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Keywords:

  • obesity;
  • diabetes;
  • chronic inflammation;
  • pneumonia

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Conclusion
  8. References

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.

Objectifs

Analyser les connaissances actuelles sur l'impact épidémiologique, clinique et biologique de la pandémie de l'obésité et du diabète sur les pneumonies.

Méthodes

Nous avons effectué une revue de la littérature en utilisant PubMed et Embase, complétée par diverses sources. Compte tenu du caractère disparate et fragmenté de la littérature, un examen systématique formel n’était pas possible.

Résultats

En 2008, globalement 10% des hommes et 14% des femmes étaient obèses et on estime que 371 millions souffraient de diabète, dont la moitié diagnostiquée et de nombreux obèses. Les chiffres sont en augmentation rapide dans les pays à revenus faibles et intermédiaires où réside la majorité, mais des données fiables font défaut. Les pneumonies les plus fréquentes dans l'obésité et le diabète sont la tuberculose, la grippe et le pneumocoque, le staphylocoque et des infections opportunistes. Le diabète affecte la lutte contre la tuberculose et augmente la résistance aux médicaments et la mortalité. La mortalité et la morbidité liées à la pneumonie à pneumocoques et à la grippe sont augmentées dans l'obésité et le diabète. Outre les effets mécaniques et physiologiques il y a des anomalies immunologiques importantes caractérisées par une inflammation chronique, à faible échelle. La up-régulation et dérégulation simultanées des réponses immunitaires à la fois innées et adaptatives entravent le contrôle et l'inactivation des organismes envahisseurs. La prévention chez les personnes à risque est mal pratiquée, quoiqu'un dépistage de la tuberculose dans le diabète commence dans les milieux les plus touchés.

Conclusions

La pneumonie est une menace mondiale dans l'obésité et le diabète avec une incidence et une sévérité accrues de la maladie. Il y a des incertitudes quant à savoir si les vaccins sont tout aussi efficaces chez les personnes soufrant d'obésité ou de diabète. Une meilleure connaissance épidémiologique, clinique et biologique sera cruciale pour faire face à ce défi du 21è siècle.

Objetivos

Revisar los conocimientos actualmente disponibles sobre la epidemiología, el impacto clínico y biológico de la pandemia de obesidad y la diabetes sobre la neumonía.

Métodos

Hemos revisado literatura existente utilizando PubMed y EMBASE, suplementando con otras fuentes. Dada la naturaleza dispar y fragmentada de la literatura, no fue posible realizar una revisión sistemática formal.

Resultados

En el 2008 a nivel global, un 10% de los hombres y un 14% de las mujeres eran obesos y aproximadamente unos 371 millones tenían diabetes: la mitad sin diagnosticar y muchos de ellos obesos. Los números aumentan con rapidez en países con ingresos bajos y medios en donde viven la mayor parte, pero no se tienen datos fiables. Las neumonías más frecuentes entre obesos y diabéticos son por tuberculosis, influenza y neumococo, estafilococo y patógenos oportunistas. La diabetes tiene un impacto sobre el control de la tuberculosis y aumenta la resistencia a los medicamentos y la mortalidad. La mortalidad y morbilidad por neumonía neumocócica e influenza aumentan con la obesidad y la diabetes. Adicionalmente a los efectos mecánicos y fisiológicos, hay anormalidades inmunológicas considerables caracterizadas por una inflamación crónica de bajo grado. Una regulación al alza y una mala regulación simultánea de las respuestas inmune innata y adaptativa afectan el control y eliminación de los organismos invasores. La prevención entre aquellos en riesgo es una práctica poco común, aunque se comienza a realizar un examen de detección de la tuberculosis en pacientes con diabetes en emplazamientos con una alta carga.

