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IMMUNODEFICIENCY IN PATIENTS WITH CHRONIC MEDICAL CONDITIONS 5th ESCMID School of Clinical Microbiology and Infectious Diseases Santander, Spain, 10 - 16 June 2006 The relevance of the problem Diabetes: 10% Renal chronic failure: 11% COPD: 7.5% Cardiac failure: 2.2 % Psychiatric illnesses: 6% Dementia: 2% Cirrhosis: 0.2% Lora-Gomez RE et al. Am J Kidney Dis 2003, 41:1–12; Halbert RJ, et al. Eur Respir J 2006, 12; Redfield MM, et al. JAMA 2003, 289:194-202; Ansseau M, et al. Eur Psychiatry 2005, 20:229-35; Wimo A, et al. Dement Geriatr Cogn Disord 2006, 21:175-81. The relevance of the problem 1987 USA: – 90 million people with “chronic conditions”. – 39 million of whom were living with more than 1 chronic condition. Hoffman C, et al. Persons with chronic conditions. JAMA 1996; 276:1473. The relevance of the problem Number of Persons Diabetes in the United States, 1980–2004 Millions of diabetics 16 14 12 10 8 6 4 2 19 80 19 82 19 84 19 86 19 88 19 90 19 92 19 94 19 96 19 98 20 00 20 02 20 04 0 Steinbrook R. Facing the diabetes epidemic. N Engl J Med 2006; 354:545-8. Immunodeficiency in chronic conditions? Epidemiological evidence – Increase of infections – Worse prognosis Animal models. Laboratory data – Immune response – Host-microorganisms relationships. Diabetes Immunosuppression? – Increase of infections immunosuppression 25% of diabetics Diabetes Increase of infections immunosuppression – Organ lesions: Vascular damage Neuropathy – Glucosuria may promote bacterial growth – Insulin injections: increase nasal carriage of S. aureus (34% vs 10% ) Diabetes: Burn wound age on admission 60 Within 48 h - 49 (40%) - 995 (63%) 50 Diabetic Non diabetic 40 % 30 20 10 0 <2 4h 48h 72h k k + wee -3 w ee onths 2 m Memmel H. Infections in diabetic burn patients. Diabetes Care 2004; 27:229. Diabetes: Burn wound age on admission 60 Diabetic Non diabetic 50 40 % 30 Outcome Diabetic (n=130) Non diabetic (n=126) Bacteremia 12 (9.2%) 38 (2.5%) Sepsis 13 (10%) 28 (2.5%) Cellulitis 35 (27%) 120 (11%) 20 10 0 <2 4h 48h 72h k k + wee -3 wee onths 2 m Memmel H. Infections in diabetic burn patients. Diabetes Care 2004; 27:229. Diabetes: immunossupression? “Contrary to common belief, the association between diabetes mellitus and increased susceptibility to infection in general is not supported by strong evidence”. Joshi N, et al. Infections in patients with diabetes mellitus. N Eng J Med 1999; 341: 1906. Diabetes: immunossupression? “However, many specific infections are more common in diabetic patients, and some occur almost exclusively in them”. Joshi N, et al. Infections in patients with diabetes mellitus. Diabetes Increased risk of infections? – Selected infections – Selected microorganisms – Global risk Worse prognosis? Diabetes: increase of selected infections Klebsiella liver abscess Klebsiellla lung abscess Zygomicosis Melioidosis Non tiphoidal Salmonellosis 0 20 40 60 80 % Patients with diabetes Wang JH, et al. CID 1998; Wang JL CID 2005; Roden MM et al. CID 2005; Farley et al. N Engl J Med 1993; Hohmann EL. CID 2001; 32:263–9; Simpson JH, et al. CID 2003. Diabetes: increase of selected infections Bacteremia S.aureus GB Strp. Pseudomonas