Community Acquired Pneumonia - sahivsoc.org Feldman - Community acquired... · • Aetiology of...

Opportunistic Infections Opportunistic Infections ––

Community Community Acquired Acquired PneumoniaPneumonia

Charles Feldman

Professor of Pulmonology and Chief PhysicianProfessor of Pulmonology and Chief Physician

Charlotte Maxeke Johannesburg Academic Hospital

University of the Witwatersrand

Introduction to the TalkIntroduction to the Talk

• Aetiology of community-acquired pneumonia

• Smoking as a major risk factor

• Clinical features of CAP and mortality

• Evolution and interpretation of the CD4 cell

countcount

• Impact of CAP on long-term prognosis

• Prevention of infection - vaccination

The WorldThe World--wide HIV Prevalencewide HIV Prevalence

www.worldmapper.org

Spectrum of HIVSpectrum of HIV--associated Pulmonary Diseaseassociated Pulmonary Disease

Opportunistic InfectionsOpportunistic Infections

Bacteria Bacteria

Streptococcus pneumoniae

Haemophilus species

Pseudomonas aeruginosa

Other bacteria

Mycobacteria Mycobacteria

FungiFungi

Pneumocystic jirovecii

Cryptococcus neoformans

Histoplasma capsulatum

Coccidiodes immitis

Penicillium marneffei

Aspergillus species (most often A. fumigatus)Mycobacterium tuberculosis

Mycobacterium avium complex

Mycobacterium kansasii

Other mycobacteria

Aspergillus species (most often A. fumigatus)

Other fungi

VirusesViruses

Cytomegalovirus

Other virsus

ParasitesParasites

Toxoplasma gondii

Other parasites

Huang L et al. Respirology 2009; 14: 474-485

S. pneumoniae

M. pneumoniae

180

97

AetiologyAetiology of CAP in Selected Studies of >100 of CAP in Selected Studies of >100

ImmunocompetentImmunocompetent HospitalisedHospitalised Patients with CAPPatients with CAP

C. pneumoniae

H. infleunzae

L. pneumophila

Viruses

Gram -ve

Other

Unknown

75

63

56

1420

4

206

Nyamande K. PhD Thesis UKZN 2007

South African Study of South African Study of AetiologyAetiology of CAPof CAP

CAP inclusion criteria metCAP inclusion criteria met

YesYes(n = 430)(n = 430)

Sputum Sputum expectorated expectorated

or inducedor induced(n = 430)(n = 430)

Urine antigen Urine antigen teststests

(n = 117) (n = 117)

Blood Blood culturescultures(n = 181)(n = 181)

SerologySerology(n = 282)(n = 282)

Nyamande K et al. Int J Tuberc Lung Dis 2007; 11: 1308-1313

71

61

18

12

5

Positive Negative

AetiologyAetiology of CAP in 430 HIVof CAP in 430 HIV--infected and HIVinfected and HIV--nonnon--

infected Subjectsinfected Subjects

M. tuberculosis

S. pneumoniae

S aureus

Other gram –ve

71

14

14

62

184

4

44

H. influenzae

Other

P. aeruginosa

8


M. tuberculosis

S. pneumoniae

M. pneumoniae

C. pneumoniae

58

AetiologyAetiology of CAP in 282 Patients who had Serology of CAP in 282 Patients who had Serology

for Atypical Organismsfor Atypical Organisms

C. pneumoniae

Other Gram -ve

S. aureus

H. influenzae

Other

P. aeruginosa

L. pneumophila

Chicken pox

77 38

11

11

88

422


Mortality in HIVMortality in HIV--negative and HIVnegative and HIV--positive positive

Patients in Relation to PathogenPatients in Relation to Pathogen

TBTB

HIV +HIV +((nn = 50)= 50)

nn (%)(%)

HIV HIV --((nn = 18)= 18)

nn (%)(%)

13 (26)13 (26) 2 (11)2 (11)

S. pneumoniaeS. pneumoniae

AtypicalAtypical

S. aureusS. aureus

OtherOther

9 (18)9 (18)

8 (16)8 (16)

1 (2)1 (2)

4 (8)4 (8)

4 (22)4 (22)

4 (22)4 (22)

3 (17)3 (17)