Conclusiones

La neumonía es una amenaza global en pacientes obesos y diabéticos produciéndose un aumento en la incidencia y severidad de la enfermedad. No existe certeza sobre si las vacunas son igual de efectivas entre aquellos con diabetes y obesidad. Se requiere profundizar en los conocimientos sobre la epidemiología, clínica y biología con el fin de enfrentarnos a este reto del siglo XXI.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Conclusion
  8. References

Obesity and diabetes are prominent in the pandemic of non-communicable diseases (NCDs) currently exploding globally, most rapidly in low- and middle-income countries (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 Organisation 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 fragmented, and the clinical impact and biological mechanisms are poorly understood. However, the impact of obesity and diabetes on the immune system is broad and complex and impacts incidence and severity of pneumonia. The pivotal pathology is the chronic inflammatory syndrome, resulting in hyper-reactive, chronically up-regulated immune responses which, paradoxically, have poor microbial killing efficiency (Peleg et al. 2007; Falagas et al. 2009). This review examines the current epidemiological, clinical and biological evidence underlying pneumonia associated with obesity and diabetes globally and the major challenges to address pneumonia in people with these conditions.

Methods

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Conclusion
  8. References

The aim of this study was to review current knowledge on the epidemiological, clinical and biological implications for pneumonia of the current pandemic in NCDs. The objective was to determine the larger risk of obesity and diabetes in increased incidence and severity of common pneumonias. To do this, we conducted a literature search using PubMed and EMBASE, supplemented by searches using Google Scholar, to derive older citations and online reports, and bibliographies of relevant literature. The fragmented and disparate nature of the literature precluded a formal systematic review or meta-analysis. Rather, we attempted to review the wide range of data that do exist. To gain an understanding, we had to consider literature from epidemiology, global public health, socio-economic issues, immunology, clinical and basic science, animal models and ornithology. Ethical approval was not required for the purposes of this review Table 1.

Table 1. Key clinical, epidemiological and public health publications
CitationKey observations
Clinical and epidemiological reports
Vaillant et al. (2009)Characteristics of 574 deaths associated with pandemic H1N1
Webb et al. (2009)Review of intensive care unit experiences in the H1N1 pandemic
Sedyaningsih et al. (2007)Epidemiology of H5N1 infections in Indonesia
Asghar et al. (2011)High rates of diabetes among all patients with pneumonia
Mugusi et al. (1990)First report of diabetes and tuberculosis in Africa
Olmos et al. (1989)Early report of type 2 diabetes and tuberculosis in Chile
Pablos-Mendez et al. (1997)Case–control study of tuberculosis and diabetes in Mexico
Ponce-De-Leon et al. (2004)Data from population-based cohort shows 6.8-fold increase in tuberculosis cases in diabetes
Restrepo et al. (2011)Between 36% and 39% of patients with tuberculosis have diabetes
Restrepo et al. (2007)Diabetes tripled risk of active tuberculosis
Allard et al. (2010)Diabetes tripled risk of hospitalisation with influenza
Public Health
Harries et al. (2010)Recommendations for studies of diabetes and tuberculosis
Harries et al. (2009)Recommendations for screening vintegrated with care
Harries et al. (2011)Recommendations for addressing the global threat of diabetes to tuberculosis control
Systematic reviews with Meta-Analysis
Jeon and Murray (2008)Review of epidemiological studies
Jeon et al. (2010)Review of screening procedures
Baker et al. (2011)Review of treatment outcomes

Results

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Conclusion
  8. References

Obesity and pneumonias

Epidemiology and clinical impact

The epidemic of obesity is now widely recognised as a major threat to both health and global economies (Bloom et al. 2011; World Health Organisation 2011). Obesity is a risk factor for nosocomial and community-acquired infections, poor wound healing and aberrant vaccine responses, although some of the data for community-acquired pneumonia are conflicting (Falagas et al. 2009; Kornum et al. 2010). The adverse impact of obesity on influenza is most consistent and best documented (Centers for Disease Control & Prevention 2009; Vaillant et al. 2009; Webb et al. 2009). Although the risks of influenza in obesity had been previously recognised, the 2009 swine influenza virus (S-OIV) H1N1 pandemic highlighted obesity as a leading risk factor for mortality in patients with influenza over the age of 20 (Centers for Disease Control & Prevention 2009; Vaillant et al. 2009; Webb et al. 2009). Influenza virus strains emerging in their natural hosts (migrating waterfowl) separate into LPAI strains and the less common, highly pathogenic avian influenza (HPAI) strains, causing significant mortality in birds and humans (Webster & Govorkova 2006; Centers for Disease Control & Prevention 2013). S-OIV is a low pathogenicity influenza virus (LPAI) not usually associated with pneumonia and death in adults below 65 years of age. Human HPAI epidemics are rare (specifically the 1918 pandemic and the current H5N1 strains) (Soper 1918; Johnson & Mueller 2002; Sedyaningsih et al. 2007).