Enterobacteria S. pneumoniae Candida 0 20 40 60 % Patients with diabetes 80 Vidal F et al. Arch Intern Med 1998; Chi et al . JAGS 2006; Thompsen RW et al. CID 2005; Kao et al. CID 1999; Khatit R et al. CID 2005. Diabetes: increase of selected infections Malignant otitis external Necrotizing fasciitis Perinephic abscess Emphysematous cholecystitis Liver abscess Lung abscess 0 20 40 60 80 100 % Patients with diabetes Edelstein H et al. Medicine 1988; Wang JL et al. CID 2005, et al. Mentzer RM, et al. Am J Surg 1975; Grandis JR et al. Lancet Inf Dis 2004; Paty R et al. Urol Clin N Am 1992. Diabetes: increase of selected infections N Engl J Med 2003;348:2329 Diabetes: increase of selected infections Diabetes: 70% Malnutrition: 25 % Alcoholism: 23% Renal chronic failure: 14% Cirrhosis: 5% BMJ 2005;330:830–3 Elliott D, et al. The microbiology of necrotizing soft tissue infections. Am J Surg 2000; 179:361. Number of Cases Diabetes: increase of selected infections 100 90 80 70 60 50 40 30 20 10 0 Zygomycosis 1940s 1950s 1960s 1970s 1980s 1990s Diabetes No Underlying Deferroxamine Transplantation Malignancy BMT Roden MM, et al. Epidemiology and outcome of zygomycosis: a review of 929 reported cases. Clin Infect Dis 2005;41:634. Diabetes: increase of infections N=337 8% 10% 43% 16% 15% Rhinocecebral Sinus Sino-orbital Pulmonary Cutaneous GI Other N=154 12% 3% 6% 60% 4% 10% 5% 8% 9% Diabetes 8% 50% Malignancy 11% No underlying condition 9% 8% 5% N=176 Roden MM, et al. Epidemiology and outcome of zygomycosis: a review of 929 reported cases. Clin Infect Dis 2005;41:634. Diabetes: increase of infections Low pH – Lack of serum activity – Higher Iron availability Macrophage defect – Murine model 85% of Rhino-cerebral zygomicosis in diabetics Diabetes: increase of infections Type 1 DM (n=705) 6 Odds ratio 5 4 3 2 1 0 LRTI UTI RecITU B. Skin F. Skin Control patients with hypertension (n= 18,911) Muller LM, et al. Increased Risk of Common Infections in Patients with Type 1 and Type 2 Diabetes Mellitus. Clin Infect Dis 2005; 41:281-8 Diabetes: increase of infections Type 2 DM (n=6712) 6 Odds ratio 5 4 3 2 1 0 LRTI UTI Rec ITU B. Skin F. Skin Control patients with hypertension (n= 18,911) Muller LM, et al. Increased Risk of Common Infections in Patients with Type 1 and Type 2 Diabetes Mellitus. Clin Infect Dis 2005; 41:281. Diabetes: increase of selected infections Enterobacteria community-acquired bacteremia 4 3.5 Odds ratio 3 2.5 2 1.5 1 Cases n= 1317 Controls n=13170 0.5 0 All E.coli Klebsiella Thomsen RW, et al. Diabetes Mellitus as a Risk and Prognostic Factor for CommunityAcquired Bacteremia Due to Enterobacteria. Clin Infect Dis 2005;40:628 Diabetes: increase of infections Diabetes Infection RR (95% CI) Ref LVAD-related BSI 7.7 ( 2.0–29.8) Simon D et al. CID 2005; 40:1108 Postcardiothoracic (SSI) 2.7 (1.64-4.66) Latham R et al. Infect Control Hosp Epidemiol. 