Tropical Medicine and International Health doi:10.1111/tmi.

12206

volume 18 no 12 pp 1510–1519 december 2013

Obesity, diabetes and pneumonia: the menacing interface of

non-communicable and infectious diseases
Susan P. Fisher-Hoch, Christine E. Mathews and Joseph B. McCormick
Division of Epidemiology, Human Genetics and Environmental Sciences, University of Texas School of Public Health, Brownsville,
TX, USA

Abstract objectives To review current knowledge on the epidemiological, clinical and biological impact of
the pandemic of obesity and diabetes on pneumonias.
methods We conducted a literature review using PubMed and EMBASE, supplemented by various
sources. Given the disparate and fragmented nature of the literature, a formal systematic review was
not possible.
results In 2008, globally 10% of men and 14% of women were obese and an estimated 371
million had diabetes; half undiagnosed and many obese. Numbers are rising rapidly in low- and
middle-income countries where the majority reside, but reliable data are lacking. The most frequent
pneumonias in obesity and diabetes are tuberculosis, influenza and pneumococcal, staphylococcal and
opportunistic pathogens. Diabetes impacts tuberculosis control and increases drug resistance and
mortality. Mortality and morbidity from pneumococcal pneumonia and influenza are increased in
obesity and diabetes. In addition to mechanical and physiological effects, there are considerable
immunological abnormalities characterised by chronic, low-grade inflammation. Simultaneous
up-regulation and dysregulation of both innate and adaptive immune responses impair control and
killing of invading organisms. Prevention in those at risk is poorly practised, although screening for
tuberculosis in diabetes is beginning in high-burden settings.
conclusions Pneumonia is a threat globally in obesity and diabetes with increased incidence and
severity of disease. There is uncertainty about whether vaccines are equally effective in those with
obesity and diabetes. Increased epidemiological, clinical and biological knowledge will be crucial to
face this 21st century challenge.

keywords obesity, diabetes, chronic inflammation, pneumonia

mechanisms are poorly understood. However, the impact

Introduction
Obesity and diabetes are prominent in the pandemic of
non-communicable diseases (NCDs) currently exploding
globally, most rapidly in low- and middle-income coun-
tries (LMICs) and particularly in urban settings such as
the Asian megacities (Horton 2013). In 2010, the World
Health Organization (WHO) stated that NCDs ‘are the
leading causes of death globally, killing more people each
year than all other causes combined’ (World Health Orga-
nisation 2011). A total of 80% of NCD-associated deaths
occur in LMICs. Although most NCD deaths are reported
due to cardiovascular disease and diabetes, it is becoming
apparent that pneumonia must be added to the list.
The complex epidemiological, clinical and biological
interfaces between chronic disease and infections have
been little studied. Published data are limited and frag-
mented, and the clinical impact and biological
of obesity and diabetes on the immune system is broad
and complex and impacts incidence and severity of pneu-
monia. The pivotal pathology is the chronic inflammatory
syndrome, resulting in hyper-reactive, chronically up-reg-
ulated immune responses which, paradoxically, have poor
microbial killing efficiency (Peleg et al. 2007; Falagas
et al. 2009). This review examines the current epidemio-
logical, clinical and biological evidence underlying pneu-
monia associated with obesity and diabetes globally and
the major challenges to address pneumonia in people
with these conditions.
Methods
The aim of this study was to review current knowledge
on the epidemiological, clinical and biological implica-
tions for pneumonia of the current pandemic in NCDs.

1510 © 2013 John Wiley & Sons Ltd

Tropical Medicine and International Health volume 18 no 12 pp 1510–1519 december 2013

