Long-term sequelae associated with pneumococcal disease

Dr. JesDr. Jesúús M. Feriss M. FerisHospital Infantil Dr. Robert Reid CabralHospital Infantil Dr. Robert Reid Cabral

RepRepúública Dominicanablica Dominicana

Simposio Subregional del Caribe Simposio Subregional del Caribe Sobre NeumococoSobre Neumococo

Hotel V CentenarioHotel V CentenarioOctubre 1 y 2, 2008Octubre 1 y 2, 2008

Santo Domingo, RepSanto Domingo, Repúública Dominicanablica Dominicana

Agentes Causales de Meningitis Bacteriana.Red SIREVA de Rep.Dom

2000-2007n=405

0102030405060708090

100

2000 2001 2002 2003 2004 2005 2006 2007

Porc

enta

je

Hib Spn Nm

Bacterial meningitis by year Hospital Infantil Dr. Robert Reid Cabral, 1994-2007

0102030405060708090

100

1994

1995

1996

1997

1998

1999

2000

*2001

2002

2003

2004

2005

2006

2007

Num

ber o

f cas

es

Introduction HibCVPartial HibCV

200

300

400

500

600

All cases

HibHib

SpnSpn

NmNm

Number of cases of acute bacterial meningitis according to study period(1993-1998 and 1999-2003) and bacterial pathogen, among 218 patients

with acute bacterial meningitis (Hospital Infantil de México Federico Gómez, (1993-2003)

59 (100)8 ( 14 )*32 ( 54 )

3 ( 5 )5 ( 8 )

11 ( 19 )

159 (100)101 ( 64 )35 ( 22 )1 ( 0.5 )9 ( 5.5 )13 ( 8 )

218 (100)109 ( 50 )67 ( 31 )

4 ( 2 )14 ( 6 )

24 ( 11 )

AllHibSpnNmOtherNo pathogen

Period after theIntrodution of Hibvaccine,1999-2003 No. Cases (%)

Period before theIntrodution of Hibvaccine,1993-1998 No. Cases (%)

Total No.Cases (%)

Bacterial pathogen

Ref: Epidemiology and outcomes of bacterial meningitis in Mexican children: 10-year experiencie(1993-2003). Franco-Paredes C, Lammoglia L, Hernandez I, Santos JI. Int J infect Dis (2007), dol:10.1016/j.ijid.2007.09.012

* 6/8 (75%) children > 4 years of age and did not received previous Hib vaccination.

Streptococcus pneumoniae Meningitis in Dominican Children: Age distribution

100317Total

12.138> 5

27.788> 1 - 5

60.2191< 1

%nAge (years)

Ref: Feris J. Fernandez J. Sanchez J. et al: 44th. ICAAC, Oct 30-Nov 2, Washington, D.C. USA, 2004, Paper # 3212

Clinical presentation and prognostic factors of Streptococcus pneumoniae

meningitis according to the focus of infections (Denmark)

n=187

Ref: Ostergaard C, Koradsen HB, Sauelsson S: BMC Infectious Diseases 2005, 5:93

42Undetermined2Other8Sinus

18Lung30Ear%Most common focus

Middle ear cultures results through Middle ear cultures results through tympanocentesistympanocentesisDepartamentoDepartamento EnfermedadesEnfermedades InfecciosasInfecciosas

Hosp. Inf. Dr. Robert Reid Cabral Hosp. Inf. Dr. Robert Reid Cabral 19881988--20042004

Negative 19%

Others 8%

S. pyogenes1%

Staph. spp8%

B. catarrhalis1%

Hi 25%

Spn 38%

n=221

Ref: Infectious Diseases Department, Hospital Infantil Dr. Robert Reid Cabral, 2005.

Long-term sequelae associated with pneumococcal disease

Long-term sequelae associated with pneumococcal disease

Factors Associated with Hearing Loss in Dominican Childrenwith Bacterial Meningitis

n=225

5.062.83Gram negative bacilli0.001.92S. agalactiae7.598.59N. meningitidis B and C

16.62011.412S. pneumoniae0.811.92H. influenzae a

70.08477.377H. influenzae b**%n=120%n=105

Hearing LossNormal HearingEtiology*

Audiolical Outcome According to Etiology of Bacterial Meningitis

*No bacteria were isolated in 77 CSF.** OR=3, CI 95%:1.8,5.2,P<0.05Ref.: Feris JM, Fernandez J, Terrero C, et al.: Abstract 147, 3rd World Congress ofPediatric Infectious Diseases, Santiago de Chile, Chile, November 19-23, 2002

LongLong--Term neurological sequelae Term neurological sequelae in the Outin the Out--patient clinic, Infectious Diseases Department,patient clinic, Infectious Diseases Department,

