Robin J GreenPhD, DSc

New Insights into the Bugs in the Airway of HIV-infected Children with Lung Disease

The Diseases to Consider

PCPALRTIHIV-associated bronchiectasisBronchiolitis / Pneumonia

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* No mention of TB

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PCP as a Syndrome

Pj

CMV

Bacteria

TB

Viruses

Bacteria (blood culture): • 5 (7.9%) non-survivors • 8 (12.7%) survivors (p=0.508)

Bacteria (NBBAL): • 6 (9.5%) non-survivors • 13 (20.6%) survivors (p=1.00)

Bacterial Co-infection in PCP

Kitchin O, et al. Pediatr Crit Care Med 2012;13:517-9

Respiratory viruses: • 1 (1.6%) non-survivors • 8 (12.7%) survivors (p=0.256)

Viral Co-infection in PCP

Kitchin O, et al. Pediatr Crit Care Med 2012;13:517-9

Cytomegalovirus and Risk of Death

Kitchin O, et al. Pediatr Crit Care Med 2012;13:517-9

CMV Status Alive Dead Total

CMV (-) 25 (56.82) 3 (15.79) 28 (44.44)

CMV <log 4 8 (18.18) 3 (15.79) 11 (17.46)

CMV >log 4 11 (25) 13 (68.42) 24 (38.10)

Total 44 (100) 19 (100) 63 (100)

Fisher’s exact 0.002

Zampoli M, et al1 Goussard P, et al2 Kitchin P, et al3

n 202 25 63Age(months) 3,2 3.3 3,7HIV 61.4% 100% 84%Mortality 38% 72% 30%PJP(+)/CMV 36% 32% 33%Other viruses RSV, Adeno, PIV PIV3 RSV,PIV3, IV, Adeno

CMV(+) 66% 63% 55%CMV VL>log 4Culture(+)

35/47 (74%) 15/25 (60%) 24/63 (38%)

CMV> log4 (survived) 17/47(36%) ? 11/63(25%)

Treated 23/44 1/24 all IPPV in days ? 14.4 (5-31) 14.1 (10.4-17.9)CMV pn(deaths) ? 13.5 days 12.9 days

1. Zampoli M, et al. Pediatr Infect Dis J 2011;30:413–417 2. Goussard P, et al. Pediatr Pulmonol 2010; 45:650–655 3. Kitchin O, et al. Pediatr Crit Care Med 2012;13:517-9

Serum Cytokines

IL-10 IL-1B IP-10 TNFa0

1000

2000

3000

4000

5000

6000

PCPBronchiectasis

P<.001

P=.0078

Green RJ, et al. J Antiviral Antiretroviral 2012;13:516-519

New Data from SBAH

Survival 5% in 2005Survival 70% in 2009Survival 82% in 2012 - 2015

Reasons for improved survival:Lung protective ventilationOral steroidsGanciclovirEarly ARV introduction (BUT NOT WITHOUT PRICE)

Cloete J, et al. S Afr J Child Health 2015;in press

ALRTI’sPneumonian = 58 (54.7%)

Bronchiolitisn = 48 (45.3%)

X2 p value

Cough 53 (91.4%) 46 (95.8%) 0.358Wheeze 14 (24.1%) 27 (56.3%) 0.001Shortness of breath 45 (77.6%) 38 (79.2%) 0.844

Fever 31 (53.4%) 29 (60.4%) 0.471Runny nose 22 (37.9%) 25 (52.1%) 0.144Nasal congestion 36 (62.1%) 31 (64.6%) 0.789Sneeze 18 (31.%) 18 (37.5%) 0.484Current antibiotics 49 (84.5%) 25 (52.1%) 0.001

HIV status 14 (24.1%) 1 (2.1%) 0.001

Abbott S, et al. SATS 2014

Viral Results

Abbott S, et al. SATS 2014

NS for all comparisonsRespiratory viruses identified in nasopharyngeal aspirates of cases and controls (n=158)

HRV Prevalence

Abbott S, et al. SATS 2014

Abbott S, et al. SATS 2014

HRV

Adeno

virus

RSV

Bocav

irus

Corona

virus

Parainf

luenz

a viru

s

Influe

nza v

irus

Metapn

uemov

irus

0.0

10.0

20.0

30.0

40.0

50.0

60.053.3

20.0

0.0

13.3

20.0 20.0

0.0

6.7

49.4

34.1 30.6

24.7

10.68.2 9.4

7.1

HIV-Infected (n=15)

HIV-Uninfected (n=85)

Per

cent

(%) w

ithin

HIV

-infe

cted

and

uni

nfec

ted

case

s P<0.001

Abbott S, et al. SATS 2014

Respiratory viruses identified in nasopharyngeal aspirates of HIV-infected and HIV-uninfected cases (n=100)

P<0.001

Sikazwe CT, et al. 9th International Respiratory Syncytial Virus Symposium 2014

RSV Viral Load

Sikazwe CT, et al. 9th International Respiratory Syncytial Virus Symposium 2014

RSV Subtypes and Disease

16s rRNA Bacterial Load in ALRTI’s

HIV-infected HIV-uninfected P HRV + HRV - P

7.22 X 106 4.93 X 106 0.047 5.95 X 106 3.96 X 106 0.049

Annamaly A, et al. ATS 2014

68% higher in HIV-infected children

67% higher in HRV-positive children

Abbott S, et al. SATS 2015

Cytokines in ALRTI’s HIV-infected vs. Uninfected• IL-13, IL-4, IL-5, TNF-α, IFN-α, IFN-γ,

MIP-1α significantly lower in HIV-infected cases

• IP-10 and MIG significantly higher in HIV-infected cases

HIV-associated Bronchiectasis

Masekela R, et al. SAMJ 2009;99:822-825 Masekela R, et al. IJTBLD 2012;16:114-119

Only one viral culture of Parainfluenza type 2

23

Haemophilus influenzae

Pseudomonas sp.

Vosloo S, et al 2015;unpublished

Bronchiectasis Airway Microbiome

Serum TREM-1

Masekela R, et al. Ped Pulmonol 2015;50:333-339

Conclusion

• Many childhood ALRTI’s have identifiable viral and bacterial organisms

• The relative contribution of each species to disease is not clear

• In HIV-infected children there is a greater relative abundance of bacteria, even in obvious viral disease

• Acute viral bronchiolitis (RSV) occurs less commonly in HIV-infected children …..

Conclusion• … But many normal children harbor viruses and bacteria

• Organisms in HIV-associated bronchiectasis are different to CF-associated bronchiectasis, possibly reflecting different immune responses

• Cytokine data does not support the pro/anti-inflammatory model (but IP-10 important in ALRTI’s)

All these conclusions may have implications for management and vaccine prevention

Thank You• Prof Refiloe Masekela

• Dr Teshni Moodley

• Dr Omolemo Kitchin

• Dr Salome Abbott

• Dr Alicia Annamaly / Prof Peter le Souef

• Dr Jeane Cloete

• Ms Solize Vosloo / Prof Fanus Venter

• Prof Max Klein