1. Robin J Green PhD, DSc New Insights into the Bugs in the Airway of HIV-infected Children with Lung Disease

2. The Diseases to Consider Bronchiolitis / Pneumonia * * * * * No mention of TB *

3. PCP as a Syndrome Pj CMV Bacteria TB Viruses

4. 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

5. 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

6. Cytomegalovirus and Risk of Death Kitchin O, et al. Pediatr Crit Care Med 2012;13:517-9 Fisher’s exact 0.002

7. Zampoli M, et al 1 Goussard P, et al 2 Kitchin P, et al 3 n2022563 Age(months)3,23.33,7 HIV61.4%100%84% Mortality38%72%30% PJP(+)/CMV36%32%33% Other virusesRSV, Adeno, PIVPIV3RSV,PIV3, IV, Adeno CMV(+)66%63%55% CMV VL>log 4 Culture(+) 35/47 (74%)15/25 (60%)24/63 (38%) CMV> log4 (survived)17/47(36%)?11/63(25%) Treated23/441/24all IPPV in days?14.4 (5-31)14.1 (10.4-17.9) CMV pn(deaths)?13.5 days12.9 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

8. Serum Cytokines P=.0078 Green RJ, et al. J Antiviral Antiretroviral 2012;13:516-519

9. New Data from SBAH Survival 5% in 2005 Survival 70% in 2009 Survival 82% in 2012 - 2015 Reasons for improved survival: Lung protective ventilation Oral steroids Ganciclovir Early ARV introduction (BUT NOT WITHOUT PRICE) Cloete J, et al. S Afr J Child Health 2015;in press

10. ALRTI’s Pneumonia n = 58 (54.7%) Bronchiolitis n = 48 (45.3%) X 2 p value Cough53 (91.4%)46 (95.8%)0.358 Wheeze14 (24.1%)27 (56.3%)0.001 Shortness of breath45 (77.6%)38 (79.2%)0.844 Fever31 (53.4%)29 (60.4%)0.471 Runny nose22 (37.9%)25 (52.1%)0.144 Nasal congestion36 (62.1%)31 (64.6%)0.789 Sneeze18 (31.%)18 (37.5%)0.484 Current antibiotics49 (84.5%)25 (52.1%)0.001 HIV status14 (24.1%)1 (2.1%)0.001 Abbott S, et al. SATS 2014

11. Viral Results Abbott S, et al. SATS 2014 NS for all comparisons Respiratory viruses identified in nasopharyngeal aspirates of cases and controls (n=158)

12. HRV Prevalence Abbott S, et al. SATS 2014

13. HRV Species Identification (49 HRV positive NPAs) Abbott S, et al. SATS 2014

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

16. P<0.001 Sikazwe CT, et al. 9th International Respiratory Syncytial Virus Symposium 2014 RSV Viral Load

17. Sikazwe CT, et al. 9th International Respiratory Syncytial Virus Symposium 2014 RSV Subtypes and Disease

18. 16s rRNA Bacterial Load in ALRTI’s HIV-infectedHIV-uninfectedPHRV +HRV -P 7.22 X 10 6 4.93 X 10 6 0.0475.95 X 10 6 3.96 X 10 6 0.049 Annamaly A, et al. ATS 2014 68% higher in HIV-infected children 67% higher in HRV-positive children

19. What Were These Organisms? Annamaly A, et al. ATS 2014 Streptococcus sp.

20. Weinberger DM, et al. PlosMedicine 2015;12:e1001776

21. 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

22. 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. 23 Haemophilus influenzae Pseudomonas sp. Vosloo S, et al 2015;unpublished Bronchiectasis Airway Microbiome

24. Phyla Clustering by Disease Type Vosloo S, et al 2015;unpublished

25. Cytokines in HIV-associated Bronchiectasis Masekela R. PhD 2013

26. Serum TREM-1 Masekela R, et al. Ped Pulmonol 2015;50:333-339

27. 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 …..

28. 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

29. 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