Epidemiology of Viral-associated Acute Lower Respiratory Tract Infection Among Children <5 Years of Age in a High HIV Prevalence Setting, South Africa, 20092012

Cohen, Cheryl MD*†; Walaza, Sibongile MD*†; Moyes, Jocelyn MD*†; Groome, Michelle MD‡§; Tempia, Stefano PhD¶‖; Pretorius, Marthi MSc*; Hellferscee, Orienka MSc*; Dawood, Halima MD**††; Chhagan, Meera MD‡‡; Naby, Fathima MD‡‡; Haffejee, Summaya MD§§; Variava, Ebrahim MD¶¶‖‖; Kahn, Kathleen MD***†††‡‡‡; Nzenze, Susan MD‡§; Tshangela, Akhona BSc*; von Gottberg, Anne MD*‡; Wolter, Nicole PhD*‡; Cohen, Adam L. MD¶‖; Kgokong, Babatyi PhD*; Venter, Marietjie PhD*§§§; Madhi, Shabir A. PhD*‡§


In the article on page 66, volume 34, issue 1, there are multiple errors in the text surrounding the reference citations.

On page 66, the first paragraph should appear as follows “In 2010, an estimated 1.4 million children died due to acute lower respiratory tract infections (LRTI) and an estimated 11.9 million were hospitalized.1,2 HIV infection is associated with increased severity of LRTI and higher case-fatality ratios.3–5 The relative

contribution of viral and bacterial etiologies to the syndrome of LRTI also varies by HIV status.6,7 Data from Europe and North America suggest that even in the presence of widespread availability of highly active antiretroviral therapy (HAART), the incidence of LRTI remains elevated in HIV-infected children.8,9

Also on page 66, the second paragraph, the 2nd, 3rd, and 4th sentences should appear as follows “In South Africa among children aged <5 years in 2011, the estimated HIV prevalence was 4% and coverage with HAART was approximately 26%.10Haemophilus influenzae type b conjugate vaccine was introduced into the South African immunization program in 1999 and the pneumococcal conjugate vaccine (PCV) in 2009.11 As bacterial etiologies decline due to vaccination, respiratory viral causes of LRTI may gain greater prominence.”

On page 67, the first paragraph, the last sentence should appear as follows “In June 2010, an additional surveillance site was introduced at Klerksdorp Hospital in a periurban area of the Northwest Province.12

On page 67, the fourth paragraph, entire section of “Evaluation of HIV Sero-status” should appear as follows “HIV-infection status was determined based on testing undertaken as part of standard-of-care,13 or through anonymized linked dried blood spot specimen testing by HIV PCR for children aged <18 months and by enzyme-linked immunosorbent assay for individuals aged ≥18 months. CD4+ T-cell counts were determined by flow cytometry.14 Patients were categorized into 2 immunosuppression

categories such as (1) severe immunosuppression (CD4+ T-lymphocytes <25% among infants, CD4+ <20% among 12–35 months children or CD4+ <15% among those 36–59 months age) or (2) mild or no immunosuppression.15

On page 67, the fifth paragraph, the second and third sentences should appear as follows “Specimens were tested by multiplex real-time reverse-transcription PCR assay for 10 respiratory viruses including influenza A and B viruses, parainfluenza virus I-III (PIV), respiratory syncytial virus (RSV), enterovirus, human metapneumovirus (hMPV), adenovirus and human rhinovirus (hRV).16 Owing to challenges with availability of reagents, we did not test for adenovirus from August to October 2009. Streptococcus pneumoniae was identified by quantitative real-time PCR detecting the lytA gene from whole blood specimens.17

On page 67, the sixth paragraph, the fourth, fifth, sixth, and seventh sentences should appear as follows “We estimated the incidence of hospitalizations per 100,000 individuals using the number of LRTI hospitalizations, adjusting for nonenrollment (refusal to participate and nonenrollment during weekends) by age groups and HIV status divided by the mid-year total population estimates18 for each year, multiplied by 100,000. HIV prevalence in the study population was estimated from the projections of the Actuarial Society of South Africa AIDS and Demographic model.10 These estimates have been validated by comparison with other estimates and compare favorably with estimates from population-based HIV prevalence studies.19 We assumed that the HIV prevalence by age group among children not tested for HIV was the same as those tested.”

On page 68, the second paragraph, the fourth sentence should appear as follows “Data on presence or absence of World Health Organisation criteria for clinical severity of pneumonia20 were only available for 44% (3841/8723) of children, of whom 23% (900/3841) would be classified as having pneumonia, 23% (894/3841) severe pneumonia and 53% (2047/3841) very severe pneumonia.”

On page 69, the second paragraph under “Characteristics of HIV-infected Children and Factors Associated With HIV Infection” should appear as “Only 25% (174/705) of HIV-infected patients had available CD4+ T-lymphocyte data, of whom 64% had severe immunosuppression.15 Forty-four percent (96/217) of those with available data reported currently receiving HAART and 30% (207/690) reported receiving prophylaxis with trimethoprim–sulfamethoxazole.”

