Marco Zampoli

Antiretroviral treatment for children

OBJECTIVE To describe the response of children during their first year on highly active antiretroviral therapy (HAART). DESIGN Retrospective, descriptive. SETTING Tertiary, referral hospital. SUBJECTS All HIV-infected children commenced on HAART from 1 August 2002 until 31 December 2004. OUTCOME MEASURES Children were retrospectively restaged using the WHO 4-stage clinical classification and CDC immunological staging system. After commencing HAART, patients were assessed at monthly intervals for the first 6 months and thereafter mostly 3-monthly. Baseline and 6- monthly CD4 counts and viral loads were performed. RESULTS Of 409 children commenced on HAART, 50.6% were < 2 years old, 62.7% had severe clinical disease and 76.6% had severe immune suppression. After 1 year, 65.8% were alive and continued HAART at the hospital, 11.2% had been transferred to another antiretroviral site, 15.4% had died, 4.6% were lost to follow-up and treatment had been discontinued in 2.9%. Kaplan-Meier survival estimate for 407 children at 1 year was 84% (95% confidence interval (CI) 80 - 87%). On multivariate analysis, survival was adversely affected in children with WHO stage 4 v. stage 2 and 3 disease (adjusted hazard ratio (HR): 5.26 (95% CI 2.25 - 12.32), p = 0.000), age < 12 months (adjusted HR: 2.46 (95% CI 1.48 - 4.09), p = 0.001) and CD4 absolute count (per 100 cell increase) (adjusted HR: 0.93 (95% CI 0.88 - 0.98), p = 0.013). In a separate multivariate model including only children with an initial viral load (N = 367), viral load > or = 1 million copies/ml (adjusted HR: 1.84 (95% CI 1.03 - 3.29)) and taking a protease inhibitor (PI)-based regimen (adjusted HR: 2.25 (95% CI 1.10 - 4.61)) were additionally independently associated with poorer survival; however, young age was not a significant predictor of mortality, after adjusting for viral load (p = 0.119). After 1 year of HAART 184/264 (69.7%) of children had a viral load < 400 copies/ml. Comparative analysis showed significant improvements in growth, immunological status and virological control. CONCLUSION HAART can improve the health of many HIV-infected children with advanced disease, including those aged less than 2 years in resource-limited settings.

Pneumocystis Pneumonia in South African Children With and Without Human Immunodeficiency Virus Infection in the Era of Highly Active Antiretroviral Therapy

Background: Pneumocystis pneumonia (PCP) is a major cause of hospitalization and mortality in human immunodeficiency virus (HIV)-infected African children. Aim: The aim of this study was to investigate the incidence and outcome of PCP in South African children living in a high HIV-prevalence area in the context of a free, available antiretroviral therapy program. Methods: Sequential children hospitalized with hypoxic pneumonia were prospectively enrolled from November 2006 to August 2008. Sociodemographic, historical, clinical, and outcome data were collected. A nasopharyngeal aspirate and lower respiratory tract sample (induced sputum or bronchoalveolar lavage) were submitted for PCP immunofluorescence. Lower respiratory tract samples were also investigated for bacterial, mycobacterial, and viral pathogens. Results: A total of 202 children were enrolled; 124 (61.4%) were HIV-infected; 34 (16.8%) were HIV-exposed but uninfected and 44 (21.8%) were HIV-unexposed. Among HIV-exposed children, 70 (44.3%) had participated in the Prevention of Mother to Child Transmission program, but only 18.4% were taking trimethoprim-sulfamethoxazole prophylaxis. PCP occurred in 43 children (21.3%) of whom 33 (76.7%) were HIV-infected. The case fatality of children with PCP was higher than those without PCP (39.5% vs. 21.4%; relative risk, 1.85; 95% confidence interval, 1.15–2.97; P = 0.01). Conclusions: PCP is a common cause of hypoxic pneumonia and mortality in HIV-infected South African infants. Underuse of the Prevention of Mother to Child Transmission program and failure to institute trimethoprim-sulfamethoxazole prophylaxis in HIV-exposed children identified through the program are important obstacles to reducing PCP incidence.

Improved detection of Pneumocystis jirovecii in upper and lower respiratory tract specimens from children with suspected pneumocystis pneumonia using real-time PCR: a prospective study.