((SpnSpn meningitis)meningitis)Hospital Hospital InfantilInfantil Dr. Robert Reid Cabral, 2000Dr. Robert Reid Cabral, 2000--20072007

35

20.422.754.591.065.0

9Motor Deficit 10Convulsions24Hearing Loss40≤5 yrs 44Sequelae

24No Sequelae

Frequency n %≥5 yrs 7 (12%)<5 yrs 61 (88%)

Age

Ref: Out-patient Clinic DEI. 2007

Pneumococcal meningitis in children: prognostic indicators and outcome

Dept. of Pediatr, Sophia Children´s Hospital/UniversityHospital Rotterdam, Netherlands 1970-1994

361925

25--

Survivors with sequelae• hearing loss• neurological

17(7-35) Mortality rate

%n=83Median age: 8 months

Ref: Kornelisse RF, Westerbeek CM, Spoor AB, et al: Clin Infect Dis. 1995 Dec;21(6):1390-7

Clinical presentation and prognostic factors of Streptococcus pneumoniae

meningitis according to the focus of infections (Denmark)

n=187

Ref: Ostergaard C, Koradsen HB, Sauelsson S: BMC Infectious Diseases 2005, 5:93

1 %• Combination of both16 %• Focal neurological deficits24 %• Hearing loss41 %Survivors with neurologic sequelae

Clinical presentation and prognostic factors of Streptococcus pneumoniae

meningitis according to the focus of infections (Denmark)

n=187

Ref: Ostergaard C, Koradsen HB, Sauelsson S: BMC Infectious Diseases 2005, 5:93

50• Others**26• Pneumonic 33• Sinusitic7• Otogenic%Mortality by infectious focus*

*Long rank test: p = 0.0005** No primary infectious focus (21%)

LongLong--termterm sequelaesequelae ofofpneumococcal meningitis in pneumococcal meningitis in childrenchildren

Ref: Pikis, A, Kavaliotis J, Andrianopoulos P et al: Clinical pediatrics 1996, 35;2:72-78

201Visual impairment2

1115171930%

01Behavioral problems05Motor defects07Seizure disorder08Hearing loss09Mental retardation14Neurological handicapnSequelae

n=90 MSpn (1967 - 1988) Thessaloniki Hospital, Greecen=47 evaluated (75%)

A retrospective study on 72 children admitted to a medical center in Taiwan due to invasive

pneumococcal infections diagnosed betweenJanuary 1990 and April 2000

Although 56.9% were penicillin resistant the outcomewas not associate with susceptibility

52.610Survived with long termsequelae

13.644Other invasive diseases

32.128Meningitis

Mortality % casesDiagnosis

Ref: Ma JS, et al: J Microbiol Immunol Infect 2002;35(1):23-8

24077Total

175 (75.8%)56 (24.2%)No

0.56,1.911.03

65 (75.5%)21 (24.4%)Yes

CI 95%ORSPSP***SPRP**Deaths

****S. pneumoniaeS. pneumoniae ResistResist toto PenicillinPenicillin*** *** S. pneumoniaeS. pneumoniae Sensible Sensible toto PenicillinPenicillin

RelationshipRelationship betweenbetween mortalitymortality in in patienspatiens withwithMeningitis Meningitis SpnSpnRPRP vsvs SpnSpnSPSP

Departamento de Enfermedades Infecciosas,Departamento de Enfermedades Infecciosas,Hospital Infantil Dr. Robert Reid Cabral, Jun 1993 Hospital Infantil Dr. Robert Reid Cabral, Jun 1993 -- Dic 2003Dic 2003

Ref: Feris J, Fernández J, Sachez J, et al: et al. ICAAC 44th Washington DC, 2004,

Paper # 3412

Clinical Outcomes of Meningitis Caused by Streptococcus pneumoniae in the Era of Antibiotic

Resistance

9/74 (124/20 (20)Discharged with neurological deficit(s)16/73 (22)3/20 (15)Discharged to long-term-care facility28/87 (32)5/22 (23)Required mechanical ventilation52/85 (61)9/19 (47)Required supplemental oxygen41/74 (55)10/20 (50)Required ICU admission

7 ± 9.39.9 ± 11.9Length of stay in ICU (d)14.1 ± 11.219.3 ± 19.9Length of hospitalization (d)13/87 (15)2/22 (9)Died during hospitalization

Cefotaxime-susceptible

(n = 87)

Cefotaxime-nonsusceptible

(n = 22)Outcome

Ref: Clinical Infectious Diseases 2000;30:71-77

CeftazidimeCeftazidime vs. standard therapy for pediatric vs. standard therapy for pediatric meningitis: therapeutic, pharmacologic and meningitis: therapeutic, pharmacologic and

epidemiologic observations. epidemiologic observations.