2001;22:607 Postgastrectomy infections 6.8 (1.7- 27.1) Yamashita et al. Anesth Analg 2000;91:1176 4.1 (1.1-17) Neal KR et al. Epidemiol Infect; 1997; 119:307 Salmonella enteritidis 3.1 (1.1-8.6) Telzak EE et al. J Infect Dis 1991; 164:538 Neumonia 1.3 (1.1-1.5) Fine M et al. JAMA 1996; 275: 174 Invasive GAS 11 (8.4-14.0) Sharkawy A et al. CID 2002; 34:454 Campylobacter gastroenteritis Diabetes: increase of infections Diabetes Outpatients Infection OR (95% IC) Per 100000 pat. Upper respiratory tract 1.18 (1.17–1.19)* 28,454 Cystitis 1.39 (1.36–1.42)* 5,491 Pneumonia 1.46 (1.42–1.49)* 4,919 Cellulitis 1.81 (1.76–1.86)* 4626 Enteric infections 1.50 (1.46–1.54)* 4,087 Otitis externa 1.14 (1.09–1.18)* 1,734 Mycoses 1.38 (1.32–1.44)* 1,396 Genital infections (male) 0.89 (0.86–0.89)* 1340 Otitis media 1.21 (1.15–1.28)* 1,071 Chicken pox/shingles 1.16 (1.09–1.22)* 816 *P 0.0001; †P 0.001. Diabetics N= 513,749. 1:1 controls matched for date of birth within 30 days, sex, region, and income quintile. Shah BR, Hux JE. Quantifying the risk of infectious diseases for people with diabetes. Diabetes Care 2003;26:510. Diabetes: increase of infections Diabetes Outpatients Infection OR (95% IC) Per 100000 pat. Viral hepatitis Pyelonephritis Tuberculosis Osteomyelitis 1.49 (1.39–1.60)* 1.95 (1.78–2.13)* 1.12 (1.03–1.23)† 4.39 (3.80–5.06)* 682 486 344 340 Genital infections (female) Mononucleosis Rectal abscess Infectious arthritis Herpes simplex virus 1.16 (1.04–1.30)† 1.60 (1.39–1.85)* 1.97 (1.67–2.32)* 1.72 (1.42–2.08)* 0.92 (0.84–1.02) 234 159 144 98 253 HIV 0.96 (0.78–1.18) 57 *P 0.0001; †P 0.001. Diabetics N= 513,749. 1:1 controls matched for date of birth within 30 days, sex, region, and income quintile. Shah BR, et al. Quantifying the risk of infectious diseases for people with diabetes. Diabetes Care 2003;26:510. Diabetes: increase of infections Diabetes Inpatients Infection OR (95% IC) Per 100000 pat. Sepsis 2.45 (2.23–2.68)* 539 Postoperative infections 2.02 (1.80–2.27)* 283 Biliary tree infections 1.60 (1.39–1.83)* 173 Peritonitis .94 (1.58–2.37)* 193 Appendicitis 1.19 (0.96–1.47) 62 *P 0.0001; †P 0.001. Diabetics N= 513,749. 1:1 controls matched for date of birth within 30 days, sex, region, and income quintile. Shah BR, et al. Quantifying the risk of infectious diseases for people with diabetes. Diabetes Care 2003;26:510. Diabetes: immunossupression? “Contrary to common belief, the association between diabetes mellitus and increased susceptibility to infection in general is not supported by strong evidence”. Joshi N, et al. Infections in patients with diabetes mellitus. N Eng J Med 1999; 341: 1906. Diabetes: increase of infections? “The association between diabetes mellitus and increased susceptibility to infection is well supported”. Diabetes: prognostic factor Uncontrolled diabetes was reported to be associated with a fatal outcome of infectious diseases in diabetic patients. Leibovici L, et al. Influence of diabetes mellitus and glycaemic control on the characteristics and outcome of common infections. Diabet Med 1996;13:457. Diabetes: prognostic factor Enterobacteria bacteremia: prognostic factors n = 225 n = 1092 90 days the mortality: -Diabetics: 23.3% -Non diabetics 19.5%. Thomsen RW, et al. Diabetes Mellitus as a Risk and Prognostic Factor for CommunityAcquired Bacteremia Due to Enterobacteria. Clin Infect Dis 2005;40:628 Diabetes: prognostic factor Staphylococcus aureus bacteremia: prognostic factors 293 patients with episodes of SAB, 68 died (23.2%) Mylotte MA, et al. Staphylococcus