Nyamande K. Int J Tuberc Lung Dis 2007; 11: 1308-1313

un

t (c

ells

/mm

)2

1 000

800

600

400

BacterialBacterial Pathogens Causing CAPPathogens Causing CAP

Chlamydiapneumoniae

Etiological agent of pneumonia

CD

4 c

ou 400

200

0Streptococcuspneumoniae

Haemophilusinfluenzae

Staphylococcusaureus

Boschini et al; CID, 1996

Boschini A et al. Clin Infect Dis 1996; 23: 107-113

Increased Risk of LRTI with SmokingIncreased Risk of LRTI with Smoking

• Study of 521 HIV-infected patients admitted

to Jackson Memorial Hospital in Miami

• 65% were current smokers

• 40% smoking more than one pack per day

• 46% were on HAART and 42% were • 46% were on HAART and 42% were

receiving PCP and/or NTM prophylaxis

• 49% admitted for pulmonary infection of

which 52% were bacterial pneumonia and

24% PCP

Miquez-Burbano MJ et al. Int J Infect Dis 2005; 9: 208-217

100

Pro

po

rtio

n o

f th

e g

rou

p

80

60

Smokers

Non-smokers

Increased Risk of LRTI with SmokingIncreased Risk of LRTI with SmokingP

rop

ort

ion

of th

e g

rou

p

40

20

0PCP

<200 CD4

PCP<200-500 CD4

CAP<200 CD4

CAP<200-500 CD4

CAP<500 CD4

Miquez-Burbano MJ et al. Int J Infect Dis 2005; 9: 208-217

Effects of Smoking on HAARTEffects of Smoking on HAART

• Analysis of association of cigarette smoking

with effectiveness of HAART in WIHS study of

924 women followed for 7.9 years (’95 – ’03)

• Of the cases 56% were current smokers and

16% were former smokers16% were former smokers

• The average amount smoked was 1 pack per

day and the median duration was 12 years

Feldman J et al. Am J Public Health 2006; 96: 1060-1065

Effects of Smoking on HAARTEffects of Smoking on HAART

• Smokers had

– Poorer virological response (0.79)

– Poorer immunological response (0.85)

– Greater risk of virological rebound (1.39)

– More frequent immunological failure(1.52)– More frequent immunological failure(1.52)

– Higher risk of death (1.53)

– Higher risk of developing AIDS (1.36)


400.00

360.00

360.00

340.00

Me

an

CD

4 c

ou

nt Nonsmoker (N=400)

Smoker (N=524)

320.00

300.00

280.00

-1 0 1 2 3 4 5 6 7 8 9

Number of visits after HAART Initiation

Me

an

CD

4 c

ou

nt

P=.01


4.20

4.00

3.80

3.60

Me

an

lo

g o

f vir

al lo

ad

Smoker (N=524)3.60

3.40

3.20

-1 0 1 2 3 4 5 6 7 8 9

Number of visits after HAART Initiation

Me

an

lo

g o

f vir

al lo

ad

P=.07

Nonsmoker (N=400)

Smoker (N=524)


90

100

80

70

60

Pe

rce

nta

ge

fre

e o

f a

n A

IDS

-de

fin

ing

co

nd

itio

n

Nonsmoker

50

40

Pe

rce

nta

ge

fre

e o

f a

n A

IDS

0 1 2 3 4 5 6 7 8

P=.01

Time from HAART Initiation (years)

Smoker


90

100

80

70

Pe

rce

nta

ge

aliv

e

Nonsmoker

Smoker

60

50

Pe

rce

nta

ge

aliv

e

0 1 2 3 4 5 6 7 8

P=.006

Time from HAART Initiation (years)