On page 69, the first full paragraph, the last sentence should appear as follows “Coverage of the primary schedule of H. influenza type b conjugate vaccine was 78% (4477/5719) and PCV was 46% (1745/3765) among eligible children with available data. Only 6 patients reported having received the influenza vaccine.”

On page 69, the second full paragraph, should appear as follows “Pneumonia is the commonest reason for hospitalization among African HIV-infected children.6 In our study, HIV-infected children experienced an elevated incidence of hospitalization compared with HIV-uninfected children but this excess risk decreased over the study period from 3.7 (95% CI: 3.4–4.0) in 2009 to 1.8 (95% CI: 1.6–2.1) in 2012, possibly related to more widespread availability of early HAART over this period.23,24 Studies have shown that HAART availability is associated with a reduction in pneumonia incidence in HIV-infected children, albeit HIV-infected children on HAART still have a higher incidence of pneumonia.3,8,9 We found that HIV-infected children experienced a 4 times increased risk of death compared with HIV-uninfected children once hospitalized. This is similar to several other studies which reported case-fatality ratios 3–6 times greater in HIV-infected children.6,7,25,26 The overall case-fatality ratios among HIV-infected children in our study are, however, lower than has previously been described in HIV-infected children from South Africa, possibly related to more widespread HAART availability.”

On page 70, the text at the bottom of the page should appear as “HRV (37%), RSV (26%) and adenovirus (26%) were the most commonly identified respiratory viruses, while influenza was identified in 7% of patients, similar to what has been found in other studies from Africa using PCR for viral diagnosis.22,27–29 Challenges remain for the attribution of a causal role for some viruses (including hRV, adenovirus and enterovirus), which are also identified at high frequency from healthy individuals.22,27,29 RSV and hMPV (both thought to have a likely pathogenic role) were identified less frequently in HIV-infected than HIV-uninfected children suggesting that the increased risk of hospitalization due…”

On page 71, the first paragraph should appear as “…to HIV-associated immunosuppression is relatively lower for these pathogens than for other etiologies. Previous studies from South Africa have shown that while the detection rate for viruses may be lower in HIV-infected children, the incidence of hospitalization is substantially higher in HIV-infected compared with HIV-uninfected children.7,30 Children with RSV were less likely to die, as has been previously described.22 This is likely because the relative contribution of viral etiologies compared with bacterial etiologies is greater for hospitalized pneumonia than among deaths.31 A high proportion of children were coinfected with multiple respiratory viruses (33%), as has been described previously, although coinfection was not associated with adverse outcome.16,29,32 HIV-infected children have been described to have an increased risk of polymicrobial infections due to multiple bacterial, viral and fungal pathogens.3 We were not able to assess this as we did not systematically test for important pathogens in HIV-infected children, particularly tuberculosis, Pneumocystis jiroveci and cytomegalovirus.”

On page 71, the second paragraph should appear as “Blood cultures were performed in less than half of children, limiting our ability to comment on the proportion with bacteremic pneumonia, but similar to other studies from South Africa, the pneumococcus and Staphylococcus aureus were the most common bacteria identified. S. pneumoniae is an important cause of pneumonia in HIV-infected and HIV-uninfected children.25,26 In our study, we identified pneumococcus from 4% of children overall using a combination of PCR and blood cultures (performed in a minority of patients). These rates are similar to other studies from South Africa before PCV introduction which used systematic blood culture collection only.25,26 Failure to observe lower detection rates after PCV introduction may be attributed to our diagnostic technique, real-time PCR, identifying more pneumococcal cases than blood culture in our setting.33 Notwithstanding this, additional cases of pneumococcal coinfection may still have been missed.34,35 Pneumococcal DNA in the blood may reflect occult bacteremia in some individuals.36–38 Patients testing positive for pneumococcus had a high prevalence of detection of respiratory viruses although many of these may have been bystander viruses.32 Influenza was the only virus to be more commonly detected in patients testing positive for pneumococcus. The association between influenza and pneumococcal infection has been described previously.12,39

On page 71, the third paragraph, the seventh sentence through the end of the paragraph should appear as “Similarly, patients who die may be less likely to be enrolled into studies such as ours and this may lead to underestimation of case-fatality ratios and potential exclusion of most severely ill children.27 The denominators for the numbers of HIV-infected and HIV-uninfected children each year were obtained from the 2008 version of the Actuarial Society of South Africa model. Subsequent to the development of this model, rates of access to prevention of mother-to-child transmission and early HAART among children have been more rapid than expected leading to possible overestimation of the numbers of children with AIDS in South Africa, which could have led to an underestimation of the relative risk of hospitalization in HIV-infected children10,24 There were a large number of statistical analyses conducted on these data and corrections were not made for multiple testing.”

