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

Summary

Background

HIV-related pneumonia is the main cause of paediatric hospital admissions in southern Africa. We aimed to measure predictors of treatment failure and the cause of non-responsive pneumonia in children admitted to hospital with severe pneumonia in Durban, South Africa.

Methods

We investigated 358 children aged 1–59 months who presented with WHO-defined severe or very severe pneumonia. Children were recruited irrespective of HIV status and started on a standard antimicrobial regimen of benzylpenicillin and gentamicin. All infants also received high-dose trimethoprim-sulfamethoxazole. The primary outcome measure was treatment failure at 48 h.

Findings

242 (68%) children were HIV infected, 41 (12%) HIV exposed, uninfected, and 75 (21%) HIV uninfected. Failure to respond by 48 h was predicted by age under 1 year (adjusted odds ratio 6·38, 95% CI 2·72–14·91, p<0·0001), very severe disease (2·47, 1·17–5·24, p=0·0181), HIV status (HIV infected 10·3, 3·26–32·51; HIV exposed, uninfected 6·02, 1·55–23·38; p=0·0003), and polymicrobial disease (one organism 2·06, 1·05–4·05; two organisms 10·75, 4·38–26·36; p<0·0001) on logistic regression analysis. All children with three organisms failed treatment. 72/110 treatment failures had at least two organisms isolated. Three of nine HIV-exposed, uninfected infants, 29/74 HIV-infected, but no HIV-uninfected infants who failed study therapy had Pneumocystis jirovecii pneumonia.

Interpretation

For children younger than 1 year, the WHO guidelines are inadequate and need to be revised since both HIV-infected and HIV-exposed, uninfected infants had more treatment failures than did HIV-uninfected infants. Polymicrobial disease is an important reason for treatment failure, and we need to identify rapid low-cost diagnostic methods to assist clinicians.

Introduction

Acute respiratory infections are the leading cause of childhood mortality worldwide.¹ Initial WHO management guidelines were based on studies undertaken in the pre-HIV era.2, 3, 4, 5, 6, 7 However, between 11% and 45% of children admitted to hosptial with severe pneumonia in southern African countries are co-infected with HIV-1,8, 9, 10 and HIV-related pneumonias are the leading cause of these admissions.¹¹

WHO guidelines for the management of acute respiratory infections in children younger than 5 years were initially published before the HIV-1 pandemic.² Children are classified according to the severity of their respiratory symptoms, and empirical management is recommended for all groups. All children younger than 2 months are given benzylpenicillin and gentamicin. For children 2 months or older, benzylpenicllin alone is recommended for severe pneumonia (ie, cough with tachypnoea and chest indrawing) and chloramphenicol alone for very severe disease (ie, the presence of danger signs, including inability to drink, central cyanosis, abnormal sleepiness, or severe malnutrition).

The term disease is used because of the similarity between symptoms in very severe pneumonia and other illnesses, such as malaria and sepsis. A study from Papua New Guinea¹² has shown that benzylpenicillin and gentamicin can be used as an alternative to chloramphenicol for very severe disease. We therefore adapted the existing pre-HIV WHO guidelines² so that all children received high-dose benzylpenicillin and gentamicin irrespective of age, and all infants received high-dose trimethoprim-sulfamethoxazole because of the increased risk of Pneumocystis jirovecii (formerly Pneumocystis carinii) pneumonia in this group.9, 13 In 2003, (after recruitment closed), a WHO consultative meeting concluded that children admitted with severe pneumonia in HIV-endemic areas should be given benzylpenicillin or ampicillin, plus gentamicin. High-dose trimethoprim-sulfamethoxazole was also recommended for infants younger than 1 year because of the high prevalence and severity of P jirovecii pneumonia.¹⁴ The guidelines suggested changing to second-line treatment if there was no clinical response by 48 h. There are no reported studies on the response to these treatment guidelines.

Previous studies in Africa of the cause of pneumonia in HIV-infected children have either used indirect means of establishing the respiratory infection such as blood cultures,9, 10, 15 studied selective populations such as intensive-care patients,16, 17 or used post-mortem findings.18, 19, 20 Identification of the cause of lower respiratory tract infections in children is technically difficult. Blood cultures yield an organism only in 10–20% of cases, and previous studies have shown discrepancies between organisms isolated from blood and lung.10, 21, 22 Sputum gram stain and culture is less useful in children than in adults because of the high bacterial nasopharyngeal colonisation rates.²³ Previously, lung aspiration was the gold-standard technique.3, 7, 21 However, HIV-infected children have high rates of interstitial lung disease, which is unsuitable for lung aspiration.15, 24 Bronchoalveolar lavage (BAL) is the technique of choice for such patients. Several studies have shown that the diagnostic accuracy of non-bronchoscopic BAL (NB-BAL) is similar to that of bronchoscopic-BAL.25, 26, 27

We therefore undertook a prospective descriptive study of children admitted to hospital with WHO-defined severe pneumonia with or without signs of very severe disease using NB-BAL. We aimed to measure the response rates to standard antimicrobial therapy in an HIV-endemic area, the cause in children who failed to respond, and the relation of response rates and treatment failure with HIV status.