Long-term immune responses and comparative effectiveness of one or two doses of 7-valent pneumococcal conjugate vaccine (PCV7) in HIV-positive adults in the era of combination antiretroviral therapy

Introduction

HIV infection impairs maintenance of immunological memory, yet few studies of HIV-positive adults receiving 7-valent pneumococcal conjugate vaccine (PCV7) have followed them beyond the first year. We determined and compared the durability of serological responses and the clinical outcomes of HIV-positive adults annually for five years following vaccination with one or two doses of PCV7.

Methods

In this non-randomized clinical trial, 221 pneumococcal vaccine-naïve HIV-positive adults receiving one (n=109) or two doses four weeks apart (n=112) of PCV7 between 2008 and 2010 were longitudinally followed for evaluation of significant serological response and for episodes of pneumonia and invasive pneumococcal disease.

Results

At the time of vaccination, the two groups were well matched for age, risk factors, combination antiretroviral therapy (cART) coverage, CD4 count and plasma HIV RNA load (PVL). At the end of five years, the CD4 counts for the one- and two-dose groups had increased from 407 and 406 to 550 and 592 cells/µL, respectively, and 82.4 and 81.6% of the participants had fully suppressed PVL. Significant immune responses to ≥2 serotypes persisted for 67.9 vs 78.6%, 64.2 vs 71.4%, 66.1 vs 71.4%, 57.8 vs 69.6% in the second, third, fourth and fifth years after one and two doses of PCV7 in the intention-to-treat analysis, respectively. In multivariate analysis, immunization with two doses of PCV7 (odds ratio (OR) 1.71, 95% confidence interval (CI) 1.10 to 2.65, p=0.016), concurrent cART (OR 2.16, 95% CI 1.16 to 4.00, p=0.015) and CD4 proliferation (OR 1.12, 95% CI 1.01 to 1.27, p=0.031) were predictive of persistent serological responses in the fifth year. Only one patient in the one-dose group had documented pneumococcal pneumonia (non-bacteraemic) and none had invasive pneumococcal disease in the 6.5 years of follow-up.

Conclusions

One or two doses of PCV7 achieve durable seroprotective responses in HIV-treated participants; however, two doses may be more robust than one dose in a larger study population or in real-world populations with less cART coverage.     

Acute bacterial rhinosinusitis and otitis media: changes in pathogenicity following widespread use of pneumococcal conjugate vaccine.

OBJECTIVE: Acute bacterial rhinosinusitis and acute otitis media are two of the most common respiratory tract infections. The common pathogenic bacteria associated with these infections are Streptococcus pneumoniae, Haemophilus influenzae, Moraxella catarrhalis, and Staphylococcus aureus. With the recent widespread use of pneumococcal conjugate vaccine, there is evidence that there is a shift of both the pneumococcal serotypes and the distribution of pathogenic bacteria. The purpose of this article was to investigate whether the literature supports changes in pathogenicity of acute bacterial rhinosinusitis and otitis media after widespread use of conjugate pneumococcal vaccine. DATA SOURCES: MEDLINE search of the literature was performed between 1995 and 2007. REVIEW METHODS: Literature review of changes in distribution of pathogens, resistance rates, and pneumococcal serotype changes before and after widespread use of conjugate pneumococcal vaccine. RESULTS: There is evidence that the distribution of pneumococcal serotypes has changed after the widespread use of conjugate pneumococcal vaccine. There appears to be both less invasive and noninvasive pneumococcal disease and with childhood immunization there also appears to be a protective effect on adults (herd immunity). Increases in nonvaccine serotypes, some with high levels of resistance are being identified in some communities. There is also growing evidence that there may be an increasing prevalence of Haemophilus influenzae in these infections. CONCLUSIONS: Widespread use of conjugate pneumococcal vaccine has led to decreasing incidence of pneumococcal otitis media and likely also acute bacterial rhinosinusitis, which may have implications for treatment recommendations for these infections.     

Childhood obesity and Pakistan

Obesity and overweight have become a problem of public health magnitude associated with substantial economic burden not only in the developed countries but also in the developing countries. The number of overweight children and adolescents has doubled in the last two decades in the United States and worldwide, including developing countries. No study on childhood obesity and overweight is available in Pakistan. Obesity in children impacts on their health in both short and long-term and obesity and its preventive strategies are poorly understood. Increasing number of these children and adolescents all over the world demand not only a substantial political will but also an investment for primary and secondary preventive measures and novel approaches in the treatment modalities.     