aureus bacteremia: predictors of 30-day mortality in a large cohort. Clinical Infectious Diseases 2000; 31:1170. Diabetes: prognostic factor Deep neck infection in diabetic patients Huang TT. Deep neck infection in diabetic patients. Otolaryngol Head Neck Surg 2005;132:943. Diabetes: prognostic factor Tuberculosis: prognostic factors Diabetes Renal failure 139 patients with tuberculosis 29 (21%) died (Baltimore). Oursler KK. Survival of patients with pulmonary tuberculosis: clinical and molecular epidemiologic factors. Clinical Infectious Diseases 2002; 34:752. Hyperglycemia: prognostic factor Van den Berghe, G. et al. N Engl J Med 2001;345:1359 Diabetes: worse prognosis Diabetic n=9,208 Infection related Non- Diabetic Bertoni AG, et al. Diabetes and the risk of infection-related mortality in the U.S. Diabetes Care 2001; 24:1044. Diabetes: “epidemiological” conclusions Increase risk of infections Worse prognosis Diabetes: altered immunity Leukocyte function – Adherence – Chemotaxis – Phagocytosis. Antioxidant systems involved in bactericidal activity Intracellular killing of microorganisms – May improve with better glycemic control. Joshi N. Infections in patients with diabetes mellitus. N Eng J Med 1999; 341: 1906 Diabetes: altered immunity Immunity Innate Adaptative Adherence Humoral Cellular Complement ↓ PMNs ↓= Cytokines without stimulation ↑ Monocytes ↓ Cytokines after stimulation ↓= Immunoglobulins = T lymphocytes ↓ ↑ Geerlings SE, et al. FEMMS 1999; Calvet HM, Inf Dis Clin N Am 2001 Diabetes: altered immunity Normal PMN Diabetes Oxidative burst Degranulation Free radial production Adhesion molecules Activated Resting PMN Tolerant Resting PMN Stimulus Calvet HM. Infect Dis Clin N Am 2001; Oxidative burst Degranulation Free radial production Adhesion molecules Risk of infection Diabetes: altered immunity Uroepithelial cell adherence Bacteria per cell 14 Non diabetics Diabetics 12 10 8 6 4 2 0 Negative P fimbriae Type 1 fimbriae No fimbriae Geerlings SE, et al. Adherence of type 1-fimbriated Escherichia coli to uroepithelial cells: more in diabetic women than in control subjects. Diabetes Care 2002; 25:1405. Diabetes: altered immunity Geerlings SE, et al. Adherence of type 1-fimbriated Escherichia coli to uroepithelial cells: more in diabetic women than in control subjects. Diabetes Care 2002; 25:1405. Diabetes: altered immunity % activity of control values Restoration of phagocytic activity 100 90 80 70 60 50 40 30 20 10 0 Before After Gin H, et al. Influence of glycaemic normalisation by an artificial pancreas on phagocytic and bactericidal functions of granulocytes in diabetic patients. J Clin Pathol 1984;37:1029. Diabetes: clinical consecuences Vaccination Influenza S. pneumoniae Others Relevance of glycemic control During infection Long term Chronic liver disease: increase of infections? Vibrio vulnificus Klebsiella liver abscess Klebsiellla lung abscess Zygomicosis Group B Strp bacteremia Liver disease Diabetes Non tiphoidal Salmonellosis 0 20 40 60 80 % Patients Wang JH, et al. CID 1998; Wang JL CID 2005; Roden MM et al. CID 2005; Farley et al. N Engl J Med 1993; Hohmann EL et al. CID 2001;Simpson JH, et al. CID 2003. Chronic liver disease: increase of infections? Spontaneous bacterial peritonitis: 60% of severe infections Impaired clearing bacteria Prolonged Bacteremia Sterile ascitis Bacterascitis Bacterial traslocation Intestinal hipomotility Intestinal oedema SBP Chronic liver disease: immunossupression? 