 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. 202) but also tuberculosis (Chap. 178), malaria

(Chap. 224), Ebola (Chap. 210), 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 notions of social justice that once were central to international

public health but had fallen out of favor during the last decades of the

twentieth century.

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 communicable 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.

At the International Conference on Primary Health Care in Alma-Ata

(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,

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 commitments of Alma-Ata.

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 governments of poor countries, the World Bank had eclipsed the WHO as the

most important multilateral institution working in the area of 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 institutions 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 imposing restrictions 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, precipitated 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 193 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.

Even as attention to and resources for health problems in poor

countries grow, the lack of coherence in and among global health

institutions may undermine efforts to forge a more comprehensive

and effective response. The WHO remains underfunded despite the

ever-growing need to engage a wider and more complex range of health

issues, such as the Ebola outbreak of 2013–2016 in West Africa. 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 burden 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 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

3704 PART 17 Global Medicine

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.

THE ECONOMICS OF GLOBAL HEALTH

Political and economic concerns have often guided global health interventions. 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,

total development assistance for health worldwide grew to $38.9 billion

in 2018—up from $5.6 billion in 1990, but down 3.3% from 2017. In

2018, the leading contributors included the United States, the United

Kingdom, and other private philanthropy, with the largest channels of

funding being nongovernmental organizations (NGOs) and U.S. bilateral aid agencies. It appears that the growth of development assistance

for health has plateaued: from 2013 to 2018, its annualized growth

rate was –0.3%, and it is unclear whether its growth will resume in the

future.

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

Priorities 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 familiarized 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. 472-1 and Table 472-1 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 Study

2010 (GBD 2010). GBD 2010 is the most comprehensive effort to date

to produce 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 population. It measures current levels and recent trends for major

diseases, injuries, and risk factors worldwide. The GBD 2010 team

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, and 2017. As analytic methods and data quality improve,

important trends can be identified in a comparison of global disease

burden estimates from 1990 to 2017.

■ GLOBAL MORTALITY

Of the 55.9 million deaths worldwide in 2017, 19% (10.4 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 communicable diseases,

maternal and neonatal conditions, and nutritional deficiencies, 75%

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, which increased between 2007 and 2017 by 23%.

The leading cause of death worldwide in 2017 was ischemic heart

disease, accounting for 8.9 million deaths (16% of total deaths). In

high-income countries, ischemic heart disease accounted for 17% of

total deaths, and in low- and middle-income countries, it accounted

for 7% and 17%, respectively. It is noteworthy that ischemic heart disease was responsible for just 5% of total deaths in sub-Saharan Africa

(Table 472-2). In second place—causing 11% of global mortality—was

stroke, which accounted for 8% of deaths in high-income countries,

6% and 12% in low- and middle-income countries, respectively, and

4% 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 countries (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, six were infectious diseases, with HIV/AIDS, lower respiratory

infections, diarrheal diseases, and malaria ranking as dominant contributors to disease burden. In high-income countries, however, only

one infectious disease—lower respiratory infection—ranked among

the top 10 causes of death.

The GBD 2017 found that the worldwide mortality figure among

children under 5 years of age dropped from 16.4 million in 1970 to

11.8 million in 1990 and to 5.4 million in 2017—a decrease that far

surpassed predictions. Of childhood deaths in 2017, 2.4 million (44%)

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 955,000

in 2017, while malaria deaths dropped from 1.2 million to 620,000 over

the same period. Despite these improvements, malaria and HIV/AIDS

continue to be major burdens in particular regions, with global implications. Although it has only a minor impact on mortality outside sub

-Saharan Africa and Southeast Asia, malaria is the fifth leading cause of

death of children under 5 years of age worldwide. HIV infection ranked

28th in global DALYs in 1990 but was the 11th leading cause of disease

burden in 2017, with sub-Saharan Africa bearing the vast majority of

this burden (Fig. 472-1).