• Studies have measured T-lymphocyte

subsets during various infections, but only in

the acute phase of infection

• Levels measured in CAP patients within 72

hours of admission

– Acute phase lymphocyte counts decreased

Lymphocyte Subsets During CAPLymphocyte Subsets During CAP

– Acute phase lymphocyte counts decreased

– Percentage CD4 cell count remained unchanged

– Changes not affected by age, HIV status or

aetiology

– In HIV-seronegative cases CD4 cell counts

<200/mm3 were associated with underlying

disease, TB, and age > 60 years

Fantin B et al. Clin Infect Dis 1996; 22: 1096-1098

• Study of 30 ARV naïve HIV-infected patients

with pneumococcal CAP

• Total Lymphocyte and CD4 cell counts were

measured upon hospital admission and one

month after resolution of CAP

Lymphocyte Subsets During CAPLymphocyte Subsets During CAP

month after resolution of CAP

• CAP diagnosis based on compatible clinical

features with new infiltrate on chest X-ray

• Pneumococcal diagnosis based on blood or

sputum culture or positive urine antigen test

Schleicher G, et al. Eur J Clin Micro Infect Dis 2004; 10: 574-592

CD4 TCD4 T--lymphocyte Counts (x 10lymphocyte Counts (x 1066 cells/L)cells/L)600

500

400

300

200

CD4 with pneumonia CD4 one month later

200

100

0

Wilcoxon matchdd pairs test (p 0.000009)

Min

14.00

7.00

Max

439.00

578.00

25%

54.00

107.00

75%

212.00

419.00

Median

112.00

270.00

On admission

One month later


Total Lymphocyte Counts (x 10Total Lymphocyte Counts (x 1066 cells/L)cells/L)3.5

3.0

2.5

2.0

1.5

1.0

A B

1.0

0.0

0.5

Wilcoxon matchdd pairs test (p 0.000009)

Min

0.15

0.82

Max

02.29

3.16

25%

0.60

1.39

75%

1.80

2.24

Median

0.99

1.73

On admission

One month later


Case profiles of CD4 count

300

400

500

600

0

100

200

CD4 with pneumonia CD4 one month later


Clinical Features and Management of Pneumococcal Pneumonia Clinical Features and Management of Pneumococcal Pneumonia

Typical in the young and possible

atypical in the elderly and in other

clinical conditions/

Often atypical frequently

bacteremia in low death risk

patients according to PSI. Bilateral

inflates common,

Clinical features

Sputum for Gram stain and culture,

blood for culture and urine for

pneumococcal UAT depending on

Sputum Gram stain and culture,

blood for culture and urine for

pneumococcal UAT in all patients.

Simple collection for

etiologic diagnosis

HIVHIV--infected patientsinfected patients HIV HIV noninfectednoninfected patientspatients

pneumococcal UAT depending on

severity of pneumonia and patient’s

risk factors.

pneumococcal UAT in all patients.

Monotherapy or combination

antibiotic therapy according to

outpatient or inpatient management,

patient’s comorbidities and local

prevalence of antibiotic resistance.

Combination antibiotic therapy

(β-lactam plus a macrolide or a

respiratory fluorquinolone alone).

Empiric therapy

Lifestyle modification,

pneumococcal vaccine.

Lifestyle modification, HAART,

pneumococcal vaccine.

Prevention

Madeddu G et al. Curr Opin Pulmon Med 2009; 15: 236-242

• Prospective, international, multicentre,

observational study

• 700 cases with bacteraemic pneumococcal

pneumonia

• Univariate analysis – no difference in 14-day

Mortality of CAP in HIV infected PatientsMortality of CAP in HIV infected Patients

• Univariate analysis – no difference in 14-day

mortality in HIV + versus HIV – cases

• Multivariate analysis – stratified by age and

severity of illness – higher mortality in HIV +

– Mortality higher in the sicker cases and stratified

according to the CD4 cell count

Feldman C et al. J Infect 2007; 55: 125-135

Management of HIVManagement of HIV--infected Patients with Bacterial CAPinfected Patients with Bacterial CAP

HIV patient with BCAP

CD4 cells

< 200 µl

CD4 cells

≥ 200 µl

PSI score

I I I I ---- IIIIIIIIIIII

PSI score

IV IV IV IV ---- VVVV I I I I ---- IIIIIIIIIIIIIV IV IV IV ---- VVVV

Outpatient Inpatient

Empiric antibiotic treatment with β-lactam plus a macrolide or a respiratory fluoroquinolone alone

Madeddu G et al. Curr Opin Pulmon Med 2010; 16: 201-207

• Patients with bacterial pneumonia and PCP hadshorter median survival time than controls

• Associations persisted when controlled for other

predictors of survival in multivariate analysis

CAP and PCP Accelerate Progression of HIVCAP and PCP Accelerate Progression of HIV

i.e. CD4 count or history of AIDS-defining OI

• Neither of the associations due to acute mortality

• ? Associated with decreased long-term survival

• Prevention of infection is important

Osmond DH et al. Clin Infect Dis 1999; 29: 536-543

0.6

1.0l p

rob

ab

ility

0.7

0.5

0.9

0.8

CAP and PCP Accelerate Progression of HIVCAP and PCP Accelerate Progression of HIV