Infected acute subdural hematoma associated with invasive pneumococcal disease

A previously healthy 68-year-old woman presented with a rare case of subdural empyema which developed at the site of preceding acute subdural hematoma (SDH). She was first admitted for treatment of an acute SDH after a fall. Since she was neurologically intact and the SDH volume decreased with conservative management, she was discharged 9 days after admission for follow up as an outpatient. Three days after discharge, she unexpectedly returned with worsening headache and altered mental status. Brain computed tomography (CT) showed increased SDH volume. Her condition deteriorated rapidly after presentation, with further increase in SDH volume. Copious pus in addition to the SDH was evacuated by emergency drainage, establishing the diagnosis of subdural empyema. Streptococcus pneumoniae was identified from bacterial cultures. Despite improvement in postoperative CT findings, she fell into septic shock and died 3 days after the drainage. Autopsy revealed meningitis and lobar pneumonia, and the postmortem diagnosis was invasive pneumococcal disease. Infection of acute SDH resulting in subdural empyema by S. pneumoniae is extremely rare. However, invasive pneumococcal disease is not uncommon in the elderly and tends to cause intracranial bleeding. Considering the high mortality rate of invasive pneumococcal disease and the low vaccination rate among the elderly in Japan, neurosurgeons should ask about the pneumococcal vaccination status.     

Comparative radiographic features of community acquired Legionnaires'' disease, pneumococcal pneumonia, mycoplasma pneumonia, and psittacosis

The features of the chest radiographs of 49 adults with legionnaires' disease were compared with those of 91 adults with pneumococcal pneumonia (31 of whom had bacteraemia or antigenaemia), 46 with mycoplasma pneumonia, and 10 with psittacosis pneumonia. No distinctive pattern was seen for any group. Homogeneous shadowing was more frequent in legionnaires' disease (40/49 cases) (p less than 0.005), bacteraemic pneumococcal pneumonia (25/31) (p less than 0.01) and non-bacteraemic pneumococcal pneumonia (42/60) (p less than 0.05) than in mycoplasma pneumonia (23/46). Multilobe disease at presentation was commoner in bacteraemic pneumococcal pneumonia (20/31) than in non-bacteraemic pneumococcal pneumonia (15/60) (p less than 0.001) or legionnaires' disease (19/49) (p less than 0.025). In bacteraemic pneumococcal pneumonia multilobe disease at presentation was associated with increased mortality. Pleural effusions and some degree of lung collapse were seen in all groups, although effusions were commoner in bacteraemic pneumococcal pneumonia. Cavitation was unusual. Lymphadenopathy occurred only in mycoplasma pneumonia (10/46). Radiographic deterioration was particularly a feature of legionnaires' disease (30/46) and bacteraemic pneumococcal pneumonia (14/27), and these groups also showed slow radiographic resolution in survivors. Radiographic resolution was fastest with mycoplasma pneumonia; psittacosis and non-bacteraemic pneumococcal pneumonia cleared at an intermediate rate. Residual intrapulmonary streaky opacities remained in over a quarter of survivors from legionnaires' disease (12/42) and bacteraemic pneumococcal pneumonia (5/19).     

Immunogenicity of Pneumococcal Vaccine in Renal Transplant Recipients—Three Year Follow-up of a Randomized Trial

Routine pneumococcal vaccination is recommended at regular intervals posttransplant. However, there is limited data on durability of vaccine response and the impact of vaccine type on antibody persistence. We determined the durability of response for patients enrolled in a randomized trial of conjugate (PCV7) versus polysaccharide (PPV23) pneumococcal vaccination. Response was defined as a twofold increase from baseline and a titer > or =0.35 microg/mL using a pneumococcal ELISA for seven serotypes (measured at 8 weeks and 3 years). Forty-seven patients were evaluated and had received either PPV23 (n = 24) or PCV7 (n = 23). Response rates and geometric mean titers varied by serotype but declined significantly at 3-years for 6 of 7 serotypes (p < 0.001). No significant difference in durability was found in patients that had received PPV23 versus PCV7. Compared to the 8-week response, 20.6% fewer patients had a response to at least one serotype by 3 years. The largest relative declines were seen for serotype 4 (response dropped from 40.4% at 8 weeks to 17.0% at 3 years) and serotype 9V (44.7% dropping to 21.3%). The only factor predictive of response durability was a strong multiserotype initial response (p < 0.001). In conclusion, vaccine responses decline significantly by 3 years and conjugate vaccine does not improve the durability of response.     