51Cr erythrocytes (RhD+) from patients sensitized with human IgG anti-RhD antibodies. Gomez F, et al. Impaired function of macrophage Fc gamma receptors and bacterial infection in alcoholic cirrhosis. N Engl J Med 1994; 331:1122. Chronic liver disease: immunossupression? Severe Moderate Mild Gomez F, Ruiz P, Schreiber AD. Impaired function of macrophage Fc gamma receptors and bacterial infection in alcoholic cirrhosis. N Engl J Med. 1994 Oct 27;331(17):1122-8. Chronic liver disease: increase of infections? Bacteremia Danish National Registry of Patients: •7033 cases of bacteremia •1339 patients with liver cirrhosis -117 cases of bacteremia and cirrhosis *SIR (95% CI) Bacteremia Liver Cirrhosis Alcoholic 13.9 (10.8-17.6) Non-alcoholic 7.8 (5.7-10.4) Total 10.5 (8.8-12.7) *Standardized incidence ratio Thulstrup AM, et al. Population-based study of the risk and short-term prognosis for bacteremia in patients with liver cirrhosis. Clin Infect Dis 2000;31:1357. Chronic liver disease: increase of infections? Liver abscess Danish National Registry of Patients: •22764 cases of liver cirrhosis •665 patients with liver abscess -21 cases of liver abscess and cirrhosis *SIR (95% CI) Bacteremia Liver Cirrhosis Alcoholic 15.5 (8.2-26.5) Non-alcoholic 15.7 (6.8-30.9) Total 15.4 (9.6-23.6) Standardized incidence ratio of 15.4 (9.6–23.6). Molle I, et al. Increased risk and case fatality rate of pyogenic liver abscess in patients with liver cirrhosis: a nationwide study in Denmark. Gut 2001;48:260. Chronic liver disease: increase of infections? 16 High Low 14 %SBP 12 Cut points: -Albumin 1 g/dL -Opsonic: 0.2 log Kill 10 8 6 4 2 0 Protein Opsonic capacity Runyon BA. Gastroenterology 1986;91:1343; Runyon BA. Hepatology 1988;8:632-5 Chronic liver disease: increase of infections? Vibrio vulnificus septicemia Predisposing % Liver Cirrhosis 80 Other immunossupression 15 Consume of raw oysters 97 Presentation % Fever 97 Skin lesions 65 Diarrhea 47 Mortality 53 Haq SM, et al. Am J Gastroenterol. 2005;100:1195-9. Falcon, L. M. et al. N Engl J Med 2005;353:1604 Chronic liver disease: increase of infections? Vibrio vulnificus septicemia Predisposing % Liver Cirrhosis 80 Other immunossupression 15 Consume of raw oysters 97 Presentation % Fever 97 Skin lesions 65 Diarrhea 47 Mortality 53 Shunting of bacteria Achlorhydria Increase of Iron serum Haq SM, et al. Am J Gastroenterol. 2005;100:1195-9. Falcon, L. M. et al. N Engl J Med 2005;353:1604 Chronic liver disease: Ferritin (ng/mL) increase of infections? 