Ref: Rodriguez WJ, Puig J, Khan WN, Feris J, et al. Pediatr Infect Dis. 1986 Jul-Aug;5(4):408-15.

5.91 / 17N. meningitidis331 / 3Salmonella spp.

478 / 17S. pneumoniae

73 / 42H. influenzae

%nMicroorganism

Mortality by pathogen

Sulbactam/ampicillinSulbactam/ampicillin vs. vs. chloramphenicol/ampicillinchloramphenicol/ampicillinfor the treatment of meningitis in infants and for the treatment of meningitis in infants and

children children

Ref: Rodríguez WJ, Khan WN, Puig J, Feris, J, et al. Rev Infect Dis. 1986 8 Suppl 5:S620–S629.Nov–Dec

205Other616No growth

08N. meningitidis

23.515S. pneumoniae

5.437H. influenzae

%nMicroorganismo

Mortality by pathogen among 81 patients with meningitis

Phagocytosis Resistency

Pneumococcal Virulence Factors

Ref: Microbiol Mol Biology Rev 2001;65:187-207

.

DEIDEI

Infections due to Infections due to SpnSpn Penicillin Resistant in USAPenicillin Resistant in USA1979 1979 -- 19991999

Streptococcus pneumoniae Penicillin Sensible from CSF Hospital Infantil Dr. Robert Reid Cabral,

Santo Domingo, Rep. Dominicana2000-2007

4242

15

61

13

26

57

18

25

4339

17

56

33

11

39

35

23

10

14 4

17

0

10

20

30

40

50

60

70

2000 2001 2002 2003 2004 2005 2006 2007

Sensible Intermediate Resistantn=197

Streptococcus pneumoniae Cefotaxime Sensible from CSF Hospital Infantil Dr. Robert Reid Cabral,

Santo Domingo, Rep. Dominicana2000-2007

77

19

3

92

4 4

74

22

4

72

20

8

87

94

79

17

3

148

28

0 4

0102030405060708090

100

2000 2001 2002 2003 2004 2005 2006 2007

Sensible Intermediate Resistantn=186

Susceptibility of Susceptibility of Streptococcus. pneumoniaeStreptococcus. pneumoniae to penicillinto penicillin20002000--2005 2005 < 6 < 6 yearsyears oldold

5963

67

42

70

29

21

33

12

21

13 11 12

25

138

75

26

Argentina Brazil Chile Dominican R Paraguay Venezuela

SIR

%

SIREVA II - LATIN AMERICAN GROUP

1. Friedland Ian R.: Antimicrobial Agents and Chemotherapy, Sept 1997, p. 1888-1891

2. Odio Pérez, Carla M.:Acta pediátr. Costarric v. 15 n.3 San José2001

Geographic region with:Geographic region with:

≥≥ 5% 5% SpnSpn PR PR Use Use CefotaximeCefotaxime or or CeftriaxoneCeftriaxone

≥≥ 5% 5% SpnSpn CR CR Use Use VancomycinVancomycin + + CefotaximeCefotaxime or or CeftriaxoneCeftriaxone ¹-²¹-²..

Cost-effectiveness using different antibiotics in Bacterial Meningitis

Cost *Antibiotics

US$325.00/dayMeropenemUS$62.00/dayVancomycin

US$160.00/dayCeftriaxoneUS$130.00/dayCefotaximeUS$27.00/dayChloramphenicolUS$29.00/dayAmpicillin

US$12.00/dayPenicillin G

* Estimates in adults at the higher doses/day

Ref.: Current Treatment options in Infectious Diseases 2000, 2:433-440

Costs* of pneumococcal disease in a cohort of 340,000 Costs* of pneumococcal disease in a cohort of 340,000 Canadian children from six months to nine years of ageCanadian children from six months to nine years of age

$125,701,000$85,477,000$40,224,000Total

$20,830,000$3,958,000$16,872,000Myringotomy with ventilation tube insertion

$84,156,000$69,008,000$15,148,000Acute otitis media$9,009,000$7,748,000$1,261,000Nonhospitalized pneumonia$9,130,000$4,108,000$5,022,000Hospitalized pneumonia$105,000$71,000$34,000Nonhospitalized bacteremia$1,725,000$655,000$1,070,000Hospitalized bacteremia$746,000$97,000$649,000Meningitis

Costs to societyCosts to families

Costs to health system

* Excluding costs of sequelae and productivity losses associated with deaths and disabilities. Assuming 22% of all cases of pneumonia, 19% of all cases of acute otitis media, and 50 % of all cases of myringotomy with ventilation tube insertion are attributable to S pneumoniae

Ref.: Can J Infect Dis. 2003 Jul–Aug; 14(4): 215–220.