S. P. Fisher-Hoch et al. Obesity, diabetes and pneumonia

The objective was to determine the larger risk of obesity Table 1 Key clinical, epidemiological and public health publica-
and diabetes in increased incidence and severity of com- tions
mon pneumonias. To do this, we conducted a literature
Citation Key observations
search using PubMed and EMBASE, supplemented by
searches using Google Scholar, to derive older citations Clinical and epidemiological reports
and online reports, and bibliographies of relevant Vaillant et al. (2009) Characteristics of 574 deaths
literature. The fragmented and disparate nature of the associated with pandemic H1N1
Webb et al. (2009) Review of intensive care unit
literature precluded a formal systematic review or meta-
experiences in the H1N1
analysis. Rather, we attempted to review the wide range pandemic
of data that do exist. To gain an understanding, we had Sedyaningsih et al. Epidemiology of H5N1 infections
to consider literature from epidemiology, global public (2007) in Indonesia
health, socio-economic issues, immunology, clinical and Asghar et al. (2011) High rates of diabetes among all
basic science, animal models and ornithology. Ethical patients with pneumonia
approval was not required for the purposes of this review Mugusi et al. (1990) First report of diabetes and
tuberculosis in Africa
Table 1.
Olmos et al. (1989) Early report of type 2 diabetes
and tuberculosis in Chile
Pablos-Mendez et al. Case–control study of tuberculosis
Results (1997) and diabetes in Mexico
Ponce-De-Leon et al. Data from population-based
Obesity and pneumonias (2004) cohort shows 6.8-fold increase in
tuberculosis cases in diabetes
Epidemiology and clinical impact. The epidemic of obes-
Restrepo et al. (2011) Between 36% and 39% of
ity is now widely recognised as a major threat to both patients with tuberculosis have
health and global economies (Bloom et al. 2011; World diabetes
Health Organisation 2011). Obesity is a risk factor for Restrepo et al. (2007) Diabetes tripled risk of active
nosocomial and community-acquired infections, poor tuberculosis
wound healing and aberrant vaccine responses, although Allard et al. (2010) Diabetes tripled risk of
some of the data for community-acquired pneumonia are hospitalisation with influenza
Public Health
conflicting (Falagas et al. 2009; Kornum et al. 2010).
Harries et al. (2010) Recommendations for studies of
The adverse impact of obesity on influenza is most con- diabetes and tuberculosis
sistent and best documented (Centers for Disease Control Harries et al. (2009) Recommendations for screening
& Prevention 2009; Vaillant et al. 2009; Webb et al. vintegrated with care
2009). Although the risks of influenza in obesity had Harries et al. (2011) Recommendations for addressing
been previously recognised, the 2009 swine influenza the global threat of diabetes to
virus (S-OIV) H1N1 pandemic highlighted obesity as a tuberculosis control
Systematic reviews with Meta-Analysis
leading risk factor for mortality in patients with influenza
Jeon and Murray (2008) Review of epidemiological studies
over the age of 20 (Centers for Disease Control & Jeon et al. (2010) Review of screening procedures
Prevention 2009; Vaillant et al. 2009; Webb et al. 2009). Baker et al. (2011) Review of treatment outcomes
Influenza virus strains emerging in their natural hosts
(migrating waterfowl) separate into LPAI strains and the
less common, highly pathogenic avian influenza (HPAI) factors, particularly obesity, but also pregnancy, predis-
strains, causing significant mortality in birds and humans pose to viral pneumonia, and death in young adults
(Webster & Govorkova 2006; Centers for Disease infected with LPAI strains, in whom the pathology is
Control & Prevention 2013). S-OIV is a low pathogenic- similar to that in HPAI human infections (Vaillant et al.
ity influenza virus (LPAI) not usually associated with 2009). In an early 2009 S-OIV report of infected obese
pneumonia and death in adults below 65 years of age. patients with influenza requiring intensive care and respi-
Human HPAI epidemics are rare (specifically the 1918 ratory support (median age 46 years), the presentation
pandemic and the current H5N1 strains) (Soper 1918; was adult respiratory distress syndrome (ARDS). All had
Johnson & Mueller 2002; Sedyaningsih et al. 2007). multilobular pneumonia consistent with primary viral
Annual influenza epidemics are mostly caused by LPAI pneumonia, and none had evidence of secondary bacterial
strains and are mild, and most deaths are in infants and infection (Centers for Disease Control & Prevention
the elderly (Webster et al. 1992; Centers for Disease 2009). In another study of 34 patients, dying of the swine
Control & Prevention 2013). However, individual risk origin S-OIV virus in New York in nearly half obesity