Annual influenza epidemics are mostly caused by LPAI strains and are mild, and most deaths are in infants and the elderly (Webster et al. 1992; Centers for Disease Control & Prevention 2013). However, individual risk factors, particularly obesity, but also pregnancy, predispose to viral pneumonia, and death in young adults infected with LPAI strains, in whom the pathology is similar to that in HPAI human infections (Vaillant et al. 2009). In an early 2009 S-OIV report of infected obese patients with influenza requiring intensive care and respiratory support (median age 46 years), the presentation was adult respiratory distress syndrome (ARDS). All had multilobular pneumonia consistent with primary viral pneumonia, and none had evidence of secondary bacterial infection (Centers for Disease Control & Prevention 2009). In another study of 34 patients, dying of the swine origin S-OIV virus in New York in nearly half obesity 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 physiological 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). Aspiration 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 susceptibility, but a complex picture of deleterious changes in the immune response is emerging in rodent models and in humans revealing complex cross-talk between adipocytes, 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, adiponectin, resistin, visfatin) important in obesity have been redefined 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 multiple proteins known to influence components of the innate immune response, such as tumour necrosis factor α (TNFα), 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-κB pathway (Schaeffler et al. 2009).

The potent immunomodulatory effects of adipocytokines in obese humans with pneumonia are not well elucidated (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 TNFα 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 TNFα 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 presentation of influenza virus antigens to the immune system, was also impaired, with downstream alterations in cytokine 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 infections 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 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 diabetes and tuberculosis has become widely recognised globally (Jeon & Murray 2008; Young et al. 2009; Harries et al. 2011). However, many other pulmonary pathogens also result in increased morbidity and mortality in diabetes, particularly influenza, pneumococcal and staphylococcal 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 million 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 documented globally (Olmos et al. 1989; Mugusi et al. 1990; Swai et al. 1990). The adjusted odds ratio for this association 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 similar associations in South Texas (Perez et al. 2006; Restrepo et al. 2007, 2011). Reports from many countries across the globe followed rapidly, particularly in Asia (Leung et al. 2008; Dooley & Chaisson 2009; Viswanathan et al. 2012). Even pre-diabetes increases the risk of tuberculosis (Viswanathan et al. 2012). In 2008, a working 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, Diabetes 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; Goldhaber-Fiebert et al. 2011; Hall et al. 2011; Harries et al. 2011). The increase in tuberculosis due to diabetes is particularly 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 hospital-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 complications 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 insensitive, 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 pneumococcal 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 significant, 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 diabetes (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 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 pneumonia and diabetes came again from the 2009 pandemic of S-OIV. In one series of hospitalised patients with influenza (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 admitted 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 diabetes 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 characteristic 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 insulin secretion leading to insulin resistance and pancreatic β-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, 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 reproducibility, 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), phagocytosis (Krol et al. 2003), production of reactive oxygen species (Marhoffer et al. 1994) and apoptosis (Tennenberg et al. 1999). The downstream effects of these impairments are decreased ability to respond to sites of infection, inability to effectively destroy and clear pathogens 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 antimicrobial activity in response to challenge with M. tuberculosis (Wang et al. 1999). Decreased populations of monocytes with complement receptor 3 (used for adherence and phagocytosis of pathogens) are associated with diabetes (Chang & Shaio 1995). Macrophages have compromised functionality of Fc receptors used for antigen processing and presentation, including diminished internalisation of Fc-receptor-bound material under conditions of insulin resistance, so that the ability to process and present 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 leucocytes to sites of infection (Andreasen et al. 2010).