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 years in 2017. 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 communicable, maternal, nutritional, and neonatal causes. By 2017, 73% of total

deaths at all ages and 62% of all DALYs were due to NCDs. Increasingly, 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 have also

increased. Globally, the total burden of disability increased by 50%

between 1950 and 2017. Despite the higher prevalence of diseases

common in older populations (e.g., dementia and musculoskeletal

disease) in developed and high-income countries, best estimates from

2017 reveal that disability resulting from cardiovascular diseases,

chronic respiratory diseases, and the long-term impact of communicable diseases was greater in low- and middle-income countries. In

3705 Global Issues in Medicine CHAPTER 472

most developing countries, people lived shorter lives and experienced

disability and poor health for a greater proportion of their lives. Indeed,

47% of the global burden of disease occurred in southern Asia and

sub-Saharan Africa, which together account for only 38% of the world’s

population.

■ HEALTH AND WEALTH

Clear disparities in burden of disease (both communicable and noncommunicable) across country income levels are strong indicators

that poverty 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 7.3 billion people alive in 2015, 10%

(736 million) lived on less than $1.90 (in 2011 U.S. dollars) per day—a

standard measurement of extreme poverty—and 25% lived on less than

$3.20 per day. Just under one-fifth of all children under the age of 14

worldwide lived in extreme poverty in 2015. The extreme poverty rate

has declined steadily since 1990, and by 2015, there were more than

one billion fewer people living in poverty despite growth in the global

population of more than two billion during that time period. However, improvement has been uneven across the globe. In sub-Saharan

Africa, people living in extreme poverty increased from 278 million to

413 million during the same period.

■ RISK FACTORS FOR DISEASE BURDEN

The GBD study found that the three leading risk factors for global disease burden in 2017 were (in order of frequency) high systolic blood

pressure, smoking, and high fasting plasma glucose—a substantial

change from 1990, when child wasting was ranked first. Although

ranking ninth in 2017, child wasting remains the third leading risk

factor for death worldwide among children under 5 years of age. In

an era that has seen obesity become a major health concern in many

developed countries—and the fourth leading risk factor worldwide—

the persistence of undernutrition is cause for consternation. Child

wasting is still a dominant risk factor for disease burden in sub-Saharan

Africa. In its rural reaches, no health care initiative, however generously funded, will be effective or comprehensive without addressing

undernutrition.

In an analysis that examined how specific diseases and injuries are

affected by environmental risk, the WHO estimated that 24% of all

deaths and 28% of deaths among children <5 years of age in 2016 were

due to modifiable environmental factors: some 1.6 million children die

every year from causes related to unhealthy environments, including

the nearly 300,000 deaths stemming from a lack of access to clean

water and sanitation. Many of these modifiable factors lead to child

and adult deaths from infectious pathologies; others lead to deaths

from malignancies. Etiology and nosology are increasingly difficult to

parse with regard to environmental harm. Risk factors such as indoor

1 Neonatal disorders

1990 Rank 2017 Rank

Global

Both sexes, all ages, DALYs

2 Lower respiratory infect

3 Diarrheal diseases

4 Ischemic heart disease

5 Stroke

6 Congenital defects

7 Road injuries

8 Tuberculosis

9 COPD

10 Measles

11 Malaria

12 Low back pain

13 Protein-energy malnutrition

14 Drowning

15 Self-harm

16 Meningitis

17 Headache disorders

18 Dietary iron deficiency

19 Diabetes

20 Cirrhosis

21 Depressive disorders

23 Falls

24 Lung cancer

28 HIV/AIDS

1 Neonatal disorders

Communicable, maternal, neonatal,

and nutritional diseases

Non-communicable diseases Injuries

2 Ischemic heart disease

3 Stroke

4 Lower respiratory infect

5

472

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

achieving health equity worldwide, with an emphasis on addressing

transnational 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 investment 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

international bodies that address 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. 202) but also tuberculosis (Chap. 178), malaria

(Chap. 224), Ebola (Chap. 210), 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 notions of social justice that once were central to international

public health but had fallen out of favor during the last decades of the

twentieth century.

