1. PCP: Introduction & Risk Factors
Dr. Immaculate Kariuki
Consultant Paediatrician
Nairobi, Kenya

2. Intended Learning Objectives
To understand the contribution of LRTI to childhood morbidity & mortality
To identify the challenges encountered in making a microbiological diagnosis of pneumonia in children
To identify the various risk factors for PCP.

3. LRTI: deadliest childhood disease
LRTIs are a leading cause of under 5 mortality in the low and middle income countries( LMICs) including HIV infected children
1 million deaths in children worldwide, majority in the developing countries
Leading causes – bacteria, viruses, fungi & atypical bacteria increasing significance
Early recognition of pneumonia averts serious complications & death
Sources:
Global Burden of Disease Pediatrics Collaboration
Global and National Burden of Diseases and Injuries Among Children and Adolescents Between 1990 and 2013Findings From the Global Burden of Disease 2013 Study
JAMA Pediatr. 2016;170(3):

4. LRTI due to Pneumocystis jirovecii
Pneumocystis jirovecii is a common cause of hypoxic LRTI leading to hospitalization and death especially in HIV infected infants and young children, even after introduction of ART
PCP is the most prevalent AIDS indicator illness in infants & young children - up to half of all AIDS defining illness by year of age
Incidence peaks in first 6 months
High case fatality (20-60%) even in tertiary centres with ICU so prevention is key

5. Challenges Difficulty of microbiological diagnosis in children
unavailable tests, specimen collection
distinguishing colonisation from pathogenic disease
Polymicrobial infection
co-infection with bacteria & CMV is increasingly being recognised
worse prognosis - up to 10-fold increased mortality
Steroid use in high TB & CMV burden areas
Follow up through maternal to child transmission preventive programmes (PMTCT) is poor including adherence to prophylaxis
Recognition of non-HIV causes of immunosuppression

6. Difficult microbiologic diagnosis
Scott et al, J Clin Invest 2008;118:

7. Risk factors for PCP HIV infection & exposure
Haematological malignancies
Primary immunodeficiencies
Immunosuppressive drugs including glucocorticoid use
Malnutrition
Prematurity

8. HIV as a risk factor for PCP
HIV compounds all-cause LRTIs in several ways:
Increases the risk of developing pneumonia from any cause
OI associated pneumonia – tuberculosis, PCP & CMV
Associated with more severe disease and attendant bacteremia
Higher rates of death and treatment failure
HIV exposed but negative children have increased risk of some opportunistic pathogen infections e.g PCP with poorer outcomes than non-exposed children
References:
Mc Nally et al.Effect of age, polymicrobial disease, and maternal HIV status on treatment response and cause of severe pneumonia in South African children: a prospective descriptive study Lancet 2007; 369: 1440–5
Mc Nally et al Lancet 2007; 369: 1440–5

9. Global paediatric HIV burden
AT RISK
2015

10. New HIV infections

11. PCP & other OIs trends
Amongst HIV- infected children hospitalized with pneumonia in Africa, prevalence 10-49%
Cause of 29-67% of respiratory related deaths amongst HIV-infected children in some post mortem studies
Yearly opportunistic infection rates per 1,000 HIV-infected children
CDC Pediatric Spectrum of Disease Project, 1994–2001.
Morris A. et al.Emerging Infectious Diseases 2004: 10 (10)

12. CD4 counts are a poor risk surrogate
CD4 counts are not good predictors of disease in infants
(present with PCP at any CD4)
While older children and adolescents:
CD4 % (<15%) or CD4+ <200 cells/ul are predictive of risk

13. PCP in children with HIV infection
Sample size
Prevalence
Specimen
studied
Method of detection
Reference
Malawi
327 5%
Lung aspirate
PCR
Graham 2011
S. Africa
124
35%
NPA/ IS
PCR/
HISTOLOGY
Morrow 2010
Ukraine
245 6%
n/a
N/A
Mahdavi 2010
Botswana 47
31%
autopsy
GMS
Arisari 2003
Zambia
180
29%
Chinta 2002
105
49%
IS/NPA IF
Ruffini& Madhi
151
10%
PCR/IF
ZAR 2000
Source: GAFFI fact sheet

14. PCP infection in the HAART era
Pneumocystis pneumonia in South African children with and without HIV infection in the era of HAART
202 children enrolled
Median age 3.2 months
HIV+
124 (61.4%)
HIV EXPOSED
34 (16.0%)
HIV UNEXPOSED
44 (21.7%)
PCP
33 (26.6%)
7 (20.3%)
3 (6.8%)
CASE FATALITY 39.5%
BM Morrow et al. Ped Infect Dis 2010; 29 (6): 553

15. LRTI among HIV exposed infants in Africa
Ref
Country
(year)
Study type; sample size
(HEU:HU)
Outcome
Follow up
Findings
[HEU vs HU (95% CI)]
Izedgndar et al
South Africa
Severe pneumonia, RCT(40:244)
Treatment failure (TF)
3-59
months
uOR 2.19
( )
Mcnally
et al
( )
Hospital cohort
(41;75)
Severe pneumonia
(TF)
0-12 months
aOR 6.02
( )
Kelly et al
Botswana
( )
Prospective hospital cohort
(64:153)
Treatment failure (TF) & mortality
1-23 months
TF aRR 1.83 ( )
Mortality
aRR 4.31 ( )
Le Roux et al
( )
Birth cohort
130;567)
Pneumonia incidence
0-12
All pneumonia
aRR 1.62( )
Severe pneumonia uRR 4.04( )
Higher risk than HIV unexposed
-poor protection from low maternal
antibody
- malnutrition
- poor innate immunity
- exposure to PCP infected household
member likely to be higher

16. PCP in HIV exposed infants
Case reports of exposed, HIV negative( HIV EU) immunocompetent infants early in HIV epidemic
Several case series describe PCP among HIV EU infants
P. jirovecii from broncho
alveolar lavage was
detected in one-third of
HIV-EU children failing
treatment at 48 hours

17. Haematological malignancy
Historically reported as the commonest cause of death in children on multi-agent therapy for leukemia in remissio
Common cause of death among children receiving chemotherapy
Without chemoprophylaxis rates of 20-40% reported
Higher mortality rates than in the non-HIV infected
Varies by:
i) cancer type – highest in lymphoid malignancy
ii) type and intensity of chemotherapy
REFERENCES:
i) Hughes et al Cancer 1975;36:
Intensity of Immunosuppressive therapy and the incidence of Pneumocystis carinii pneumonitis.
Overgaard et al Scand J Infect Dis 2007;39:
Pneumocystis jirovecii pneumonia(PCP) in HIV-1-negativepatients: a retrospective study

18. Steroids increase risk for PCP
Research in adults
Doses equivalent to >30mg/day (0.4mg/kg/day)
Steroids for prolonged duration (typically> 4 weeks) as indicated for brain tumours or nephrotic syndrome
Confounders - other immunosuppressive medications & conditions
Stuck AE et al.Rev Infect Dis 1989;11: Risk of infectious Complications in patients taking glucocorticoids.
Slivka et al Am J med 1993;94: Pneumocystis pneumonia during steroid taper in patients with primarybrain tumors.

19. Malnutrition & prematurity
Historical case reports around world war II.
Prophylaxis after treatment in the acute phase did not prevent additional mortality in Kenya

20. Summary
HIV infection is still the most common risk factor for Pneumocystis pneumonia
PCP rates increase as economic conditions improve (i.e. GDP)
As new HIV infections in children decline, other subcategories like HIV exposure and non-HIV related immunosuppression become more significant risk factors

21. END