INFLAMMATION

The silent killer staring

us in the face

What we will be talking about

• A brief introduction

• Its common role in various disease processes

• Clinical Correlation and studies

• Emerging trends in anti inflammatory agents

• Anticipating future trends in therapy

Causes of mortality :CDC 2010

‘In flames’

Acute versus Chronic

In the end we are a one big chemical

reaction

Inflammation : the chemical dance

IL

TNF

Inflammation

&

Atherosclerosis

You are only as old as your endothelium-- Paul VanHoutte, Mayo Clinic (1983)

Acute Phase reactants

Acute phase reactants

Inflammatory triggers

Immune response

Inflammatory cytokines

Endothelial dysfunction

Atherosclerotic events

So therefore

• Atherosclerosis is an inflammatory process

• Please note involvement of WBC’s and cytokines in the process

• Higher levels of inflammatory markers in atherosclerosis (acute or chronic)

• Cytokine levels correlate with acute events as well as future outcomes

What we will not talk about

Emerging risk factors : Inflammation and atherosclerosis

ACUTE CONDITIONS

• Infections

Pneumonias, Flu

• Role of vaccines

CHRONIC CONDITIONS

• Poor oral-dental hygiene

• Chronic Osteomyelitis

• HIV, HCV

• Rheumatologic disease/ vasculitis

More the inflammation worse the atherosclerosis

Acute Chronic

Inflammation Inflammation

Atherosclerotic events

Strokes & MI’s

Infections

as an example for

enhanced risk of atherosclerosis

Infections and Atherosclerotic events

• First questioned in 1911 and 1921

• Now we have new diagnostic tools to explore the same

1.Frothingham C. The relationship between acute infectious diseases and arterial lesions. Arch Intern Med. 1911; 8: 153–162.

2. Ophuls W. Arteriosclerosis and cardiovascular disease: their relation to infectious diseases. JAMA. 1921; 76: 700–701.

Infections and

Risk of Strokes and MI’s

Is there a link ?

Simultaneous factors acting at levels of systemic homeostasis and local vascular wall.

Lindsberg P J , and Grau A J Stroke. 2003;34:2518-2532.

Risk of MI and Stroke

after

Acute Infection or Vaccination

N Engl J Med 2004; 351:2611-2618 : Smeeth et al

Methods : 5,767,499 people

• GPRD : General Practice Research Database

• Largest source of continuous data in the U.K

• Patients remained registered for at least 1 year

Methods : continued

• Data was also extracted regarding :

Influenza

• Vaccinations Tetanus

Pneumococcus

• Acute infections UTI’s

Acute systemic RTI

Pneumonias Acute bronchitis Influenza

Null Hypothesis

Vascular-events are not affected by

Acute exposure

to

Vaccination or Infection.

Definition of Exposure

• 91 days

• Period of exposure divided into groups of

• 1 - 3 days, 4 - 7 days, 8 - 14 days, 15 - 28 days, and 29 - 91 days after the exposure.

A Single Participant Exposed Twice to an Inflammatory Stimulus.

Smeeth L et al. N Engl J Med 2004;351:2611-2618.

Risk for Post exposure MI’s

Majority were first time MI’s

61556 post exposure MI’s

53709

First MI’s

Remaining

60061

12134 Recurrent MI

1495 EXCLUDED

Age-Adjusted Incidence Ratios of a First MI and a First Stroke in Risk Periods

.

Incidence ratios: Recurrent MI and stroke

Smeeth L et al. N Engl J Med 2004;351:2611-2618.

Conclusion

• Acute infections cause a transient increase in the risk of vascular events.

• By contrast, influenza, tetanus, and pneumonia vaccinations do not

So in retrospect …

If Infections do increase risk of atherosclerotic events …

Vaccines should protect

Prevention of Acute Myocardial Infarction and Stroke among Elderly Persons

with

Dual Pneumococcal and Influenza Vaccination

Hung I F N et al : Clin Infect Dis. (2010) 51 (9): 1007-1016.