There are elevated levels of pro-inflammatory cytokines in diabetes, both at baseline and after immune stimulation. In diabetes, interleukin-8, interleukin-1b, IL-6 and TNF-α have higher baseline and expression levels after experimental stimulation of cells with bacterial lipopolysaccharide. Innate and type 1 cytokine responses were significantly higher in tuberculosis patients with diabetes, nevertheless these patients fail to control the mycobacterium adequately (Restrepo et al. 2008). Conversely, in a rodent model, Th1-related cytokines and expression of inducible nitric oxide synthetase were reduced in experimentally infected animals with diabetes (Yamashiro et al. 2005). In our own studies, we have documented significantly higher levels of pro-inflammatory cytokines in resting plasma samples from our cohort of Mexican Americans with high rates of diabetes (Mirza et al. 2012). Stimulation of whole blood from diabetes patients with heat-killed pneumococci resulted in a 10-fold increase in the secretion of interferon-γ, IL-6 and interleukin-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-producing 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-1β (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 regulatory 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

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Conclusion
  8. References

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 characteristic 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.

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 countries, diabetes clinics do not have anything like the structure 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

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Conclusion
  8. References

Although it is not possible to estimate the overall morbidity and mortality, the data that exist do serve as a warning that this combination of chronic and acute diseases is an increasing public health threat. The unifying hypothesis 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 severity 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 definition 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 knowledge, 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 developing as well as developed countries.