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 communicable 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.

At the International Conference on Primary Health Care in Alma-Ata

(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,

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 commitments of Alma-Ata.

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 governments of poor countries, the World Bank had eclipsed the WHO as the

most important multilateral institution working in the area of 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 institutions 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 imposing restrictions 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, precipitated 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 193 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.

Even as attention to and resources for health problems in poor

countries grow, the lack of coherence in and among global health

institutions may undermine efforts to forge a more comprehensive

and effective response. The WHO remains underfunded despite the

ever-growing need to engage a wider and more complex range of health

issues, such as the Ebola outbreak of 2013–2016 in West Africa. 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 burden 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 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

3704 PART 17 Global Medicine

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.

THE ECONOMICS OF GLOBAL HEALTH

Political and economic concerns have often guided global health interventions. 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,

total development assistance for health worldwide grew to $38.9 billion

in 2018—up from $5.6 billion in 1990, but down 3.3% from 2017. In

2018, the leading contributors included the United States, the United

Kingdom, and other private philanthropy, with the largest channels of

funding being nongovernmental organizations (NGOs) and U.S. bilateral aid agencies. It appears that the growth of development assistance

for health has plateaued: from 2013 to 2018, its annualized growth

rate was –0.3%, and it is unclear whether its growth will resume in the

future.

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

Priorities 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 familiarized 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. 472-1 and Table 472-1 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 Study

2010 (GBD 2010). GBD 2010 is the most comprehensive effort to date

to produce 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 population. It measures current levels and recent trends for major

diseases, injuries, and risk factors worldwide. The GBD 2010 team

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, and 2017. As analytic methods and data quality improve,

important trends can be identified in a comparison of global disease

burden estimates from 1990 to 2017.

■ GLOBAL MORTALITY

Of the 55.9 million deaths worldwide in 2017, 19% (10.4 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 communicable diseases,

maternal and neonatal conditions, and nutritional deficiencies, 75%

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, which increased between 2007 and 2017 by 23%.

The leading cause of death worldwide in 2017 was ischemic heart

disease, accounting for 8.9 million deaths (16% of total deaths). In

high-income countries, ischemic heart disease accounted for 17% of

total deaths, and in low- and middle-income countries, it accounted

for 7% and 17%, respectively. It is noteworthy that ischemic heart disease was responsible for just 5% of total deaths in sub-Saharan Africa

(Table 472-2). In second place—causing 11% of global mortality—was

stroke, which accounted for 8% of deaths in high-income countries,

6% and 12% in low- and middle-income countries, respectively, and

4% 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 countries (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, six were infectious diseases, with HIV/AIDS, lower respiratory

infections, diarrheal diseases, and malaria ranking as dominant contributors to disease burden. In high-income countries, however, only

one infectious disease—lower respiratory infection—ranked among

the top 10 causes of death.

The GBD 2017 found that the worldwide mortality figure among

children under 5 years of age dropped from 16.4 million in 1970 to

11.8 million in 1990 and to 5.4 million in 2017—a decrease that far

surpassed predictions. Of childhood deaths in 2017, 2.4 million (44%)

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 955,000

in 2017, while malaria deaths dropped from 1.2 million to 620,000 over

the same period. Despite these improvements, malaria and HIV/AIDS

continue to be major burdens in particular regions, with global implications. Although it has only a minor impact on mortality outside sub

-Saharan Africa and Southeast Asia, malaria is the fifth leading cause of

death of children under 5 years of age worldwide. HIV infection ranked

28th in global DALYs in 1990 but was the 11th leading cause of disease

burden in 2017, with sub-Saharan Africa bearing the vast majority of

this burden (Fig. 472-1).

