IMMUNODEFICIENCY IN PATIENTS WITH CHRONIC MEDICAL CONDITIONS

1
IMMUNODEFICIENCY IN PATIENTS WITH CHRONIC MEDICAL
CONDITIONS

• 5th ESCMID School of Clinical Microbiology and
  Infectious DiseasesSantander, Spain, 10 - 16
  June 2006

2
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,
41112 Halbert RJ, et al. Eur Respir J 2006,
12 Redfield MM, et al. JAMA 2003, 289194-202
Ansseau M, et al. Eur Psychiatry 2005, 20229-35
Wimo A, et al. Dement Geriatr Cogn Disord 2006,
21175-81.
3
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 2761473.
4
The relevance of the problem
Number of Persons Diabetes in the United States,
19802004
Steinbrook R. Facing the diabetes epidemic. N
Engl J Med 2006 354545-8.
5
Immunodeficiency in chronic conditions?

• Epidemiological evidence
• Increase of infections
• Worse prognosis
• Animal models.
• Laboratory data
• Immune response
• Host-microorganisms relationships.

6
Diabetes

• Immunosuppression?
• Increase of infections ?immunosuppression

25 of diabetics
7
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 )

8
Diabetes
Burn wound age on admission
Within 48 h - 49 (40) - 995 (63)
Memmel H. Infections in diabetic burn patients.
Diabetes Care 2004 27229.
9
Diabetes
Burn wound age on admission
Memmel H. Infections in diabetic burn patients.
Diabetes Care 2004 27229.
10
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.
11
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. N Eng J Med 1999 341 1906.
12
Diabetes

• Increased risk of infections?
• Selected infections
• Selected microorganisms
• Global risk
• Worse prognosis?

13
Diabetes increase of selected infections
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 322639
Simpson JH, et al. CID 2003.
14
Diabetes increase of selected infections
Bacteremia
Patients with diabetes
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.
15
Diabetes increase of selected infections
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.
16
Diabetes increase of selected infections
N Engl J Med 20033482329
17
Diabetes increase of selected infections

• Diabetes 70
• Malnutrition 25
• Alcoholism 23
• Renal chronic failure 14
• Cirrhosis 5

BMJ 20053308303
Elliott D, et al. The microbiology of necrotizing
soft tissue infections. Am J Surg 2000 179361.
18
Diabetes increase of selected infections
Zygomycosis
Roden MM, et al. Epidemiology and outcome of
zygomycosis a review of 929 reported cases. Clin
Infect Dis 200541634.
19
Diabetes increase of infections
N337
N154
Diabetes
Malignancy
No underlying condition
N176
Roden MM, et al. Epidemiology and outcome of
zygomycosis a review of 929 reported cases. Clin
Infect Dis 200541634.
20
Diabetes increase of infections

• Low pH
• Lack of serum activity
• Higher Iron availability
• Macrophage defect
• Murine model

85 of Rhino-cerebral zygomicosis in diabetics
21
Diabetes increase of infections
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 41281-8
22
Diabetes increase of infections
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 41281.
23
Diabetes increase of selected infections
Enterobacteria community-acquired bacteremia
Cases n 1317 Controls n13170
Thomsen RW, et al. Diabetes Mellitus as a Risk
and Prognostic Factor for Community- Acquired
Bacteremia Due to Enterobacteria. Clin Infect
Dis 200540628
24
Diabetes
Diabetes increase of infections
25
Diabetes
Diabetes increase of infections
Outpatients
P 0.0001 P 0.001.
Diabetics N 513,749. 11 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 200326510.
26
Diabetes
Diabetes increase of infections
Outpatients
P 0.0001 P 0.001.
Diabetics N 513,749. 11 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 200326510.
27
Diabetes
Diabetes increase of infections
Inpatients
P 0.0001 P 0.001.
Diabetics N 513,749. 11 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 200326510.
28
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.
29
Diabetes increase of infections?

• The association between diabetes mellitus and
  increased susceptibility to infection is well
  supported.