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Conclusion
  8. References
  • Abrass CK (1991) Fc-receptor-mediated phagocytosis: abnormalities associated with diabetes mellitus. Clinical Immunology and Immunopathology 58, 117.
  • Aldridge JR Jr, Moseley CE, Boltz DA et al. (2009) TNF/iNOS-producing dendritic cells are the necessary evil of lethal influenza virus infection. Proceedings of the National Academy of Sciences of the United States of America 106, 53065311.
  • Allard R, Leclerc P, Tremblay C & Tannenbaum TN (2010) Diabetes and the severity of pandemic influenza A (H1N1) infection. Diabetes Care 33, 14911493.
  • Andreasen AS, Pedersen-Skovsgaard T, Berg RM et al. (2010) Type 2 diabetes mellitus is associated with impaired cytokine response and adhesion molecule expression in human endotoxemia. Intensive Care Medicine 36, 15481555.
  • Asghar AH, Ashshi AM, Azhar EI, Bukhari SZ, Zafar TA & Momenah AM (2011) Profile of bacterial pneumonia during Hajj. Indian Journal of Medical Research 133, 510513.
  • Baker MA, Harries AD, Jeon CY et al. (2011) The impact of diabetes on tuberculosis treatment outcomes: a systematic review. BMC Medicine 9, 81.
  • Bastard JP, Maachi M, Lagathu C et al. (2006) Recent advances in the relationship between obesity, inflammation, and insulin resistance. European Cytokine Network 17, 412.
  • Bell J & Hockaday T (1996) Diabetes Mellitus. In: Oxford Textbook of Medicine 3rd edn (eds DJ Wetherall, JGG Ledingham & DA Warrell) Oxford University Press, Oxford, pp. 14481504.
  • Bertoni AG, Saydah S & Brancati FL (2001) Diabetes and the risk of infection-related mortality in the U.S. Diabetes Care 24, 10441049.
  • Bloom DE, Cafiero ET, Jane-Llopis E et al. (2011) The Global Economic Burder of Non-Communicable Diseases. 1–46. World Economic Forum, Geneva, Switzerland, 146.
  • Breen JD & Karchmer AW (1995) Staphylococcus aureus infections in diabetic patients. Infectious Disease Clinics of North America 9, 1124.
  • Bygbjerg IC (2012) Double burden of noncommunicable and infectious diseases in developing countries. Science 337, 14991501.
  • Centers for Disease Control and Prevention (2006) Chronic Disease Prevention: Preventing Diabetes and its Complications.
  • Centers for Disease Control and Prevention (2009) Intensive-care patients with severe novel influenza A (H1N1) virus infection — Michigan, June 2009. Morbidity and Mortality Weekly Report 58, 749752.
  • Centers for Disease Control and Prevention (2013) Information on Avian Influenza. Department of Health and Human Services.
  • Chang FY & Shaio MF (1995) Decreased cell-mediated immunity in patients with non-insulin-dependent diabetes mellitus. Diabetes Research and Clinical Practice 28, 137146.
  • Dooley KE & Chaisson RE (2009) Tuberculosis and diabetes mellitus: convergence of two epidemics. The Lancet Infectious Diseases 9, 737746.
  • Droemann D, Aries SP, Hansen F et al. (2000) Decreased apoptosis and increased activation of alveolar neutrophils in bacterial pneumonia. Chest 117, 16791684.
  • Dye C & Williams BG (2010) The population dynamics and control of tuberculosis. Science 328, 856861.
  • Dye C, Bourdin TB, Lonnroth K, Roglic G & Williams BG (2011) Nutrition, diabetes and tuberculosis in the epidemiological transition. PLoS One 6, e21161.
  • Falagas ME, Athanasoulia AP, Peppas G & Karageorgopoulos DE (2009) Effect of body mass index on the outcome of infections: a systematic review. Obesity Reviews 10, 280289.
  • Fantuzzi G & Faggioni R (2000) Leptin in the regulation of immunity, inflammation, and hematopoiesis. Journal of Leukocyte Biology 68, 437446.
  • Fedson DS & Scott JA (1999) The burden of pneumococcal disease among adults in developed and developing countries: what is and is not known. Vaccine 17(Suppl. 1), S11S18.
  • Feuerer M, Herrero L, Cipolletta D et al. (2009) Lean, but not obese, fat is enriched for a unique population of regulatory T cells that affect metabolic parameters. Nature Medicine 15, 930939.
  • Gill JR, Sheng ZM, Ely SF et al. (2010) Pulmonary pathologic findings of fatal 2009 pandemic influenza A/H1N1 viral infections. Archives of Pathology and Laboratory Medicine 134, 235243.
  • Goldhaber-Fiebert JD, Jeon CY, Cohen T & Murray MB (2011) Diabetes mellitus and tuberculosis in countries with high tuberculosis burdens: individual risks and social determinants. International Journal of Epidemiology 40, 417428.