36,636 outpatients aged ≥65 years

Divided into 3 groups

Pneumonia Pneumonia Influenza

and Influenza alone alone

A Prospective Cohort Study :64 weeks

Eligibility criteria

• Age ⩾65 years

• Had 1 or more chronic illness as follows

Asthma COPD CAD

HTN DM CVA

CKD Liver disease Malignancy

TIV alone versus unvaccinated

Hung I F N et al. Clin Infect Dis. 2010;51:1007-1016

© 2010 by the Infectious Diseases Society of America

PPV alone versus unvaccinated

Hung I F N et al. Clin Infect Dis. 2010;51:1007-1016

© 2010 by the Infectious Diseases Society of America

Pneumonia + Influenza vaccine

Hung I F N et al. Clin Infect Dis. 2010;51:1007-1016

© 2010 by the Infectious Diseases Society of America

Hospitalization for ischemic stroke.

Hung I F N et al. Clin Infect Dis. 2010;51:1007-1016

© 2010 by the Infectious Diseases Society of America

Hospitalization for myocardial infarction.

Hung I F N et al. Clin Infect Dis. 2010;51:1007-1016

© 2010 by the Infectious Diseases Society of America

Conclusion

• Dual Vaccination prevents complications in sick individuals

• Respiratory

• Cardiovascular and not just MI’s

• Cerebrovascular diseases lesser strokes

• Reducing hospitalization

• CCU and ICU admissions

• Death.

Study 2 : Ramirez et al. Infections precipitate MI’s

• 500 patients with CAP studied

• Clinical failure was defined as respiratory failure or shock

Clin Infect Dis. (2008) 47 (2): 182-187.

Incidence of acute myocardial infarction (AMI) in patients

with community-acquired pneumonia (CAP), according to

the severity of disease at hospital admission and the

development of clinical failure during hospitalization.

Ramirez J et al. Clin Infect Dis. 2008;47:182-187

© 2008 by the Infectious Diseases Society of America

Propensity-adjusted risk of acute myocardial infarction (AMI) with 95% CIs

by pneumonia severity index

Ramirez J et al. Clin Infect Dis. 2008;47:182-187

© 2008 by the Infectious Diseases Society of America

The point being….

More severe the infection

more severe the atherosclerosis

More common the acute events

(CVA’s, MI)

Seasonal variations in atherosclerotic disease

The inflammation link

Higher risk of mortality in winter

Date of download:

8/18/2014

Copyright © The American College of Cardiology.

All rights reserved.

From: Seasonal Distribution of Acute Myocardial Infarction in the Second National Registry of Myocardial

Infarction 1

J Am Coll Cardiol. 1998;31(6):1226-1233. doi:10.1016/S0735-1097(98)00098-9

Cases of AMI reported each month to the NRMI-2. Monthly counts were normalized to a 30-day length.

Figure Legend:

Date of download:

8/18/2014

Copyright © The American College of Cardiology.

All rights reserved.

Increased winter mortality from acute myocardial infarction and

stroke: the effect of age

J Am Coll Cardiol. 1999;33(7):1916-1919. doi:10.1016/S0735-1097(99)00137-0

Mortality from acute myocardial infarction (AMI) and stroke by month. Relative risks for high and low months are compared with the

average of all months combined. For both AMI and stroke, deaths peak in January (AMI p < 0.001, stroke p < 0.001) and then

progressively decrease to a low in September (AMI p < 0.001, stroke p < 0.001). The difference in mortality from January to

September is 18.6% for AMI and 19.9% for stroke.

Figure Legend:

Peak Month of Flu Activity 1982-83 through 2013-14 (CDC)

Role of flu vaccine ?

Chronic Infections and

Atherosclerosis

Microbes and us

• For every cell in our body, we carry 10 bacteria

• Bacteria comprise 1-3 % of our body weight

Chronic Infections and Atherosclerosis

• H. Pylori

• Periodontal disease : Porphyromonas gingivalis

• HCV

• HIV

• HSV

• Chlamydia pneumoniae

Chronic Infection

Is it plaque infection as well ?

The link between

Chlamydia Pneumoniae, CMV, and HSV

in

Atherosclerosis of the Carotid Artery

Chiu et al : Circulation.1997; 96: 2144-2148

76 patients with carotid artery stenosis

Endarterectomy specimens stained for Chlamydia, CMV, and HSV

IgG antibodies measured to CMV and Chlamydia

IgG’s correlated with plaque morphology and the presence of the microorganisms detected using immunohistochemistry

Results

• C pneumoniae detected in 71%

(95% confidence interval [CI], 59.5% to 80.9%)

• CMV was detected in 35.5%

(CI, 24.9% to 47.3%)

• HSV-1 10.5%

(CI, 4.7% to 19.7%)

Rates of detection of C pnuemoniae, CMV, and HSV-1 singly and concurrently in 76 carotid

atheromatous plaques.

