Prakash Mohan Jeena1
Department of Paediatrics and Child Health, University of Kwazulu-Natal, Private bag X1, Congella, Durban 4013, South Africa
Of the approximately 2.1 million children who are infected with human immunodeficiency virus type 1 (HIV-1),1 more than 80% will develop a respiratory illness sometime during the course of their disease.2 The prevalence of HIV-1 infection among African children admitted for very severe pneumonia (under the WHO case definition) varies from 55% to 65% and is associated with a case fatality rate of 20% to 34%; three- to six-times higher than children who are not infected with HIV.3,4 In infancy, pneumonia caused by Pneumocystis jiroveci is often the first HIV/AIDS indicator disease that prompts HIV testing and, consequently, early antiretroviral treatment for those infected.5
Approximately 2 million children less than 5 years of age die of pneumonia each year in countries with a high prevalence of HIV. The standard case management guidelines for pneumonia recommended by WHO for use in areas with low HIV burdens are less effective in areas where HIV burdens are high.6 Modifications to these guidelines have been suggested, but their use, as reported in a recently published study of children with very severe pneumonia, resulted in a 45% treatment failure rate among HIV-infected infants in tertiary care settings.4 Polymicrobial infections with Staphylococcus aureus, nontyphoidal Salmonella spp. and other Gram-negative pathogens, Mycobacterium tuberculosis, P. jiroveci, cytomegalovirus and other viruses were commonly seen among the treatment failures and carried a greater than 10-fold risk of a poorer outcome. Randomized controlled studies of alternative antimicrobial agents that are active against some of the pathogens identified among these treatment failures are urgently required.
A second major challenge for standard case management in the HIV era is to develop a management guideline to care for the largest group of HIV-affected children: HIV-exposed but HIV-uninfected children, who are at increased risk of acquiring pneumonia. Such children, who live in close contact with HIV-infected persons who persistently harbour a multitude of different pathogens, are at higher risk of pneumonia treatment failure than HIV-unexposed control children; however, the risk of an adverse outcome is lower than for HIV-infected children.7 Studies on the impact of pneumonia on HIV-exposed but HIV-uninfected children are essential.
The other major intervention to reduce pneumonia-related morbidity and mortality among HIV-infected children requires the implementation of preventive strategies. Routine immunizations against Streptococcus pneumoniae, Haemophilus influenzae and varicella are safe and effective in HIV-infected children, even though their primary immunological response is inferior and they experience faster decay in immunological memory. Despite the lower efficacy of the conjugate pneumococcal (65% versus 83%) and H. influenzae type b vaccines (55% versus 91%) against invasive disease in HIV-infected and HIV-uninfected control children, respectively, introduction of these vaccines would considerably reduce the 1.6 million pneumococcal and 300 000 H. influenzae deaths that occur each year.810 Other preventive strategies, such as the provision of co-trimoxazole prophylaxis against bacterial and P. jiroveci infections, improvement in the provision of prevention of mother-to-child transmission (PMTCT) interventions and early use of highly active antiretroviral therapy (HAART) require urgent scaling-up. In a randomized controlled study of co-trimoxazole prophylaxis versus placebo in HIV-infected older Zambian children, a significant reduction in the hazards ratio for death of 0.57 (95% confidence interval: 0.430.77) was seen in the treated group.11 Although there is undoubted benefit in providing co-trimoxazole prophylaxis to HIV-infected children, its widespread implementation does carry risks such as development of resistance to a drug used for treating P. jiroveci pneumonia. This needs to be studied urgently as ineffective treatment of these conditions could increase mortality substantially. The effective implementation of PMTCT programmes, involving at least dual antiretroviral therapy and effective nutritional advice, will help to reduce to less than 4% the incidence of transmission of HIV to newborns and infants.12 Such a reduction is likely to have a significant impact on cutting the prevalence of pneumonia among HIV-infected children. Furthermore, use of HAART with HIV-infected children has been associated with a fourfold reduction in the rate of opportunistic infections and a threefold reduction in hospitalizations.13 The role of nutritional inventions, such as exclusive breastfeeding and zinc supplements, in the prevention of pneumonia among HIV-infected children needs to be explored more thoroughly.