  • Hall V, Thomsen RW, Henriksen O & Lohse N (2011) Diabetes in Sub Saharan Africa 1999–2011: epidemiology and public health implications. A systematic review. BMC Public Health 11, 564.
  • Harries AD, Billo N & Kapur A (2009) Links between diabetes mellitus and tuberculosis: should we integrate screening and care? Transactions of the Royal Society of Tropical Medicine and Hygiene 103, 12.
  • Harries AD, Murray MB, Jeon CY et al. (2010) Defining the research agenda to reduce the joint burden of disease from diabetes mellitus and tuberculosis. Tropical Medicine and International Health 15:659663. NIHMS ID: 259253.
  • Harries AD, Yan L, Srinath S et al. (2011) The looming epidemic of diabetes-associated tuberculosis–learning lessons from HIV-associated tuberculosis. Tropical Medicine and International Health 15,659663.
  • Horton R (2013) Non-communicable diseases: 2015 to 2025. Lancet 381, 509510.
  • Ikejima S, Sasaki S, Sashinami H et al. (2005) Impairment of host resistance to Listeria monocytogenes infection in liver of db/db and ob/ob mice. Diabetes 54, 182189.
  • International Diabetes Federation (2012) IDF Diabetes Atlas, 5th edn. [article online] . http://www.idf.org/diabetesatlas/5e/the-global-burden. Accessed 4 April 2012.
  • Jagannathan-Bogdan M, McDonnell ME, Shin H et al. (2011) Elevated proinflammatory cytokine production by a skewed T cell compartment requires monocytes and promotes inflammation in type 2 diabetes. The Journal of Immunology 186, 11621172.
  • Jeon CY & Murray MB (2008) Diabetes mellitus increases the risk of active tuberculosis: a systematic review of 13 observational studies. PLoS Medicine 5, e152.
  • Jeon CY, Harries AD, Baker MA et al. (2010) Bi-directional screening for tuberculosis and diabetes: a systematic review. Tropical Medicine and International Health 15, 13001314.
  • Jimenez-Corona ME, Cruz-Hervert LP, Garcia-Garcia L et al. (2013) Association of diabetes and tuberculosis: impact on treatment and post-treatment outcomes. Thorax 68, 214220.
  • Johnson NP & Mueller J (2002) Updating the accounts: global mortality of the 1918–1920 “Spanish” influenza pandemic. Bulletin of the History of Medicine 76, 105115.
  • Joshi N, Caputo GM, Weitekamp MR & Karchmer AW (1999) Infections in patients with diabetes mellitus. New England Journal of Medicine 341, 19061912.
  • Kobayashi SD, Braughton KR, Palazzolo-Ballance AM et al. (2010) Rapid neutrophil destruction following phagocytosis of Staphylococcus aureus. Journal of Innate Immunity 2, 560575.
  • Kopelman PG (2000) Obesity as a medical problem. Nature 404, 635643.
  • Kornum JB, Norgaard M, Dethlefsen C et al. (2010) Obesity and risk of subsequent hospitalisation with pneumonia. European Respiratory Journal 36, 13301336.
  • Krol E, Agueel R, Banue S, Smogorzewski M, Kumar D & Massry SG (2003) Amlodipine reverses the elevation in [Ca2+]i and the impairment of phagocytosis in PMNLs of NIDDM patients. Kidney International 64, 21882195.
  • Lamas O, Marti A & Martinez JA (2002) Obesity and immunocompetence. European Journal of Clinical Nutrition 56(Suppl. 3), S42S45.
  • Leibovici L, Yehezkelli Y, Porter A, Regev A, Krauze I & Harell D (1996) Influence of diabetes mellitus and glycaemic control on the characteristics and outcome of common infections. Diabetic Medicine 13, 457463.
  • Leung CC, Lam TH, Chan WM et al. (2008) Diabetic control and risk of tuberculosis: a cohort study. American Journal of Epidemiology 167, 14861494.
  • Lin Y, Li L, Mi F et al. (2012) Screening patients with Diabetes Mellitus for Tuberculosis in China. Tropical Medicine and International Health 17, 13021308.
  • Lipsky BA, Pecoraro RE, Chen MS & Koepsell TD (1987) Factors affecting staphylococcal colonization among NIDDM outpatients. Diabetes Care 10, 483486.
  • Macia L, Delacre M, Abboud G et al. (2006) Impairment of dendritic cell functionality and steady-state number in obese mice. The Journal of Immunology 177, 59976006.
  • Mancuso P, Gottschalk A, Phare SM, Peters-Golden M, Lukacs NW & Huffnagle GB (2002) Leptin-deficient mice exhibit impaired host defense in Gram-negative pneumonia. The Journal of Immunology 168, 40184024.
  • Marhoffer W, Stein M, Schleinkofer L & Federlin K (1994) Monitoring of polymorphonuclear leukocyte functions in diabetes mellitus–a comparative study of conventional radiometric function tests and low-light imaging systems. Journal of Bioluminescence and Chemiluminescence 9, 165170.