Chiu B et al. Circulation. 1997;96:2144-2148

Copyright © American Heart Association, Inc. All rights reserved.

Immunocytochemical staining (through ABC method) of carotid intimal atheromatous plaque

with (arrowhead) strong positivity for Chlamydia-Cel-Pn in macrophage and endothelial cell.

Chiu B et al. Circulation. 1997;96:2144-2148

Copyright © American Heart Association, Inc. All rights reserved.

Thrombus(N=46)

No thrombosis

(N=30)P

valueUlceration

(N=16)

NoUlceration

(N=60)P

value

ChlamydiaPneum.

37(80.4%)

17(56.7%)

0.038 14(87.5%)

40(66.6%)

0.12

CMV 22 (47.8%)

5 (16.7%)

0.007 8(50%)

19(31.7%)

0.24

ChlamydiaPneum.

andCMV/HSV

18 (39.1%)

6(20%)

0.12 7(43.8%)

17(28.3%)

0.24

AnyOrganism

41(89.1%)

18(60%) 0.004

14(87.5%)

46(76.7%) 0.49

Plaque morphology and Microbe detection

Conclusion

• Higher incidence of organism in plaques as compared to none in normal arteries

• Thrombus formation in atherosclerosis is associated with an even higher presence of these organisms

• Innocent bystander theory …. However …..

• C pneumoniae has even been successfully cultured from arteries as well **

• Positive correlation between worse plaque morphology and the presence of microorganisms

• Surely they are up to no good if they are not meant to be there

**Jackson et al :Chemotherapy, September 15-18, 1996

**Ramirez et al : Ann Intern Med. 1996;125:979-982

Chlamydia and mycoplasma in an atherosclerotic plaque

Continued

• Several other studies involving H. pylori, HCV as well

• HIV is widely known as a risk factor for CAD

• Chronic infections may therefore make the inflammatory process we call atherosclerosis worse

HCV as an example of

chronic inflammation and

its multisystem manifestations

Hep C infection as an example of

chronic inflammation

and it’s associations

HCV

Hepatitis C : Extrahepatic manifestations

• Autoimmunity

• Vasculitis

• Malignancy

• Renal Disease

• Hormonal

• Arthritis

• Neurological

Chronic Hepatitis C

and

Autoimmunity

40-65% of HCV pts. have Autoantibodies

ANA’s Rheumatoid factor Anti Cardiolipin antibodiesSmooth muscle antibodiesAntithyroid antibodies

--J Rheumatol. 2009;36(7):1442. (prospective multicenter study of 321 patients)--Medicine (Baltimore). 2000;79(1):47

Autoimmune phenomena associated with Hep C

Autoantibodies

• - Autoimmune hepatitis

• - Thyroid disease

• ITP

• Hemolytic anemia

• Myasthenia gravis

• Sarcoidosis

• Sjogrens

Hep C infection as an example of

chronic inflammation

and it’s associations

HCV

Chronic Hepatitis C

and

ATHEROSCLEROSIS

Ishizaka et al : Lancet. 2002;359:133–135

Association between HCV seropositivity,

carotid-artery plaque,

and intima-media thickening

Methods

• 4784 individuals enrolled

• 104 (2·2%) were seropositive for HCV

• high-resolution carotid ultrasound

• Plaque defined as a thickening of the intima media of 1·3 mm or more

Results

• Plaques were twice as common in seropositives

40 of 1070 [3·7%] vs 64 of 3714 [1·7%]

• Intima-media thickening 4 times as common

(38 of 605 [6·3%] and 66 of 4179 [1·6%]

Odds ratio and p values• Increased risk of carotid-artery plaque

(odds ratio 1.92 [95% CI 1.56-2.38], p=0.002)

• Also with carotid intima-media thickening (odds ratio 2.85 [2.28-3.57], p<0.0001)