In conclusion, significant attention has to be paid to revising the standard case management guidelines for HIV-infected children with pneumonia through properly conducted randomized controlled studies. The implementation of preventative strategies that include co-trimoxazole prophylaxis, pneumococcal and H. influenzae type b vaccinations, PMTCT programmes and early introduction of HAART carry the greatest immediate hope for helping these children. There is a need to rapidly scale up these measures globally.
1. UNAIDS epidemic update: special report on HIV/AIDS: December 2007. Geneva: UNAIDS/WHO; 2007. Available from: http://whqlibdoc.who.int/unaids/2007/9789291736218_eng.pdf [accessed on 3 April 2008] .
2. UNAIDS epidemic update: December 2005. Geneva: UNAIDS/WHO; 2005. Available from: http://www.unaids.org/epi/2005/doc/EPIupdate2005_pdf_en/epi-update2005_en.pdf [accessed on 3 April 2008] .
3. Nathoo KJ, Gondo M, Gwanzura L, Mhlanga BR, Mavetera T, Mason PR. Fatal Pneumocystis carinii pneumonia in HIV seropositive infants in Harare, Zimbabwe. Trans R Soc Trop Med Hyg 2001;95:37-9. PMID:11280062 doi:10.1016/S0035-9203(01)90325-6
4. McNally LM, Jeena PM, Gajee K, Thula SA, Sturm AW, Cassol S, 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;369:1440-51. PMID:17467514 doi:10.1016/S0140-6736(07)60670-9
5. Graham SM, Mtitimila EI, Kamanga HS, Walsh AL, Hart CA, Molyneux ME. The clinical presentation and outcome of Pneumocystis carinii pneumonia in Malawian children. Lancet 2000;355:369-73. PMID:10665557 doi:10.1016/S0140-6736(98)11074-7
6. Jeena P, Thea DM, Macleod MB, the APPIS Group. Failure of standard antimicrobial therapy in children aged 3-59 months with mild or asymptomatic HIV infection and severe pneumonia. Bull World Health Organ 2006;84:269-75. PMID:16628299
7. Jeena PM, Minkara AK, Corr P, Bassa F, McNally LM, Coovadia HM, et al. Impact of HIV-1 status on the radiological presentation and clinical outcome of children with WHO defined community-acquired severe pneumonia. Arch Dis Child 2007;92:976-9. PMID:17595201 doi:10.1136/adc.2006.104406
8. Klugman KP, Madhi SA, Huebner RE, Kohberger R, Mbelle N, Pierce N, for the vaccine trialists group. A trial of a 9valent pneumococcal conjugate vaccine in children with and without HIV infection. N Engl J Med 2003;349:1341-8. PMID:14523142 doi:10.1056/NEJMoa035060
9. Madhi SA, Petersen K, Khoosal M, Huebner RE, Mbelle N, Mothupi R, et al. Reduced effectiveness of Haemophilus influenzae type b conjugate vaccine in children with a high prevalence of human immunodeficiency virus type 1 infection. Pediatr Infect Dis J 2002;21:315-21. PMID:12075763 doi:10.1097/00006454-200204000-00011
10. Centers for Disease Control and Prevention. Vaccine preventable deaths and the Global Immunization Vision and Strategy, 2006-2015. MMWR Morb Mortal Wkly Rep 2006;55:511-5. PMID:16691182
11. Chintu C, Bhat GJ, Walker AS, Mulenga V, Sinyinza F, Lishimpi K, et al. Co-trimoxazole prophylaxis against opportunistic infections in HIV infected Zambian children CHAP: a double blind placebo trial. Lancet 2004; 364:1865-71. PMID:15555666 doi:10.1016/S0140-6736(04)17442-4
12. Lallemant M, Jourdain G, Le Coeur S, Mary JY, Ngo-Giang-Huong N, Koetsawang S, et al. Single dose perinatal nevirapine plus standard zidovudine to prevent mother-to-child transmission of HIV-1 in Thailand. N Engl J Med 2004;351:217-28. PMID:15247338 doi:10.1056/NEJMoa033500
13. Nesheim SR, Kapogiannis BG, Soe MM, Sulivan KM, Abrams E, Farley J, et al. Trends in opportunistic infections in the pre- and post-highly active antiretroviral therapy eras among HIV-infected children in the Perinatal AIDS Collaborative Transmission Study, 1986-2004. Pediatrics 2007;120:100-9. PMID:17606567 doi:10.1542/peds.2006-2052