© 2013 John Wiley & Sons Ltd 1511

Tropical Medicine and International Health
S. P. Fisher-Hoch et al. Obesity, diabetes and pneumonia
was a significant comorbidity (Gill et al. 2010). Thus,
although S-OIV is low pathogenicity, the disturbing
pathology reported in these fatal cases (characteristically
ARDS) was consistent with the pathology reported from
1918 pandemic autopsies and also that seen in lungs of
mice experimentally infected with the reconstructed 1918
HPAI strain (Tumpey et al. 2005). The HPAI H5N1
strain currently circulating widely in wild birds and
domestic poultry in Asia would likely be an even greater
risk to the obese, if and when it or a similar strain
mutates and acquires the ability to become pandemic in
humans (Van Kerkhove et al. 2011).
Pathogenesis and immunology. Mechanical and physio-
logical effects of obesity on the respiratory tract are
considerable. In obesity, reduced lung volume, altered
ventilation patterns and higher risk of aspiration are
important in predisposing to pneumonia (Kopelman
2000). Obesity is also characterised by abnormalities in
respiratory muscle function, control of breathing and gas
exchange, resulting in increased work in breathing, often
compounded by sleep apnoea and chronic inflammation
in the respiratory tract itself (Falagas et al. 2009). Aspira-
tion pneumonia is also more common in association with
gastric reflux. Immunological abnormalities though
poorly understood may be equally important (Falagas
et al. 2009). There is no simple explanation for this sus-
ceptibility, but a complex picture of deleterious changes
in the immune response is emerging in rodent models and
in humans revealing complex cross-talk between adipo-
cytes, adipose tissue and the immune system (Lamas
et al. 2002; Macia et al. 2006; Tilg & Moschen 2006;
Smith et al. 2007, 2009; Nathan 2008; Aldridge et al.
2009). The roles of certain adipokines (leptin, adiponec-
tin, resistin, visfatin) important in obesity have been rede-
fined in a rapidly growing family of adipocytokines
having central roles in both insulin metabolism and
immune responses (Tilg & Moschen 2006). The chronic,
low-grade inflammation characteristic of obesity is related
to infiltration of adipose tissue, particularly visceral
adipose tissue, by subsets of immune cells, predominantly
inflammatory macrophages and T cells. T-cell subset
populations may also be altered (O’rourke et al. 2005).
Cytokines also involved in the inflammation include mul-
tiple proteins known to influence components of the
innate immune response, such as tumour necrosis factor
a (TNFa), interleukin-6 (IL-6), monocyte chemoattractant
factor-1 and components of the complement cascade.
Finally, free fatty acids, which circulate at elevated levels
in obesity, also promote inflammation via stimulation of
toll-like receptors and subsequent activation of the
NF-jB pathway (Schaeffler et al. 2009).
1512
volume 18 no 12 pp 1510–1519 december 2013
The potent immunomodulatory effects of adipocytokin-
es in obese humans with pneumonia are not well eluci-
dated (Falagas et al. 2009). Adiponectin levels are
characteristically low in obesity. As adiponectin has
potent anti-inflammatory properties affecting macrophage
functions, this may be one mechanism (Wolf et al. 2004).
Leptin, which is elevated in obesity, may also modulate
the immune response (Fantuzzi & Faggioni 2000). Leptin
activates polymorphonuclear neutrophils (PMNs) via
TNFa release from monocytes (Zarkesh-Esfahani et al.
2004). Rodent studies also show that leptin influences
circulating levels of cytokines and chemokines, as well as
the killing ability of granulocytes. There is some evidence
that immune cells in the obese may be leptin-resistant
(Mancuso et al. 2002; Mito et al. 2004; Ikejima et al.
2005).
Diet-induced obese mice infected with LPAI seasonal
influenza viruses have significantly higher mortality than
normal weight mice. Expression of the antiviral cytokines
interferon alpha 2 and interferon beta 1 and the
pro-inflammatory cytokines IL-6 and TNFa was reduced
or delayed in the lungs of these obese mice resulting in
reduced or inappropriate responses to the virus (Smith
et al. 2007). Dendritic cell function, critical in the presen-
tation of influenza virus antigens to the immune system,
was also impaired, with downstream alterations in cyto-
kine levels and ultimately affecting the number of virus-
specific CD3(+) and CD8(+) T cells in the lung (Smith
et al. 2009).
Diabetes and pneumonias
Epidemiology and clinical impact. In the 1920s, before
the introduction of insulin, it was estimated that infec-
tions killed 20% of all diabetes patients, commonly