30
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 199613457.
31
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 Community- Acquired
Bacteremia Due to Enterobacteria. Clin Infect
Dis 200540628
32
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
311170.
33
Diabetes prognostic factor
Deep neck infection in diabetic patients
Huang TT. Deep neck infection in diabetic
patients. Otolaryngol Head Neck Surg 2005132943.
34
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 34752.
35
Hyperglycemia prognostic factor
Van den Berghe, G. et al. N Engl J Med
20013451359
36
Diabetes worse prognosis
Infection related
Diabetic
n9,208
Non- Diabetic
Bertoni AG, et al. Diabetes and the risk of
infection-related mortality in the U.S. Diabetes
Care 2001 241044.
37
Diabetes epidemiological conclusions

• Increase risk of infections
• Worse prognosis

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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
39
Diabetes altered immunity
Geerlings SE, et al. FEMMS 1999 Calvet HM, Inf
Dis Clin N Am 2001
40
Diabetes altered immunity
Normal PMN
Diabetes
Oxidative burst Degranulation Free radial
production Adhesion molecules
Activated Resting PMN
Tolerant Resting PMN
Oxidative burst Degranulation Free radial
production Adhesion molecules
Risk of infection
Stimulus
Calvet HM. Infect Dis Clin N Am 2001
41
Diabetes altered immunity
Uroepithelial cell adherence
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 251405.
42
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 251405.
43
Diabetes altered immunity
Restoration of phagocytic activity
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
1984371029.
44
Diabetes clinical consecuences

• Vaccination
• Influenza
• S. pneumoniae
• Others
• Relevance of glycemic control
• During infection
• Long term

45
Chronic liver disease increase of infections?
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 2001Simpson JH,
et al. CID 2003.
46
Chronic liver disease increase of infections?
Spontaneous bacterial peritonitis 60 of severe
infections
Impaired clearing bacteria
Prolonged Bacteremia
SBP
Bacterascitis
Sterile ascitis
Bacterial traslocation
Intestinal hipomotility
Intestinal oedema
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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 3311122.
48
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 27331(17)1122-8.
49
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

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
2000311357.
50
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

Standardized incidence ratio of 15.4 (9.623.6).
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 200148260.
51
Chronic liver disease increase of infections?
Cut points -Albumin 1 g/dL -Opsonic 0.2 log Kill
Runyon BA. Gastroenterology 1986911343 Runyon
BA. Hepatology 19888632-5
52
Chronic liver disease increase of infections?
Vibrio vulnificus septicemia
Haq SM, et al. Am J Gastroenterol.
20051001195-9. Falcon, L. M. et al. N Engl J
Med 20053531604
53
Chronic liver disease increase of infections?
Vibrio vulnificus septicemia

• Shunting of bacteria
• Achlorhydria
• Increase of Iron serum

Haq SM, et al. Am J Gastroenterol.
20051001195-9. Falcon, L. M. et al. N Engl J
Med 20053531604
54
Chronic liver disease increase of infections?
Ferritin
Phagocytosis
Vibrio survival
E. coli survival
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 1999179275.
55
Chronic liver disease
SARM nosocomial endocarditis risk factors


Hsu RB . Risk factors for nosocomial infective
endocarditis in patients with methicillin-resistan
t staphylococcus aureus bacteremia . Infect
Control Hosp Epidemiol 2005 26654.
56
Chronic liver disease immunossupression?
Johnson DH, Cunha BA. Infections in cirrhosis.
Infect Dis Clin North Am 200115363-71.
57
Chronic conditions increase of infections?
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. CID 2001 322639
Simpson JH, et al. CID 2003.
58
Chronic conditions increase of infections?
N308 (Bacteremic 18.5)
Peralta G et al. Risk factors for bacteremia in
patients with limb cellulitis. Eur J Clin
Microbiol Infect Dis (in press)
59
Chronic conditions increase of infections?
Peralta G et al. Risk factors for bacteremia in
patients with limb cellulitis. Eur J Clin
Microbiol Infect Dis
60
Chronic conditions increase of infections?
Charlson index
Charlson ME, et al. A new method of classifying
prognostic comorbidity in longitudinal studies
development and validation. J Chron Dis 1987 40
373.
61
Chronic conditions prognosis
n 91
Marra AR et al. Time to blood culture positivity
as a predictor of clinical outcome of
Staphylococcus aureus bloodstream infection. J
Clin Microbiol 2006 441342.

62
Chronic conditions prognosis
n 3102
Murray SB, et al. Charlson Index is associated
with one-year mortality in emergency department
patients with suspected infection. Acad Emerg Med
200613530.

63
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.

64
Infections in patients with chronic medical
conditions? What we dont to know?