900 800 700 600 500 400 300 200 100 0 Ferritin Healthy 4 3.5 3 Chronic hepatitis 100 90 80 70 60 50 40 30 20 10 0 Cirrhosis Hepatoma Healthy 7 Vibrio survival Phagocytosis 6.8 Chronic hepatitis Cirrhosis Hepatoma E. coli survival 6.6 2.5 2 1.5 1 0.5 0 6.4 6.2 6 5.8 5.6 Healthy Chronic hepatitis Cirrhosis Hepatoma Healthy Chronic hepatitis Cirrhosis Hepatoma Hor LI, et al. Survival of Vibrio vulnificus in whole blood from patients with chronic liver diseases: association with phagocytosis by neutrophils and serum ferritin levels. J Infect Dis 1999;179:275. Chronic liver disease SARM nosocomial endocarditis: risk factors 45 40 35 30 25 20 15 Endocarditis n=31 Non-endocarditis n=142 ** 10 5 0 * Diabetes Renal CF Cirrhosis IDU Dyalisis Hsu RB . Risk factors for nosocomial infective endocarditis in patients with methicillinresistant staphylococcus aureus bacteremia . Infect Control Hosp Epidemiol 2005; 26:654. Chronic liver disease: immunossupression? ABNORMALITIES Impaired rethiculoendothelial system Impaired hepatic clearance for bacteria Impaired killing Splenic hypofunction Complement defect Acquired C3 defect Neutrophil defect Defective chemotaxis Presence of chemotatic inhibitors T and B defect Decreased Lympocyte response to PHA Delayed type hypersensitivity Immunoglobulin defect Policlonal gammapathy Johnson DH, Cunha BA. Infections in cirrhosis. Infect Dis Clin North Am 2001;15:363-71. Chronic conditions: increase of infections? Vibrio vulnificus Klebsiella liver abscess Any Renal failure Alcoholism Liver disease Diabetes Klebsiellla lung abscess Zygomicosis Group B Strp bacteremia 0 20 40 60 80 100 % Patients Wang JH, et al. CID 1998; Wang JL CID 2005; Roden MM et al. CID 2005; Farley et al. N Engl Chronic conditions: increase of infections? N=308 (Bacteremic 18.5%) 18 16 14 12 10 8 6 4 2 0 Dia Bacteremic Non-bacteremic es t e b R C l a en F rh Cir b. m r s o i ol om h o C c >1 Al s osi Peralta G et al. Risk factors for bacteremia in patients with limb cellulitis. Eur J Clin Microbiol Infect Dis (in press) Chronic conditions: increase of infections? 12 Mortality (%) 10 8 6 4 2 0 No AB Proximal >1 Comorb. < 2 days Peralta G et al. Risk factors for bacteremia in patients with limb cellulitis. Eur J Clin Microbiol Infect Dis Chronic conditions: increase of infections? Charlson index CONDITIONS Myocardial infarct Heart failure Peripheral vascular dis. Dementia COPD Connective tissue dis. Ulcer disease Mild liver disease Diabetes Hemiplegia POINTS 1 1 1 1 1 1 1 1 1 1 CONDITIONS Moderate-severe renal disease Diabetes + organ damage Tumor Leukemia Lymphoma Moder-severe liver dis. Metastatic AIDS POINTS 2 2 2 2 2 3 6 6 Charlson ME, et al. A new method of classifying prognostic comorbidity in longitudinal Chronic conditions: prognosis n = 91 30 Odds ratio 25 20 15 10 5 0 SARM TTP <12h Charlson >3 Marra AR et al. Time to blood culture positivity as a predictor of clinical outcome of Staphylococcus aureus bloodstream infection. J Clin Microbiol 2006; 44:1342. Chronic conditions: prognosis Mortality (%) 50 40 30 20 10 0 0 n = 3102 1 2 3 4 >5 Charlson score Murray SB, et al. Charlson Index is associated with one-year mortality in emergency department patients with suspected infection. Acad Emerg Med 2006;13:530. Infections in patients with chronic medical conditions? What we don't to know? Global risk of infection associated with chronic illnesses. Interaction among chronic illnesses. Clinical presentation of infections. Specific immune and non-immune mechanisms. Potential restoration of immunity. Prevention in high risk situations. Infections in patients with chronic medical conditions? What we don´t to know?