tuberculosis (Bell & Hockaday 1996). At that time, most
diabetes was insulin-dependent, juvenile diabetes (type 1
diabetes). As mortality from type 1 diabetes declined with
effective treatment, type 2 diabetes gained in significance.
Towards the end of the 20th century, type 2 diabetes
predominates. Today, more than 90% of diabetes is type
2 diabetes, and much is associated with the global
pandemic of obesity (Centers for Disease Control &
Prevention 2006).
The total number of people with diabetes (half of
whom are undiagnosed) rose to an estimated 371 million
in 2012 and is projected to rise further (International
Diabetes Federation 2012; World Health Organisation
2012). Even in sub-Sahara Africa, where obesity has not
been generally considered a major problem, the estimated
number of persons with diabetes is expected to nearly
double to 23.9 million by 2030 (82% undiagnosed) (Hall
© 2013 John Wiley & Sons Ltd
Tropical Medicine and International Health
S. P. Fisher-Hoch et al. Obesity, diabetes and pneumonia
et al. 2011; International Diabetes Federation 2012).
China with 92 million and India with 63 million have the
largest numbers of people with diabetes. Four-fifths of
people with diabetes live in LMICs where infectious
diseases remain highly prevalent and medical care less
available.
Recently, the re-emergence of the association of diabe-
tes and tuberculosis has become widely recognised glob-
ally (Jeon & Murray 2008; Young et al. 2009; Harries
et al. 2011). However, many other pulmonary pathogens
also result in increased morbidity and mortality in diabe-
tes, particularly influenza, pneumococcal and staphylo-
coccal pneumonias. Also important are pneumonia with
opportunistic pathogens such as Klebsiella pneumonia,
Pseudomonas aeruginosa and many fungi (Peleg et al.
2007; Santhosh et al. 2011). Other pneumonias are also
seen in association with diabetes, particularly those due
to Mycoplasma pneumoniae, Chlamydia pneumoniae,
Legionella spp. and Hemophilus influenzae. Interestingly,
one report of all hospitalised patients with pneumonia
returning to India from Makkah following the Hajj found
55% had diabetes (Asghar et al. 2011). With the current
estimated burden of diabetes predicted to rise to 553 mil-
lion by 2030, all-cause pneumonia deaths in patients with
diabetes will have increasing global impact (International
Diabetes Federation 2012).
The re-emergence of tuberculosis associated with type
2 diabetes is relatively recent, but is now well docu-
mented globally (Olmos et al. 1989; Mugusi et al. 1990;
Swai et al. 1990). The adjusted odds ratio for this associ-
ation in Hispanics was reported in 1997 to range from
2.95 (95% CI 2.61, 3.33) to in 2004, 6.4-fold (95% CI
5.7, 8.2) (Pablos-Mendez et al. 1997; Ponce-De-Leon
et al. 2004). Independently our own studies showed simi-
lar associations in South Texas (Perez et al. 2006; Restre-
po et al. 2007, 2011). Reports from many countries
across the globe followed rapidly, particularly in Asia
(Leung et al. 2008; Dooley & Chaisson 2009; Viswana-
than et al. 2012). Even pre-diabetes increases the risk of
tuberculosis (Viswanathan et al. 2012). In 2008, a work-
ing group met to review a comprehensive meta-analysis
of the literature, assess the global situation and determine
the research agenda (Jeon & Murray 2008; Harries et al.
2009, 2010). This group then developed the WHO
framework for management of diabetes and tuberculosis
(Harries et al. 2011; World Health Organisation, Diabe-
tes Program 2011). Predictions of the impact of diabetes
on tuberculosis have been extensively reviewed by
Harries et al., and it is now recognised that diabetes
threatens tuberculosis control globally (Young et al.
2009; Dye & Williams 2010; Ruslami et al. 2010; Gold-
haber-Fiebert et al. 2011; Hall et al. 2011; Harries et al.
© 2013 John Wiley & Sons Ltd
volume 18 no 12 pp 1510–1519 december 2013
2011). The increase in tuberculosis due to diabetes is par-
ticularly felt in high-burden countries such as Peru and
the Russian Federation, and in India, where diabetes is
estimated to have increased the number of cases by 46%
(Dye et al. 2011; Bygbjerg 2012).
Severity of diabetes is also important. A large study in
Hong Kong among elderly persons found those with
poorly controlled diabetes had higher risk of tuberculosis
(HR 1.77 95% CI 1.41, 2.24) (Leung et al. 2008). In
people with HbA1c >7% the hazard ratio was 3.11
(95% CI 1.63, 5.92) for active pulmonary tuberculosis.
Also of considerable significance is that diabetes makes
tuberculosis management much more challenging and
may increase drug resistance (including XDR-TB) and