Evidence was irrespective of known atherogenic risk factors

---Ishizaka et al : Lancet. 2002;359:133–135

There are many more similar studies

There was even one with Hepatitis A carriers …

(and the numbers looked good)

Role of interferons

• Immunomodulation

• Affects the cytokine cascade

• Have several anti-inflammatory properties

• Impart mortality and morbidity benefit

Chronic Inflammation

and

Cancer

Chronic inflammation in any organ

can

cause cancer in the same

To name a few …

• GERD

• Gastritis

• Chronic osteomyelitis

• Pancreatitis

• Cystitis

• Chronic hepatitis and Cirrhosis

• Cervicitis

• Cholecytitis

• ESRD

• Kangri cancer

C

H

R

O

N

I

C

I

N

N

O

I

T

A

M

M

A

L

F

Cancer

ESOPHAGITIS

HEPATITIS

CIRRHOSIS

PANCREATITIS

GASTRITIS

CERVICITIS

ESRD

OSTEOMYELITIS

IBD

CHRONIC INFECTIONS

Chronic inflammation and malignancyJukka Vakkila & Michael T. Lotze

Nature Reviews Immunology 4, 641-648 (August 2004)

Kangri Cancer

Erythema ab Igne (Toasted skin syndrome)

Bowens disease

Closer to home …

Similar cancers elsewhere

• Kang Cancer --- Northwest China

• Kairo Cancer in Japan : coal-fired clothing warmers.

• In the U.S : heating pads and lap tops and occupational risk factors ---chronic heat exposure

Obesity and inflammation

Access adipose tissue

causesInflammation

NASH and Cirrhosis

Aging and inflammation

Aging : Also called inflammaging

• Fall in T and B cell population

• Decrease in their receptor diversity as well

• Less brisk immune responses

• Oxidative stress from infections and cell death

• Higher levels of inflammatory markers

• More gene defects in cells and less self tolerance

Depression and neurological disorders

Neuropsychiatry and Inflammation

• Interferon alpha and depression

• Hepatitis C and depression

• Depression/Mood changes and SLE

Neuropsychiatry & Inflammation

• Hepatitis C and dementia

• HIV and dementia

• Syphilis and dementia

• SLE and multi infarct dementia

• Vascular dementia from atherosclerosis

• Alzheimers : inflammatory markers in the csf

• Worsening of CNS disease during infections

Emerging therapeutic trends

to counter

Inflammatory mechanisms of various diseases

Anti inflammatory drugs and cancer

• ASA and colon cancer risk reduction

• COX 2 inhibitors and reduction in colon cancer

• NSAIDS and breast cancer

• ASA/PPI’s for Barrett's esophagus (AspECT )

Anti inflammatory drugs and cancer

• Steroids as adjuvants to chemotherapy

• NSAIDS combined with chemotherapy (COX 2)

Nitric Oxide :Molecule of the year 1992

Recent developments in

Nitric Oxide donor drugs

Nitric oxide :The Nobel prize winning molecule

Robert F. FurchgottSUNY Downstate

Louis J. IgnarroUCLA

Ferid MuradUniversity of Texas

Medical School

NO donating drugs

NO donating drugs• NO with NSAIDS to enhance their

antiinflammatory effects

• NO with chemotherapy agents have higher cytotoxicity

• NO with ASA

• Nitroso captopril

• Furaxan + Calcium channel blocker and other antihypertensives

• Emergence of new biological agents as the inflammatory mechanisms of disease become better understood

• TNF alpha inhibitors in RA eg infliximab

• T cell targeted therapy :

• Interleukin inhibitors : toclizumab

• nuclear factor kappa B (RANKL) inhibition for treatment of osteoporosis

• They are also being used to treat cancer

In conclusion

We have only touched the tip of the iceberg

For the House staff

All pathology triggers inflammation

Always see if your patient has SIRS or not

Have fun and correlate : Avoid isolating diseases to a single system

Look for disease associations

For the faculty

More anti-inflammatory and immuno-modulatory agents especially biological ones are coming

There will be even more stress on vaccination as time passes because of their cost effectivity

As life expectancy increases and obesity epidemic grows, inflammation will be talked more about

Reducing inflammation imparts mortality benefit

What more could we ask for as clinicians ?

Questions ?