Controls

0 365 730 1 825

Time (days)

Su

rviv

al

1 095 1 460

Osmond et al; CID, 1999

0.4

0.3

0.2

0.1

0

Bacterial pneumonia

PCP

- 200

- 100 BPBP

BP

PCPPCP

- 2.0

- 1.0

Hg- 200

- 100 BPBP

BP

PCPPCP

- 2.0

- 1.0

Hg

Permanent Decline in Lung FunctionPermanent Decline in Lung Function

FEV1

ml

- 500

- 400

- 300

PCP

FVC DLCO

- 2.0

- 3.0

- 4.0

ml/m

in/m

mH

FEV1

ml

- 500

- 400

- 300

PCP

FVC DLCO

- 2.0

- 3.0

- 4.0

ml/m

in/m

mH

Morris AM et al. Am J Respir Crit Care Med 2000; 162: 621-616

Prevention of CAP in HIVPrevention of CAP in HIV--infected Personsinfected Persons

• Lifestyle modification - smoking cessation

• Anti-pneumocystis prophylaxis

• HAART

• Pneumococcal vaccine• Pneumococcal vaccine

• 23 valent polysaccharide

• Protein conjugate

• ? Haemophilus cover

IPD According to Prior Vaccination Status (PPV)IPD According to Prior Vaccination Status (PPV)

Death and/or ICU admission

In-hospital mortality

ICU admission

Orotracheal intubation

34/162 (21)

25/162 (15.4)

21/162 (13)

15/162 (9.3)

0/22

0/22

0/22

0/22

25/112 (22.3)

16/112 (14.3)

19/112 (17)

13/112 (11.6)

0.013

0.073

0.042

0.126

Unvaccinated

(n = 22) P

Vaccinated

(n = 22)

0/23

0/23

0/23

0/23

34/139 (24.5)

25/139 (18)

21/139 (15.1)

15/129 (10.8)

0.004

0.026

0.046

0.132

P

Unvaccinated

(n = 139)

Vaccinated

(n = 23)

All patients

(n = 162)

Patients with chronic liver disease

excluded

All patients included

Shock

Empyema

PSI high risk classes

Days of hospital stay (mean SD)

Days to defervescence (mean SD)

17/135 (12.6)

10/129 (7.8)

43/125 (34.4)

12.62 (13.87)

3.11 (4.09)

1/20 (5)

0/20

2/17 (11.8)

8.5 (6.29)

2.62 (2/76)

14/96 (14.6)

10/95 (10.5)

29/95 (30.5)

14.29 (15.88)

3.17 (3.52)

0.463

0.206

0.146

0.007

0.497

1.21 (4.8)

0/21

3/18 (16.7)

8.48 (6.14)

2.55 (2.72)

16/114 (14)

10/108 (9.3)

40/107 (37.4)

13.27 (14.62)

3.21 (4.28)

0.471

0.365

0.111

0.011

0.484

Imaz A et al. HIV Medicine 2009; 10: 356-363

IPD in Adults 18 IPD in Adults 18 –– 64 years of Age with and without HIV Infection or AIDS64 years of Age with and without HIV Infection or AIDS

Annual mean population of individuals aged 18 to 64 years in surveillance area, 1998-2007

n = 10 466843

Population without HIV infection or AIDS

n = 10 431385

99.7% of surveillance population

Population with HIV infection, not AIDS

(estimate not available)

Population living with AIDS

n = 35 459

(0.3% of surveillance population)

IPD in adults with HIV infection, not AIDS

IPD in adults with AIDS

n = 1313

Pneumococcal isolates serotyped

n = 2930

(95% of IPD cases)