tuberculosis mortality (Baker et al. 2011; Tang et al.
2011; Jimenez-Corona et al. 2013). The risk ratio in a
recent meta-analysis for treatment failure and/or death in
tuberculosis with diabetes is 1.69 (95% CI 1.36, 2.12)
(Baker et al. 2011).
Epidemiological data on pneumococcal, staphylococcal
and influenza pneumonia in diabetes are scarcer than
those for tuberculosis. However, it has been widely
recognised from the early 20th century that certain
pathogens have higher morbidity and mortality in the
patient with diabetes (Smith & Poland 2000). This has
been amply demonstrated in an extensive review of hos-
pital-based and community-acquired studies of influenza
and pneumococcal pneumonia mostly from developed
countries (Smith & Poland 2000). Some of the deaths in
influenza were, however, attributed to secondary bacterial
infections particularly in patients with end-organ compli-
cations of diabetes such as renal failure (Smith & Poland
2003).
Streptococcus pneumoniae kills more than 40 000
people in the United States and one million globally each
year. However, bacteriological diagnosis, particularly in
LMICs, is often unavailable and is in any event insensi-
tive, leading to major under-reporting. Where data are
available, minimum estimates of incidence range from 35
per 100 000 in adults aged 20–59 years to 69 per
100 000 in those over 60 years (Fedson & Scott 1999).
A case–control study of community-acquired pneumococ-
cal pneumonia found an adjusted odds ratio for having
diabetes of 1.5 (95% CI 1.1, 2.0), particularly in younger
adults without coexisting morbid conditions and in males
(Thomsen et al. 2005). Although not statistically signifi-
cant, the risk of death from pneumococcal pneumonia in
a US-based study from 1978 to 1997 was reported to be
twice as high in patients over 50 years of age with diabe-
tes (95% CI 0.8, 4.7) (Mufson & Stanek 1999). Nasal
carriage of staphylococcus aureus is reported in 30.5%
persons with diabetes compared with 11.4% in controls
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Tropical Medicine and International Health
S. P. Fisher-Hoch et al. Obesity, diabetes and pneumonia
without diabetes (Lipsky et al. 1987). Staphylococcal
infections are common in diabetes patients; however, the
increased risk of staphylococcal pneumonia in diabetes is
not clear (Breen & Karchmer 1995; Joshi et al. 1999).
The most complete documentation of influenza pneu-
monia and diabetes came again from the 2009 pandemic
of S-OIV. In one series of hospitalised patients with influ-
enza (n = 160), the adjusted odds ratio (OR) for having
diabetes was 4.72 (95% CI 1.81, 12.3), making this a
greater risk than that from cardiac disease (adjusted OR
1.77, 95% CI 0.61, 5.16). Interestingly, these patients
were over three times as likely to be 20–40 years of age
(average age 28 years). Among the 31 who were admit-
ted to the intensive care unit, ten had diabetes. Although
small and biased towards hospitalised patients, this study
shows the clearest evidence of the increased risk of diabe-
tes for influenza pneumonia, independent of other risk
factors (Allard et al. 2010). Other reports do not allow
discrimination of risks independent of obesity, but risks
are compounded when the conditions coexist (Gill et al.
2010).
Pathogenesis and immunology. The increased morbidity
and mortality due to pneumonia in diabetes is rooted in
similar defects in immune surveillance and responses to
those in obesity. Damage to lung microvasculature char-
acteristic of diabetes could also be involved, but there is
little evidence to support this hypothesis. The defects
appear once more to be closely related to the chronic
inflammatory syndrome in which both the innate and
adaptive immune systems are chronically up-regulated.
Although responses to infectious antigens are brisk, we
are beginning to understand that, similar to obesity, the
effectiveness of both innate and immune systems in
controlling infections and killing invading organisms is
considerably impaired.
In type 2 diabetes, there are more data implicating
specific immune system defects. Diabetes is characterised
by a progressive impairment of glucose control and insu-
lin secretion leading to insulin resistance and pancreatic
b-cell dysfunction, and disposing to cardiovascular, renal
and other chronic conditions (Seshasai et al. 2011).
Hazard ratios for morbidity and mortality in diabetes are
nonlinear, increasing markedly with deteriorating glucose
control, and other comorbidities of diabetes, including
obesity, compound the risks (Leibovici et al. 1996;
Bertoni et al. 2001). As previously stated, many patients
with type 2 diabetes are obese, and with the addition of