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 years in 2017. 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 communicable, maternal, nutritional, and neonatal causes. By 2017, 73% of total

deaths at all ages and 62% of all DALYs were due to NCDs. Increasingly, 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 have also

increased. Globally, the total burden of disability increased by 50%

between 1950 and 2017. Despite the higher prevalence of diseases

common in older populations (e.g., dementia and musculoskeletal

disease) in developed and high-income countries, best estimates from

2017 reveal that disability resulting from cardiovascular diseases,

chronic respiratory diseases, and the long-term impact of communicable diseases was greater in low- and middle-income countries. In

3705 Global Issues in Medicine CHAPTER 472

most developing countries, people lived shorter lives and experienced

disability and poor health for a greater proportion of their lives. Indeed,

47% of the global burden of disease occurred in southern Asia and

sub-Saharan Africa, which together account for only 38% of the world’s

population.

■ HEALTH AND WEALTH

Clear disparities in burden of disease (both communicable and noncommunicable) across country income levels are strong indicators

that poverty 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 7.3 billion people alive in 2015, 10%

(736 million) lived on less than $1.90 (in 2011 U.S. dollars) per day—a

standard measurement of extreme poverty—and 25% lived on less than

$3.20 per day. Just under one-fifth of all children under the age of 14

worldwide lived in extreme poverty in 2015. The extreme poverty rate

has declined steadily since 1990, and by 2015, there were more than

one billion fewer people living in poverty despite growth in the global

population of more than two billion during that time period. However, improvement has been uneven across the globe. In sub-Saharan

Africa, people living in extreme poverty increased from 278 million to

413 million during the same period.

■ RISK FACTORS FOR DISEASE BURDEN

The GBD study found that the three leading risk factors for global disease burden in 2017 were (in order of frequency) high systolic blood

pressure, smoking, and high fasting plasma glucose—a substantial

change from 1990, when child wasting was ranked first. Although

ranking ninth in 2017, child wasting remains the third leading risk

factor for death worldwide among children under 5 years of age. In

an era that has seen obesity become a major health concern in many

developed countries—and the fourth leading risk factor worldwide—

the persistence of undernutrition is cause for consternation. Child

wasting is still a dominant risk factor for disease burden in sub-Saharan

Africa. In its rural reaches, no health care initiative, however generously funded, will be effective or comprehensive without addressing

undernutrition.

In an analysis that examined how specific diseases and injuries are

affected by environmental risk, the WHO estimated that 24% of all

deaths and 28% of deaths among children <5 years of age in 2016 were

due to modifiable environmental factors: some 1.6 million children die

every year from causes related to unhealthy environments, including

the nearly 300,000 deaths stemming from a lack of access to clean

water and sanitation. Many of these modifiable factors lead to child

and adult deaths from infectious pathologies; others lead to deaths

from malignancies. Etiology and nosology are increasingly difficult to

parse with regard to environmental harm. Risk factors such as indoor

1 Neonatal disorders

1990 Rank 2017 Rank

Global

Both sexes, all ages, DALYs

2 Lower respiratory infect

3 Diarrheal diseases

4 Ischemic heart disease

5 Stroke

6 Congenital defects

7 Road injuries

8 Tuberculosis

9 COPD

10 Measles

11 Malaria

12 Low back pain

13 Protein-energy malnutrition

14 Drowning

15 Self-harm

16 Meningitis

17 Headache disorders

18 Dietary iron deficiency

19 Diabetes

20 Cirrhosis

21 Depressive disorders

23 Falls

24 Lung cancer

28 HIV/AIDS

1 Neonatal disorders

Communicable, maternal, neonatal,

and nutritional diseases

Non-communicable diseases Injuries

2 Ischemic heart disease

3 Stroke

4 Lower respiratory infect

5 COPD

6 Diarrheal diseases

7 Diabetes

8 Road injuries

9 Low back pain

10 Congenital defects

11 HIV/AIDS

12 Headache disorders

13 Malaria

14 Tuberculosis

15 Depressive disorders

16 Cirrhosis

17 Lung cancer

18 Falls

21 Self-harm

24 Dietary iron deficiency

32 Meningitis

39 Drowning

41 Protein-energy malnutrition

67 Measles

FIGURE 472-1 Global disability-adjusted life-year (DALY) ranks for the top causes of disease burden in 1990 and 2017. COPD, chronic obstructive pulmonary disease.