On page 71, the final paragraph, third, fourth, fifth and sixth sentences should appear as “Vaccines for RSV are currently under development and could be expected to have a substantial impact on pneumonia burden if they become available.40 Ongoing reductions in burden of pneumococcal pneumonia may be expected following PCV introduction. Influenza was identified in 7% of children and influenza vaccination is recommended for children <5 years in South Africa but very few children in our study reported being vaccinated.41 Influenza vaccines are less effective in children <5 years than healthy adults and efficacy has not been demonstrated in HIV-infected children.42

The Pediatric Infectious Disease Journal. 34(5):555-556, May 2015.

Pediatric Infectious Disease Journal: January 2015 - Volume 34 - Issue 1 - p 66–72
doi: 10.1097/INF.0000000000000478
HIV Reports

Background: Data on the epidemiology of viral-associated acute lower respiratory tract infection (LRTI) from high HIV prevalence settings are limited. We aimed to describe LRTI hospitalizations among South African children aged <5 years.

Methods: We prospectively enrolled hospitalized children with physician-diagnosed LRTI from 5 sites in 4 provinces from 2009 to 2012. Using polymerase chain reaction (PCR), nasopharyngeal aspirates were tested for 10 viruses and blood for pneumococcal DNA. Incidence was estimated at 1 site with available population denominators.

Results: We enrolled 8723 children aged <5 years with LRTI, including 64% <12 months. The case-fatality ratio was 2% (150/8512). HIV prevalence among tested children was 12% (705/5964). The overall prevalence of respiratory viruses identified was 78% (6517/8393), including 37% rhinovirus, 26% respiratory syncytial virus (RSV), 7% influenza and 5% human metapneumovirus. Four percent (253/6612) tested positive for pneumococcus. The annual incidence of LRTI hospitalization ranged from 2530 to 3173/100,000 population and was highest in infants (8446–10532/100,000). LRTI incidence was 1.1 to 3.0-fold greater in HIV-infected than HIV-uninfected children. In multivariable analysis, compared to HIV-uninfected children, HIV-infected children were more likely to require supplemental-oxygen [odds ratio (OR): 1.3, 95% confidence interval (CI): 1.1–1.7)], be hospitalized >7 days (OR: 3.8, 95% CI: 2.8–5.0) and had a higher case-fatality ratio (OR: 4.2, 95% CI: 2.6–6.8). In multivariable analysis, HIV-infection (OR: 3.7, 95% CI: 2.2–6.1), pneumococcal coinfection (OR: 2.4, 95% CI: 1.1–5.6), mechanical ventilation (OR: 6.9, 95% CI: 2.7–17.6) and receipt of supplemental-oxygen (OR: 27.3, 95% CI: 13.2–55.9) were associated with death.

Conclusions: HIV-infection was associated with an increased risk of LRTI hospitalization and death. A viral pathogen, commonly RSV, was identified in a high proportion of LRTI cases.

From the *Centre for Respiratory Diseases and Meningitis, National Institute for Communicable Diseases of the National Health Laboratory Service; School of Public Health, Faculty of Health Sciences, University of the Witwatersrand; Medical Research Council, Respiratory and Meningeal Pathogens Research Unit, Faculty of Health Sciences, University of the Witwatersrand; §Department of Science and Technology/National Research Foundation, Vaccine Preventable Diseases, University of the Witwatersrand, Johannesburg, South Africa; Influenza Division, Centers for Disease Control and Prevention, Atlanta, GA; Influenza Programme, Centers for Disease Control and Prevention–South Africa, Pretoria; **Department of Medicine, Pietermaritzburg Metropolitan Hospital; †Department of Medicine, University of KwaZulu Natal; ‡Department of Paediatrics, Pietermaritzburg Metropolitan Hospital §§School of Pathology, University of KwaZulu Natal, Pietermaritzburg; ¶Department of Medicine, Klerksdorp Tshepong Hospital, Klerksdorp; ‖Department of Medicine, Faculty of Health Sciences, University of the Witwatersrand; ***MRC/Wits Rural Public Health and Health Transitions Research Unit (Agincourt), School of Public Health, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa; ††Centre for Global Health Research, Umeå University, Umeå, Sweden; ‡‡INDEPTH Network, Accra, Ghana; and §§§Zoonoses Research Unit, Department of Medical Virology, University of Pretoria, Gauteng, South Africa

Accepted for publication May 19, 2014.

The authors have no conflicts of interest to disclose.

This study received funding from the National Institute for Communicable Diseases of the National Health Laboratory Service and was supported in part by funds from the United States Centers for Disease Control and Prevention (CDC), Atlanta, Georgia Preparedness and Response to Avian and Pandemic Influenza in South Africa (Cooperative Agreement Number: U51/IP000155-04). The contents are solely the responsibility of the authors and do not necessarily represent the official views of the CDC. The funders had no role in study design, implementation, manuscript writing or the decision to submit for publication. The corresponding author had full access to all the data in the study and takes final responsibility for the decision to submit for publication.

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Address for correspondence: Cheryl Cohen, MD, Centre for Respiratory Diseases and Meningitis, National Institute for Communicable Diseases, Private Bag X4, Sandringham 2131, Gauteng, South Africa. E-mail: cherylc@nicd.ac.za.

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