diabetes, metabolic dysregulation broadly affects both the
innate and adaptive immune systems (Bastard et al.
2006; Mathis & Shoelson 2011). Defects specifically
affect minimum lung function, antibody response,
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volume 18 no 12 pp 1510–1519 december 2013
neutrophil and macrophage function, CD4+/CD8 ratios,
and natural killer cell function (Pickup 2004).
Innate and acquired immune responses are not separate
entities but operate in concert with a complex response
both to new invaders and recognised antigens. Alterations
in innate immune responses in diabetes are documented,
but laboratory data have been difficult to reconcile in
part due to variations in methodology and lack of repro-
ducibility, such that the picture is fragmented and hard
to relate to clinical observations (Peleg et al. 2007). In
summation, it appears that neutrophil adherence to
vascular endothelium is increased, but chemotaxis and
transmigration into tissue reduced (Peleg et al. 2007).
Neutrophils from persons with diabetes have been found
to have impairments in migration (Sawant 1993), phago-
cytosis (Krol et al. 2003), production of reactive oxygen
species (Marhoffer et al. 1994) and apoptosis (Tennen-
berg et al. 1999). The downstream effects of these
impairments are decreased ability to respond to sites of
infection, inability to effectively destroy and clear patho-
gens and promotion of excessive, damaging inflammation
(Droemann et al. 2000; Kobayashi et al. 2010).
Macrophages and monocytes in diabetes have also been
shown to have functional impairments in phagocytosis,
activation and antigen presentation (Dooley & Chaisson
2009) Alveolar macrophages from persons with diabetes
have been shown to have reduced activation and antimi-
crobial activity in response to challenge with M. tubercu-
losis (Wang et al. 1999). Decreased populations of
monocytes with complement receptor 3 (used for adher-
ence and phagocytosis of pathogens) are associated with
diabetes (Chang & Shaio 1995). Macrophages have com-
promised functionality of Fc receptors used for antigen
processing and presentation, including diminished inter-
nalisation of Fc-receptor-bound material under conditions
of insulin resistance, so that the ability to process and pres-
ent information to other immune effector cells is inhibited
(Abrass 1991). Dysregulation of adhesion molecules
E-selectin, vascular adhesion molecule-1 and intracellular
adhesion molecule-1 have been reported. These molecules
are up-regulated during the innate immune response and
aid in the recruitment of macrophages and other leuco-
cytes to sites of infection (Andreasen et al. 2010).
There are elevated levels of pro-inflammatory cytokines
in diabetes, both at baseline and after immune stimula-
tion. In diabetes, interleukin-8, interleukin-1b, IL-6 and
TNF-a have higher baseline and expression levels after
experimental stimulation of cells with bacterial lipopoly-
saccharide. Innate and type 1 cytokine responses were
significantly higher in tuberculosis patients with diabetes,
nevertheless these patients fail to control the mycobacte-
rium adequately (Restrepo et al. 2008). Conversely, in a
© 2013 John Wiley & Sons Ltd
Tropical Medicine and International Health
S. P. Fisher-Hoch et al. Obesity, diabetes and pneumonia
rodent model, Th1-related cytokines and expression of
inducible nitric oxide synthetase were reduced in experi-
mentally infected animals with diabetes (Yamashiro et al.
2005). In our own studies, we have documented signifi-
cantly higher levels of pro-inflammatory cytokines in rest-
ing plasma samples from our cohort of Mexican
Americans with high rates of diabetes (Mirza et al.
2011). Stimulation of whole blood from diabetes patients
with heat-killed pneumococci resulted in a 10-fold
increase in the secretion of interferon-c, IL-6 and interleu-
kin-17 compared with blood from normal controls. For
example, we found that neutrophils from diabetes
patients producing neutrophil extracellular traps (NetS)
when exposed to S. pneumoniae exhibited impaired
ability to killed bacteria.
Also promising are mouse studies that have implicated
a shift in the balance of subsets of T cells in diabetes,
including increases in pro-inflammatory cytokine-produc-
ing T helper (Th)-17 cells and decreases in regulatory T
cells (T regs) that mediate and control inflammation
(Feuerer et al. 2009; Jagannathan-Bogdan et al. 2011).
An emerging hypothesis suggests that the elevated levels
of cytokines IL-6 and interleukin-1b (which promote
Th-17 cell differentiation) in diabetes skew the balance of