(From the Institute for Health Metrics and Evaluation [IHME]. GBD Compare. Seattle, WA: IHME, University of Washington, 2017. Available at http://vizhub.healthdata.org/

gbd-compare. Accessed May 1, 2020.)

3706 PART 17 Global Medicine

TABLE 472-1 Leading Causes of Burden of Disease (DALYs), 2017

DISEASE OR INJURY

DALYs

(MILLIONS)

PERCENTAGE OF

TOTAL DALYs

World 2464.9 100

1. Neonatal disorders 185.8 7.4

2. Ischemic heart disease 170.3 6.8

3. Stroke 132.1 5.3

4. Lower respiratory infection 106.5 4.3

5. COPD 81.6 3.3

6. Diarrheal diseases 81.0 3.2

7. Diabetes 67.9 2.7

8. Road injuries 67.8 2.7

9. Low back pain 64.9 2.6

10. Congenital defects 60.9 2.4

Low- and Middle-Income Countriesa

1. Neonatal disorders 179.7 8.3

2. Ischemic heart disease 145.3 6.7

3. Stroke 117.1 5.4

4. Lower respiratory infection 101.1 4.7

5. Diarrheal disease 79.9 3.7

6. COPD 69.4 3.2

7. Road injuries 60.3 2.8

8. Congenital defects 57.2 2.6

9. Diabetes 56.0 2.6

10. HIV/AIDS 53.6 2.5

High-Income Countriesa

1. Ischemic heart disease 24.3 7.3

2. Low back pain 19.0 5.7

3. Stroke 14.2 4.3

4. Lung cancer 12.2 3.7

5. COPD 11.8 3.6

6. Diabetes 11.7 3.5

7. Alzheimer’s disease 10.9 3.3

8. Headache disorders 10.1 3.0

9. Falls 8.9 2.7

10. Drug use disorders 8.4 2.5

Sub-Saharan Africa

1. Neonatal disorders 66.8 12.8

2. Lower respiratory infection 44.7 8.6

3. HIV/AIDS 41.8 8.0

4. Malaria 40.1 7.7

5. Diarrheal diseases 39.3 7.5

6. Congenital defects 19.9 3.8

7. Tuberculosis 16.9 3.2

8. Meningitis 12.6 2.4

9. Protein-energy malnutrition 10.7 2.0

10. Road injuries 10.2 2.0

a

The World Bank classifies high-income countries as those whose gross national income

(GNI) per capita is ≥$12,376. Low- and middle-income countries are categorized as low

income (GNI per capita, <$1025), lower-middle income (GNI per capita, $1026–$3995), and

upper-middle income (GNI per capita, $3996–$12,375) (http://data.worldbank.org/about/

country-classifications).

Abbreviations: COPD, chronic obstructive pulmonary disease; DALYs, disability-adjusted

life-years.

Source: Institute for Health Metrics and Evaluation, University of Washington (2020). Data

available at http://www.healthdata.org/gbd/data-visualizations. Accessed April 30, 2020.

TABLE 472-2 Leading Causes of Death Worldwide, 2017

DISEASE OR INJURY

DEATHS

(MILLIONS)