N ENGL J MED 2004 351;1826-1828

Mortalility associated to Bacterial Meningitis in the last 90 years

DEIDEI

Comparison of oral cefuroxime axetil and oral amoxycillin/clavulanate in the treatment of community-

acquired pneumonia

18-Haemophilus influenzae

38-Streptococcus pneumoniae60%n=97/162Organism Isolated*

• Pretreatment. Respiratory tract fluid specimen:• deep expectorated sputum,• endotracheal suction, • bronchial washing, • transtracheal aspirate. • Gram stain of sputum: <10 epithelial cells/pf and >25polymorphonuclear leucocytes/pf.

Ref: Higuera F, Hidalgo H, Feris J, et al: Journal of Antimicrolbial Chemotherapy (1996) 37, 555-564.

Empiema Pleural en el Departamento de InfectologíaHospital Infantil Dr. Robert Reid Cabral

Santo Domingo, 1994-2004

721

203

731

172

637

127

781

213

735

168

892

148

1070

121

901

165

886

180

1019

126

1071

112

846

180

1067

125

1220

68

1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007

Hospitalizaciones Empiemas pleurales

DEIDEI

X=151/year

ParapneumonicParapneumonic effusions and empyema in hospitalized effusions and empyema in hospitalized children: retrospective review of 227 caseschildren: retrospective review of 227 cases

227 Clinical records in 19 years review: Parkland Memorial Hospital and Children’s Medical Center, Dallas.

Ref: Ref: FreijFreij, BJ, MD, , BJ, MD, Lkusmiesz,HLkusmiesz,H RN, Nelson, JC, MD, and RN, Nelson, JC, MD, and MccrackenMccracken, GH, jr., MD:, GH, jr., MD: Pediatr

Inf Dis 1984;3:578-591

227 (100)102 (100)125 (100)All cases54 (24)22 (22)32 (26)Sterile18 (8)10 (10)8 (6)Otras bacterias40 (18)25 (25)15 (12)Haemophilus49 (22)22 (22)27 (22)S. pneumoniae66 (29)23 (23)43 (34)S. aureus

TotalJul 73-Dec 82Jan 64-Jun 73No. CasesEtiology

Empyema associated with community-acquired pneumonia: A Pediatric Investigator's Collaborative Study on Infections in

Canada (PICNIC) studyn=251

8 pediatric hospitals in a period of 3 years

< 5 years of age 57% of the cases. The median length of hospitalization was 9 days. Oxygen supplementation was required in 77%, of children 75% had chest tube placement 33% were admitted to an intensive care unit. While similarity in use of pain medication, antipyretics and antimicrobial use was observed.wide variation in number of chest radiographs and invasive procedures (thoracentesis, placement of chest tubes) was observed between centers. The most common organism found:Streptococcus pneumoniae

Ref: Joanne M Langley , James D Kellner , Nataly Solomon et al: BMC Infectious Diseases 2008, :129doi:10.1186/1471-2334-8-129

More Frequent Distribution Bacterial Isolated by year from Pleural Fluid Departamento de Infectología del Hospital Infantil Dr. Robert Reid Cabral,

República Dominicana, 1994-2007

0

10

20

30

40

50

60

70

80

1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007S. pneumoniae S. aureus H. influenzae DEIDEI

Cases of Pleural Empyema by ageadmitted to Infectious Diseases Department

Hospital Infantil Dr. Robert Reid Cabral, 1994-2003

1001001,130Total

1000.44Unknown

99.519.1216> 5 years

80.429.03282-5 years

51.520.923613-23 months

30.623.52667-12 months

7.17.1800-6 months

% accumulate%nAge

Ref: 2008. Infectious Diseases Department, Hospital Infantil Robert Reid Cabral

S.pneumoniae Serotypes-serogroups Identify in Patients with Pneumonia,

Dominican Republic, 2000-2005n=146

82

21

135 6 4 4 5 2 2 2 0

0

10

20

30

40

50

60

70

80

90

14 6A/6B 1 3 19/19A 23/23F 7/7F 9/9V 5 18/18A Otros 4

* PCV7: 4, 6B, 9V, 14, 18C, 19F y 23F* PCV7: 4, 6B, 9V, 14, 18C, 19F y 23F

PCV7 coverage: 78%

Conclusions• Streptococcus pneumoniae is the leading cause of

bacterial meningitis and pneumonia.

• Spn meningitis causes high rate long termsequelae, principally neurological and hearingloss.

• Spn meningitis mortality rate is high even penicillin susceptibility or not.

• The cost of treatment is very high for the Family, Society and Heath System.