BackgroundPneumocystis pneumonia (PCP) is a major cause of hospitalization and mortality in HIV-infected African children. Microbiologic diagnosis relies predominantly on silver or immunofluorescent staining of a lower respiratory tract (LRT) specimens which are difficult to obtain in children. Diagnosis on upper respiratory tract (URT) specimens using PCR has been reported useful in adults, but data in children are limited. The main objectives of the study was (1) to compare the diagnostic yield of PCR with immunofluorescence (IF) and (2) to investigate the usefulness of upper compared to lower respiratory tract samples for diagnosing PCP in children.MethodsChildren hospitalised at an academic hospital with suspected PCP were prospectively enrolled. An upper respiratory sample (nasopharyngeal aspirate, NPA) and a lower respiratory sample (induced sputum, IS or bronchoalveolar lavage, BAL) were submitted for real-time PCR and direct IF for the detection of Pneumocystisjirovecii. A control group of children with viral lower respiratory tract infections were investigated with PCR for PCP.Results202 children (median age 3.3 [inter-quartile range, IQR 2.2 - 4.6] months) were enrolled. The overall detection rate by PCR was higher than by IF [180/349 (52%) vs. 26/349 (7%) respectively; p < 0.0001]. PCR detected more infections compared to IF in lower respiratory tract samples [93/166 (56%) vs. 22/166 (13%); p < 0.0001] and in NPAs [87/183 (48%) vs. 4/183 (2%); p < 0.0001]. Detection rates by PCR on upper (87/183; 48%) compared with lower respiratory tract samples (93/166; 56%) were similar (OR, 0.71; 95% CI, 0.46 - 1.11). Only 2/30 (6.6%) controls were PCR positive.ConclusionReal-time PCR is more sensitive than IF for the detection of P. jirovecii in children with PCP. NPA samples may be used for diagnostic purposes when PCR is utilised. Wider implementation of PCR on NPA samples is warranted for diagnosing PCP in children.

Prevalence and Outcome of Cytomegalovirus-associated Pneumonia in Relation to Human Immunodeficiency Virus Infection

Aim: To investigate the antemortem prevalence and outcome of cytomegalovirus (CMV)-associated pneumonia in African children. Methods: A total of 202 children (median age, 3.2 months; 124 human immunodeficiency virus [HIV]-infected, 62%; 87 severely malnourished, 43%) sequentially hospitalized for severe pneumonia were prospectively investigated. In addition to routine microbiologic investigations, respiratory tract secretions and blood were submitted for CMV culture and qualitative and quantitative CMV polymerase chain reaction. Results: CMV-associated pneumonia was common (28%, 47/169) and more prevalent in HIV-infected than uninfected children (36% vs. 15%; odds ratio [OR], 3.0; 95% confidence interval, 1.3–7.4). CMV-associated pneumonia was more common than Pneumocystis pneumonia (27%) and other viral-associated pneumonia (19%) in HIV-infected children. In-hospital mortality was 25% (51/202) with increased mortality in HIV-infected compared with uninfected children (43/124 [35%] vs. 8/76 [11%]; OR, 4.5; 1.9–11.8). Increased mortality occurred in HIV-infected children with CMV-associated pneumonia (OR, 2.5; 1.04–6.5) but this association was not evident after adjusting for CD4 <15% (adjusted OR, 1.78; 0.6–4.6). Conclusions: CMV-associated pneumonia is common and associated with a poor outcome in children with advanced HIV disease. Improved diagnostic testing and increased access to antiviral therapy might improve the outcome of HIV-infected children with CMV-associated pneumonia.

Cytomegalovirus viraemia in HIV exposed and infected infants: prevalence and clinical utility for diagnosing CMV pneumonia.