  • Mathews CE, Brown EL, Martinez PJ et al. (2012) Impaired function of antibodies to pneumococcal surface protein a but not to capsular polysaccharide in mexican american adults with type 2 diabetes mellitus. Clinical and Vaccine Immunology 19, 13601369.
  • Mathis D & Shoelson SE (2011) Immunometabolism: an emerging frontier. Nature reviews. Immunology 11, 8183.
  • Mirza S, Hossain M, Mathews C et al. (2012) Type 2-diabetes is associated with elevated levels of TNF-alpha, IL-6 and adiponectin and low levels of leptin in a population of Mexican Americans: a cross-sectional study. Cytokine 57, 136142.
  • Mito N, Yoshino H, Hosoda T & Sato K (2004) Analysis of the effect of leptin on immune function in vivo using diet-induced obese mice. Journal of Endocrinology 180, 167173.
  • Mufson MA & Stanek RJ (1999) Bacteremic pneumococcal pneumonia in one American City: a 20-year longitudinal study-1997. American Journal of Medicine 107, 34S43S.
  • Mugusi F, Swai AB, Alberti KG & McLarty DG (1990) Increased prevalence of diabetes mellitus in patients with pulmonary tuberculosis in Tanzania. Tubercle 71, 271276.
  • Nam JS, Kim AR, Yoon JC et al. (2011) The humoral immune response to the inactivated influenza A (H1N1) 2009 monovalent vaccine in patients with Type 2 diabetes mellitus in Korea. Diabetic Medicine 28, 815817.
  • Nathan C (2008) Epidemic inflammation: pondering obesity. Molecular Medicine 14, 485492.
  • Olmos P, Donoso J, Rojas N et al. (1989) [Tuberculosis and diabetes mellitus: a longitudinal-retrospective study in a teaching hospital]. Revista Medica de Chile 117, 979983.
  • O'rourke RW, Kay T, Scholz MH et al. (2005) Alterations in T-cell subset frequency in peripheral blood in obesity. Obesity Surgery 15, 14631468.
  • Pablos-Mendez A, Blustein J & Knirsch CA (1997) The role of diabetes mellitus in the higher prevalence of tuberculosis among Hispanics. American Journal of Public Health 87, 574579.
  • Peleg AY, Weerarathna T, McCarthy JS & Davis TM (2007) Common infections in diabetes: pathogenesis, management and relationship to glycaemic control. Diabetes/metabolism research and reviews 23, 313.
  • Perez A, Brown HS III & Restrepo BI (2006) Association between tuberculosis and diabetes in the Mexican border and non-border regions of Texas. American Journal of Tropical Medicine and Hygiene 74, 604611.
  • Pickup JC (2004) Inflammation and activated innate immunity in the pathogenesis of type 2 diabetes. Diabetes Care 27, 813823.
  • Ponce-De-Leon A, Garcia-Garcia Md ML, Garcia-Sancho MC et al. (2004) Tuberculosis and diabetes in southern Mexico. Diabetes Care 27, 15841590.
  • Restrepo BI, Fisher-Hoch SP, Crespo JG et al. (2007) Type 2 diabetes and tuberculosis in a dynamic bi-national border population. Epidemiology and Infection 135, 483491.
  • Restrepo BI, Fisher-Hoch SP, Pino PA et al. (2008) Tuberculosis in poorly controlled type 2 diabetes: altered cytokine expression in peripheral white blood cells. Clinical Infectious Diseases 47, 634641.
  • Restrepo BI, Camerlin AJ, Rahbar MH et al. (2011) Cross-sectional assessment reveals high diabetes prevalence among newly-diagnosed tuberculosis cases. Bulletin of the World Health Organization 89:352359. PMCID: PMC3089389.
  • Ruslami R, Aarnoutse RE, Alisjahbana B, van der Ven AJ & Van CR (2010) Implications of the global increase of diabetes for tuberculosis control and patient care. Tropical Medicine and International Health 15, 12891299.
  • Santhosh YL, Ramanath KV & Naveen MR (2011) Fungal Infections in diabetes Mellitus: an Overview. International Journal of Pharmaceutical Sciences Review and Research 7, 221225.
  • Sawant JM (1993) Biochemical changes in polymorphonuclear leucocytes in diabetic patients. Journal of Postgraduate Medicine 39, 183186.
  • Schaeffler A, Gross P, Buettner R et al. (2009) Fatty acid-induced induction of Toll-like receptor-4/nuclear factor-kappaB pathway in adipocytes links nutritional signalling with innate immunity. Immunology 126, 233245.
  • Sedyaningsih ER, Isfandari S, Setiawaty V et al. (2007) Epidemiology of cases of H5N1 virus infection in Indonesia, July 2005–June 2006. Journal of Infectious Diseases 196, 522527.
  • Seshasai SR, Kaptoge S, Thompson A et al. (2011) Diabetes mellitus, fasting glucose, and risk of cause-specific death. New England Journal of Medicine 364, 829841.
  • Smith SA & Poland GA (2000) Use of influenza and pneumococcal vaccines in people with diabetes. Diabetes Care 23, 95108.