PERCENTAGE OF

TOTAL DEATHS

World 55.8 100

1. Ischemic heart disease 8.9 15.9

2. Stroke 6.2 11.0

3. COPD 3.2 5.7

4. Lower respiratory infection 2.6 4.6

5. Alzheimer’s disease 2.5 4.5

6. Lung cancer 1.9 3.4

7. Neonatal disorders 1.8 3.2

8. Diarrheal diseases 1.6 2.8

9. Diabetes 1.4 2.4

10. Cirrhosis 1.3 2.4

Low- and Middle-Income Countriesa

1. Ischemic heart disease 7.2 15.8

2. Stroke 5.3 11.7

3. COPD 2.7 6.0

4. Lower respiratory infection 2.1 4.7

5. Neonatal disorders 1.8 3.9

6. Diarrheal diseases 1.5 3.4

7. Alzheimer’s disease 1.4 3.2

8. Lung cancer 1.2 2.7

9. Tuberculosis 1.2 2.6

10. Diabetes 1.1 2.5

High-Income Countriesa

1. Ischemic heart disease 1.7 16.6

2. Alzheimer’s disease 1.0 10.1

3. Stroke 0.8 7.9

4. Lung cancer 0.6 6.0

5. COPD 0.5 4.6

6. Lower respiratory infection 0.4 4.1

7. Colorectal cancer 0.4 3.4

8. Chronic kidney disease 0.3 2.4

9. Diabetes 0.2 2.1

10. Cirrhosis 0.2 2.0

Sub-Saharan Africa

1. Neonatal disorders 0.7 9.4

2. HIV/AIDS 0.7 9.3

3. Lower respiratory infection 0.7 9.2

4. Diarrheal diseases 0.6 7.3

5. Malaria 0.5 7.1

6. Ischemic heart disease 0.4 5.4

7. Tuberculosis 0.4 5.2

8. Stroke 0.3 4.4

9. Congenital defects 0.2 2.7

10. Road injuries 0.2 2.2

a

The World Bank classifies high-income countries as those whose gross national

income (GNI) per capita is ≥$12,376. Low- and middle-income countries are

categorized as low income (GNI per capita, <$1025), lower-middle income (GNI per

capita, $1026–$3995), and upper-middle income (GNI per capita, $3996–$12,375)

(http://data.worldbank.org/about/country-classifications).

Abbreviation: COPD, chronic obstructive pulmonary disease.

Source: Institute for Health Metrics and Evaluation, University of Washington (2020).

Data available at http://www.healthdata.org/gbd/data-visualizations. Accessed

April 30, 2020.

air pollution due to use of solid fuels, exposure to secondhand tobacco

smoke, and outdoor air pollution account for 55% 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 evidence-based

recommendations and cost-effectiveness analyses for numerous interventions, with attention to strategies for strengthening health systems. Cost-effectiveness analyses that compare relatively equivalent

3707 Global Issues in Medicine CHAPTER 472

FIGURE 472-2 An HIV and tuberculosis (TB)–co-infected patient in Rwanda before (left) and

after (right) 6 months of treatment.

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 interventions 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 202 provides an overview of the global HIV epidemic today.

Approximately 36 million people worldwide were living with HIV

infection in 2017, and it has been the underlying cause of death for

almost 1 million people—especially concentrated in sub-Saharan

Africa—annually. As of 2017, 54 countries were on track to meet the

2020 target of 81% antiretroviral therapy (ART) coverage, but only

12 countries are expected to meet the 2030 target of 90% coverage.

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 moving 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 unchallenged

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 millions 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 international 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. 472-2).

During the past decade, the availability of ART has

increased sharply in the low- and middle-income countries

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 2018, 62% of people

living with HIV infection were receiving ART, including

64% of people living with HIV in sub-Saharan Africa and

53% in Southeast Asia. In light of these dramatic gains,

coverage targets have grown more ambitious; for example,

in 2014, UNAIDS set the 90-90-90 targets, 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. These are to be

followed by the 95-95-95 targets for 2030, with the objective of ending

the AIDS epidemic by 2030.

This scale-up was made possible by several developments: a staggering 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.

Starting in the early 2000s, a combination of factors, including work

by the Clinton HIV/AIDS 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 <$75 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 ambitious target: to have 3 million people in

developing countries on treatment 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 fight HIV/AIDS in such settings increased dramatically during this period and beyond, rising from $300 million in 1996

to $9.1 billion in 2017. 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.