BACKGROUND Human cytomegalovirus (HCMV) is an important pathogen in HIV exposed infants with pneumonia. However, the diagnosis of HCMV pneumonia in this setting is challenging due to limited access to bronchoscopy, lung biopsy and direct sampling of the lower respiratory tract. HCMV viraemia is more accessible, but their diagnostic performance in this context has not been studied. OBJECTIVE To describe the prevalence of HCMV viraemia and evaluate its clinical utility in HIV exposed infants. STUDY DESIGN In this cross-sectional study, we performed qualitative and quantitative PCR to detect HCMV viraemia in HIV exposed asymptomatic infants and in infants with severe pneumonia in the Western Cape province of South Africa. RESULTS 283 asymptomatic HIV exposed infants and 142 HIV exposed infants with severe pneumonia were studied. Infants with pneumonia had a higher prevalence of HCMV viraemia compared to asymptomatic infants (68% vs 24% OR 6.7, 95% CI 4.2-10.8). This increased prevalence remained significant (OR 4.3 95% CI 2.6-7.0) after adjusting for HIV infection. Of the infants with pneumonia, the level of HCMV viraemia was significantly higher in a subset of infants diagnosed with HCMV pneumonia (median HCMV viral load 4.6 vs 2.5 log copies/ml p<0.001). Receiver operator characteristic (ROC) analysis showed the area under the curve was 0.78 (95% CI 0.71-0.86) and a threshold of 4.1 log copies/ml was able to correctly identify 70% of HCMV pneumonia cases. CONCLUSION Prevalence and level of HCMV viraemia in sub-Saharan HIV-exposed and infected infants peaks at 3-4 months of age. Quantitative HCMV PCR may be useful in diagnosing HCMV pneumonia.

Pneumocystis pneumonia in South African children diagnosed by molecular methods

BackgroundPneumocystis pneumonia (PCP) is an important cause of hospitalization and mortality in HIV-infected children. However, the incidence of PCP has been underestimated due to poor sensitivity of diagnostic tests. The use of polymerase chain reaction (PCR) for pneumocystis has enabled more reliable diagnosis. This study describes the incidence, clinical features and outcome of PCP in South African children diagnosed using PCR.MethodsA prospective study of children hospitalised in South Africa with suspected PCP was done from November 2006 to August 2008. Clinical, laboratory and radiological information were collected. Lower respiratory tract specimens were obtained for PCP immunofluorescence (IF), real- time PCR for pneumocystis, bacterial and mycobacterial culture. Nasopharyngeal aspirates were taken for immunofluorescence (IF), real-time PCR for pneumocystis and PCR for respiratory viruses. A blood specimen for bacterial culture and for cytomegalovirus PCR was taken. Children were followed for the duration of their hospitalisation and the outcome was recorded.Results202 children [median (interquartile range, IQR) age 3.2 (2.1– 4.6) months] were enrolled; 124 (61.4%) were HIV infected. PCP was identified in 109 (54%) children using PCR, compared to 43 (21%) using IF and Grocott staining (p < 0.0001). Most PCP cases (88, 81%) occurred in HIV-infected children. All 21 cases (19%) occurring in HIV- negative children had another risk factor for PCP. On logistic regression, predictive factors for PCP were HIV infection, lack of fever, high respiratory rate and low oxygen saturation whilst cotrimoxazole prophylaxis was protective (OR 0.24; 95% CI 0.1 to 0.5; p < 0.002). The case fatality of children with PCP was higher than those without PCP (32.1% versus 17.2%; relative risk 1.87; 95% confidence interval (CI) 1.11 – 3.15). Amongst HIV-infected children, a CD4 less than 15% was the only independent predictor of mortality.ConclusionsThe diagnostic yield for PCP is more than 2.5 times higher on PCR than other detection methods. PCP is a very common cause of severe hypoxic pneumonia and is associated with high mortality in HIV-infected African infants.

Microbiological yield from induced sputum compared to oropharyngeal swab in young children with cystic fibrosis

BACKGROUND Standard respiratory sampling in young children with cystic fibrosis (CF) is by oropharyngeal swab (OPS) as they cannot spontaneously expectorate. Sputum induction (IS) has been poorly investigated in this population. We aimed to compare the bacteriological yield of OPS vs. IS in young children with CF. METHODS Sequentially paired OPS followed by IS samples was collected in children <5years of age attending a CF clinic in Cape Town, South Africa. RESULTS IS was successfully paired with OPS in 98/113 (85%) attempts in 32 children (mean±SD 19±16months), with no serious adverse events. IS culture yield for any CF-associated bacteria from IS was 46% vs. 28% from OPS (p=0.01). The sensitivity, specificity, PPV and NPV of OPS compared to IS in isolating CF-associated bacteria were 56%, 96%, 93%, and 72% respectively. CONCLUSION Sputum induction is feasible, safe and superior to OPS for detecting CF-associated bacteria in young children with CF.