  • Smith SA & Poland GA (2003) Immunization and the prevention of influenza and pneumococcal disease in people with diabetes. Diabetes Care 26(Suppl. 1), S126S128.
  • Smith SA & Poland GA (2004) Influenza and pneumococcal immunization in diabetes. Diabetes Care 27(Suppl. 1), S111S113.
  • Smith AG, Sheridan PA, Harp JB & Beck MA (2007) Diet-induced obese mice have increased mortality and altered immune responses when infected with influenza virus. Journal of Nutrition 137, 12361243.
  • Smith AG, Sheridan PA, Tseng RJ, Sheridan JF & Beck MA (2009) Selective impairment in dendritic cell function and altered antigen-specific CD8+ T-cell responses in diet-induced obese mice infected with influenza virus. Immunology 126, 268279.
  • Soper GA (1918) THE INFLUENZA PNzrEUMONIA PANDEMIC IN THE AMERICAN ARMY CAMPS DURING SEPTEMBER AND OCTOBER. 1918. Science 48, 451456.
  • Swai AB, McLarty DG & Mugusi F (1990) Tuberculosis in diabetic patients in Tanzania. Tropical Doctor 20, 147150.
  • Tang S, Zhang Q, Yu J et al. (2011) Extensively drug-resistant tuberculosis at a tuberculosis specialist hospital in Shanghai, China: clinical characteristics and treatment outcomes. Scandinavian Journal of Infectious Diseases 43, 280285.
  • Tennenberg SD, Finkenauer R & Dwivedi A (1999) Absence of lipopolysaccharide-induced inhibition of neutrophil apoptosis in patients with diabetes. Archives of Surgery 134, 12291233.
  • Thomsen RW, Hundborg HH, Lervang HH, Johnsen SP, Schonheyder HC & Sorensen HT (2005) Diabetes mellitus as a risk and prognostic factor for community-acquired bacteremia due to enterobacteria: a 10-year, population-based study among adults. Clinical Infectious Diseases 40, 628631.
  • Tilg H & Moschen AR (2006) Adipocytokines: mediators linking adipose tissue, inflammation and immunity. Nature Reviews Immunology 6, 772783.
  • Tumpey TM, Basler CF, Aguilar PV et al. (2005) Characterization of the reconstructed 1918 Spanish influenza pandemic virus. Science 310, 7780.
  • Vaillant L, La RG, Tarantola A & Barboza P (2009) Epidemiology of fatal cases associated with pandemic H1N1 influenza. Eurosurveillance Weekly 14, pii: 19309.
  • Van Kerkhove MD, Mumford E, Mounts AW et al. (2011) Highly pathogenic avian influenza (H5N1): pathways of exposure at the animal-human interface, a systematic review. PLoS One 6, e14582.
  • Viswanathan V, Kumpatla S, Aravindalochanan V et al. (2012) Prevalence of diabetes and pre-diabetes and associated risk factors among tuberculosis patients in India. PLoS One 7, e41367.
  • Wang CH, Yu CT, Lin HC, Liu CY & Kuo HP (1999) Hypodense alveolar macrophages in patients with diabetes mellitus and active pulmonary tuberculosis. Tubercle and Lung Disease 79, 235242.
  • Webb SA, Pettila V, Seppelt I et al. (2009) Critical care services and 2009 H1N1 influenza in Australia and New Zealand. New England Journal of Medicine 361, 19251934.
  • Webster RG & Govorkova EA (2006) H5N1 influenza–continuing evolution and spread. New England Journal of Medicine 355, 21742177.
  • Webster RG, Bean WJ, Gorman OT, Chambers TM & Kawaoka Y (1992) Evolution and ecology of influenza A viruses. Microbiological Reviews 56, 152179.
  • Wolf AM, Wolf D, Rumpold H, Enrich B & Tilg H (2004) Adiponectin induces the anti-inflammatory cytokines IL-10 and IL-1RA in human leukocytes. Biochemical and Biophysical Research Communications 323, 630635.
  • World Health Organisation (2011) Global Status Report on non-communicable diseases. Alwan A. 1-176.World Health Organisation, Italy.
  • World Health Organisation (2012) Diabetes Fact Sheet No 312. Geneva. 1-22-2013.
  • World Health Organisation, Diabetes Program (2011) Collaborative Framework for Care and Control of Tuberculosis and Diabetes. World Health Organization, Geneva.
  • Yamashiro S, Kawakami K, Uezu K et al. (2005) Lower expression of Th1-related cytokines and inducible nitric oxide synthase in mice with streptozotocin-induced diabetes mellitus infected with Mycobacterium tuberculosis. Clinical and Experimental Immunology 139, 5764.
  • Young F, Critchley JA, Johnstone LK & Unwin NC (2009) A review of co-morbidity between infectious and chronic disease in Sub Saharan Africa: TB and diabetes mellitus, HIV and metabolic syndrome, and the impact of globalization. Global Health 5, 9.
  • Zarkesh-Esfahani H, Pockley AG, Wu Z, Hellewell PG, Weetman AP & Ross RJ (2004) Leptin indirectly activates human neutrophils via induction of TNF-alpha. The Journal of Immunology 172, 18091814.