Pneumococcal isolates serotyped

n = 9441

(83.3% of IPD cases)

not AIDS

n = 1952n = 1313

IPD in adults without HIV infection or AIDS

n = 10 576

IPD in adults with HIV infection or AIDS

n = 3236

Cohen AL, et al. AIDS 2010; 24: 2253-2262

1400

1200

1100

800

600

400

200

01998 1999 2000 2001 2002 2003 2004 2005 2006 2007

IPD

ca

se

s w

ith

HIV

pe

r 1

00

00

0

pe

rso

ns w

ith

AID

S

16All serotypes

16

12

10

8

6

4

2

01998 1999 2000 2001 2002 2003 2004 2005 2006 2007

IPD

ca

se

s w

ith

HIV

pe

r 1

00

00

0

pe

rso

ns w

ith

ou

t A

IDS

14

Calendar year

All serotypes

Conjugate vaccine serotypes

Non-vaccine serotypes

Cohen AL, et al. AIDS 2010; 24: 2253-2262

Effect of the 23Effect of the 23--valent Pneumococcal Polysaccharide Vaccine:valent Pneumococcal Polysaccharide Vaccine:Uganda 1985Uganda 1985--1998 1998

Invasive

S. pneumoniae (all)

Invasive

S. pneumoniae

(vaccine)

1.5 (0.7-3.3)

2.1 (0.9-5.3)

Hazard ratio

(95% CI)

Placebo

Vaccine

0 10 20 30 40

All

S. pneumoniae

All-cause

pneumonia

1.5 (0.7-2.9)

2.0 (1.2-3.5)*

Vaccine

Feikin DR et al. Lancet Infect Dis 2004; 4: 445-455

Study of 7Study of 7--valent PCV in HIVvalent PCV in HIV--infected Adultsinfected Adults

1375 patients had an episode of invasive pneumococcal disease

960 had bacteremia

415 had meningitis

879 were excluded398 died before recruitment

51 declined83 ineligible

347 not interviewed

496 underwent randomization496 underwent randomization

75 died73 HIV +2 HIV -

37 lost to follow-up26 HIV +11 HIV -

136 survived121 HIV +15 HIV -

67died63 HIV +4 HIV -

44 lost to follow-up38 HIV +6 HIV -

137 survived118 HIV +19 HIV -

248 assigned to receive vaccine220 HIV+28 HIV-

248 assigned to receive placebo219 HIV+29 HIV-

French N et al. New Engl J Med 2010; 362: 812-822

Effectiveness of PCV7 in 437 Patients with HIV infectionEffectiveness of PCV7 in 437 Patients with HIV infection

Vaccine serotype or serotype 6A(intention-to-treat analysis)

19

No. of patients

19

No. of events

Vaccine serotype or serotype 6A(per-protocol analysis)

18 18

PRIMARY ENDPOINT

5

No. of patients

5

No. of events

4 4

VACCINE

0.26 (0.10-0.70)

Unadjusted

0.31 (0.11-0.84)

Adjusted

0.22 (0.08-0.66) 0.25 (0.08-0.78)

Unadjusted Adjusted

PLACEBO Hazard ratio for First Event (95%)

Hazard ratio for Recurrent Events (95%)

Any cause 63

DEATH

Definite, probable or association with IPD

35

Loss to follow-up 38

Vaccine serogroup 19 20

SECONDARY ENDPOINT

Any invasive pneumococcal disease

30 38

Any type of pneumonia

73

35

26

7 7

22 29

32 44 41 58

1.18 (0.84-1.66) 1.24 (0.88-1.75)

1.02 (0.64-1.63) 1.14 (0.71-1.85)

0.37 (0.15-0.87) 0.42 (0.18-1.02)

0.72 (0.02-1.25) 0.80 (0.45-1.44)

0.77 (0.47-1.19) 0.71 (0.43-1.17)

0.19 (0.06-0.66) 0.30 (0.09-1.02)

0.35 (0.12-1.01) 0.34 (0.11-1.02)

0.54 (0.26-1.17) 0.49 (0.20-1.21)

French N et al. New Engl J Med 2010; 362: 812-822

Summary and ConclusionsSummary and Conclusions

• Incidence of pulmonary opportunistic infections has

declined with HAART

• Bacterial pneumonia and influenza infection are commonly

seen and vaccination strategies in HIV infected adults

needs to be better evaluated

• Episodes of bacterial pneumonia provide an important • Episodes of bacterial pneumonia provide an important

opportunity for HIV testing

• TB/HIV remains frequent and difficult to diagnose and

simple clinical algorithms appear to be helpful

• New TB diagnostic test, such as Xpert MTB/RIF are

showing exciting results but even cheaper and simpler

tests would be welcome

• Lifestyle modification is important

Adapted from Raju R et al. Curr Opin Pulmon Med 2012; 18: 253-258

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