Empyema and parapneumonic effusions in children: an update

Childhood empyema is an important complication of bacterial pneumonia. The incidence of empyema is increasing worldwide. Streptococcus pneumoniae and Staphylococcus aureus are the most common aetiologies in high and low-income countries respectively. The diagnosis is based on clinical, radiographic and pleural fluid examination. Tuberculosis (TB) is an important cause of a pleural effusion in high TB prevalence areas. There is controversy about the optimal treatment for empyema in children. Sepsis should be controlled with antibiotics and drainage of the pleural cavity. Intrapleural fibrinolysis and Video Assisted Thorascopic Surgery (VATS) are modern interventions widely used in high-income countries but mostly unavailable in the developed world. There are however few properly conducted studies that would support one therapeutic approach over the other. Despite this, the clinical outcome of paediatric empyema is usually good regardless of therapeutic approach. This review summarises aetiology, pathogenesis and clinical presentation of childhood empyema and discusses the various treatment modalities with an emphasis on clinical practice in developing countries.

Etiology and Incidence of Pleural Empyema in South African Children.

Background: South Africa introduced the 7-valent pneumococcal conjugate vaccine (PCV7) in 2009 and PCV13 in 2011. The etiology and incidence of childhood empyema in an 8-year period overlapping the introduction of PCV was investigated. Methods: Children younger than 12 years admitted with empyema at a tertiary pediatric hospital in Cape Town, South Africa, from December 2006 to December 2011 (cohort A) and January 2012 to December 2014 (cohort B) were investigated. Pathogens were identified by culture of pleural fluid and blood. In addition, polymerase chain reaction targeting bacterial pathogens and Streptococcus pneumoniae serotypes was conducted on pleural fluid in a subset of patients enrolled 2009–2011. Results: Cohort A: 142 children were prospectively enrolled, with a median age of 17 months (interquartile range 8–43). Most (92%) children were unimmunized with PCV. S. pneumoniae and Staphylococcus aureus were the most common culture-identified pathogens (each 25 of 142; 18%); polymerase chain reaction of pleural fluid increased yield of S. pneumoniae detection by 31% [26 of 54 (48%) vs. 9 of 54 (17%), P < 0.001]. Serotypes were identified for 24 of 26 (92%) patients with S. pneumoniae, of which 22 of 24 (92%) were included in PCV13. Cohort B: 22 patients were retrospectively identified. No pathogen was found in 12 of 22 (54.5%) patients and S. pneumoniae in 1 patient (4.5%). Empyema incidence declined by 50% in cohort B compared with that of cohort A (4.2 vs. 10.4 cases per 1000 pneumonia admissions; risk ratio: 0.5; 95% confidence incidence: 0.3–0.7). Conclusion: S. pneumoniae is the commonest cause of childhood empyema in South Africa. PCV has been highly effective at reducing empyema incidence in South African children.

Paediatric tracheostomy and ventilation home care with challenging socio-economic circumstances in South Africa

BACKGROUND Children discharged home with a tracheostomy need a safe home environment and access to health care. We described the indications, clinical characteristics, socio-economic circumstances and outcomes of children enroled in a tracheostomy home care programme in South Africa. METHODS We performed a retrospective chart review of children receiving a tracheostomy and enroled in the Breatheasy programme at the Red Cross War Memorial Childrens Hospital, Cape Town. Medical and background characteristics were recorded. Influences of socio-economic variables and underlying medical conditions on length of hospital stay, unplanned readmissions and mortality in the first year after discharge were evaluated. RESULTS In the period 2008-2012, 157 patients were discharged home with a tracheostomy. Median hospital stay after tracheostomy insertion was significantly longer when parents had incomplete schooling compared to completed secondary school or higher education; 30 days (IQR 21-53) versus 23 days (IQR 16-33), respectively. Unplanned readmissions in the first year were documented for 72 patients (45.9%). The risk for unplanned readmission was 2.6 times higher in families with substance abuse the risk of respiratory infections was two-fold in case of household cigarette smoke exposure (OR 2.3.) Tracheostomy-related mortality was low (1.2%). An underlying medical condition was the only independent significant risk factor for mortality (OR 5.1, 95% CI 1.8-14.3). CONCLUSION This study demonstrates that despite difficult socio-economic circumstances, home ventilation of children with a tracheostomy is safe, provided caregivers are adequately trained and supported.