Download IMMUNODEFICIENCY IN PATIENTS WITH CHRONIC MEDICAL

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?