T cells to produce higher levels of Th-17 cells and
suppresses the levels of inflammation-mediating regula-
tory T cells (T regs) (Jagannathan-Bogdan et al. 2011).
The end result of this is the chronic, heightened pro-
inflammatory state that further contributes to tissue
injury and dysregulation of immune responses. This
hypothesis provides a novel explanation for the role of
effector T cells in immune impairment among persons
with diabetes. Additional studies are necessary to further
elucidate the mechanisms behind these observations as
the targeting of this balance of Th-17 and T regs could
provide novel approaches to future therapies.
Discussion
It is now clear that pneumonias are more frequent and
often more difficult to treat in people with obesity and/or
diabetes and that major pathogens include influenza
viruses, pneumococci, staphylococci, tuberculosis as well
as fungal and other opportunistic pathogens. This
increased susceptibility is in great part due to the charac-
teristic chronic inflammatory state, which results in
impairment of a wide range of immune responses, but
knowledge is fragmented and studies are difficult to
compare. A major concern is that most of the data on
the epidemiology of this interface between chronic and
acute disease come from the developed world, whereas
most of the people at risk globally are in LMICs.
© 2013 John Wiley & Sons Ltd
volume 18 no 12 pp 1510–1519 december 2013
Given the scale of the NCD pandemic, prevention of
pneumonia in obesity and diabetes is an important goal.
Screening for diabetes in tuberculosis patients is now
becoming widely accepted, but screening for tuberculosis
among diabetes patients is more problematical (Harries
et al. 2009, 2011; Jeon et al. 2010). A recent report from
China, where the convergence of diabetes and tuberculosis
is a major problem, shows that tuberculosis case detection
could be several times higher in diabetes clinics than in the
general population (804 active tuberculosis cases detected
per 100 000 screened compared with 111/10 000 in the
general population) (Lin et al. 2012). Successful screening
depends on the local burdens of disease and presents many
logistic problems. A major barrier is that in most coun-
tries, diabetes clinics do not have anything like the struc-
ture of national tuberculosis programmes.
In the case of pneumococcal disease and influenza, the
best available tools for prevention are existing vaccines,
but additional doses may be required (Smith & Poland
2004). Some vaccines may be less effective in diabetes
and require booster doses, particularly pneumococcal and
influenza vaccines (Smith & Poland 2000; Nam et al.
2011; Mathews et al. 2012). The prospect of an effective
vaccine for tuberculosis in adults would be a major
advance for patients with diabetes. Hopes for better
treatment using immune modulation might be possible
with better understanding of the precise defects.
Conclusion
Although it is not possible to estimate the overall morbid-
ity and mortality, the data that exist do serve as a warn-
ing that this combination of chronic and acute diseases is
an increasing public health threat. The unifying hypothe-
sis is that that the chronic hyperactive inflammatory state
of obesity and diabetes leads to dysfunction of a whole
range of immune responses in the face of infection. These
responses fail to kill or control the invading organisms,
presumably due to downstream defects in complex innate
and immune pathways. A consistent finding is that sever-
ity of obesity and lack of control of diabetes aggravate
the susceptibility to agents of pneumonia. There is a need
for research into the mechanisms to understand how to
compensate for the defects. Particularly needed is a defi-
nition of the epidemiology in LMICs, where the greatest
risk will emerge and where diagnosis and treatment are
least available. Finally, preventive and therapeutic
approaches need to be developed based on new knowl-
edge, and applied on a global scale. Pneumonia from a
range of agents is a threat to the obese and those with
diabetes, and will be an increasing challenge in develop-
ing as well as developed countries.
1515
Tropical Medicine and International Health
S. P. Fisher-Hoch et al. Obesity, diabetes and pneumonia
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Corresponding Author Susan P. Fisher-Hoch, Division of Epidemiology, Human Genetics and Environmental Sciences, University
of Texas School of Public Health, Brownsville Campus, 80 Fort Brown, Brownsville, TX 78520, USA. Tel.: +1 956 882 5167;
Fax: +1956 882 5152; E-mail: susan.p.fisher-hoch@uth.tmc.edu

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