Epidemiologic, clinical and laboratory observations of some Streptococcus pneumoniae serotypes implicated in the evolution of asthma in children

The Authors present the results of a multidisciplinary study carried out on a sample of 103 children comprised in a programme of vaccination against Streptococcus pneumoniae infections, in order to avoid the worsening of their asthma. In the nasopharyngeal exudate of 39 children, we detected the presence of S. pneumoniae strains of serotypes 6, 8, 14, and 19 and their absence after vaccination with PNEUMO 23. This was followed by a significant decrease in the incidence of pneumococcal infections and also by the reduction in the frequency of crises and severity of the disease.     

Immunizations for pediatric dialysis patients

Children maintained on chronic dialysis are at high risk for infection, and although the burden of vaccine-preventable disease in this population has not been fully documented, primary care of these patients should include careful compliance with the routine childhood immunization schedule. There have been considerable changes in this schedule in recent years, and an update is provided. In addition the supplemental vaccines for pneumococcal and influenza vaccines are discussed. Where available, data regarding vaccine response in children on dialysis are presented.     

Pneumococcal polysaccharide vaccine responses are impaired in a subgroup of children with cystic fibrosis

BackgroundPneumococcal immunization is recommended in children with cystic fibrosis (CF). To date, however, there are no published studies on the efficacy of pneumococcal vaccination in this group of patients.MethodsWe carried out a retrospective study of serotype-specific pneumococcal antibody responses to immunization with Prevenar 7 and Pneumovax II in a cohort of children with CF.ResultsNine children had been immunized with Prevenar 7, and all had serotype-specific pneumococcal antibody levels in the protective range (> 0.35 mg/L) to all 7 immunizing serotypes. In contrast, only 7 of 33 patients (21%) immunized with Pneumovax II made protective antibody responses to all 7 serotypes, and 3 failed to make protective antibodies to any of the serotypes. Controlling for age as a confounder in the analysis, children with impaired antibody responses to pneumococcal polysaccharide (Pneumovax II) immunization had lower Shwachman–Kulczycki scores than children with normal polysaccharide antibody responses. All isolates of Pseudomonas aeruginosa occurred in patients with impaired anti-pneumococcal antibody responses, and a broader range of respiratory pathogens was isolated from these children.ConclusionsImpaired antibody responses to immunization with Pneumovax II are common in children with CF and this may be associated with increased disease severity.     

Trends in deaths from respiratory illness in children in England and Wales from 1968 to 2000

BACKGROUND: Childhood mortality has decreased markedly over the last three decades. A study was undertaken to determine trends in deaths from respiratory illness in children in England and Wales. METHODS: Mortality data collected by the Office for National Statistics were analysed. The data included all deaths registered from all causes in children aged between 28 days and 16 years in England and Wales from 1 January 1968 to 31 December 2000. The main outcome measures were overall and age-specific mortality rates due to all respiratory disorders and specific rates for pneumonia, asthma, cystic fibrosis (CF), and bronchiolitis. RESULTS: In children aged 1-16 years the overall mortality rate (per 100,000 children) declined from 49.9 in 1968 to 16.3 in 2000, and rates due to respiratory illness fell from 8.6 to 1.3. The proportion of all deaths caused by respiratory illness in children aged 28 days to 16 years fell from 30.8% in 1968 to 9.9% in 2000. In post-neonatal infants (aged 28-364 days), the "all cause" mortality rate fell from 592.8 in 1968 to 176 in 2000 and the rates due to respiratory illness fell from 280 to 22.8. In 2000, pneumonia, asthma and CF together accounted for 73% of all respiratory deaths in 1-16 year olds. In this age group, mortality rates per 100,000 for pneumonia fell from 4.22 to 0.57, for asthma from 0.83 to 0.25, and for CF from 0.66 to 0.12 between 1968 and 2000. Over the same period mortality rates for pneumonia in post-neonatal infants fell from 165 to 6.78 per 100,000 and for CF from 4.88 to 0.33. Bronchiolitis mortality rates per 100,000 in post-neonatal infants fell from 21.47 in 1979 to 1.82 in 2000. CONCLUSIONS: Mortality rates due to all respiratory illnesses in children have fallen markedly in the last three decades. This decline has been more rapid than the overall decline in childhood mortality and respiratory diseases are now responsible for a smaller proportion of deaths in children. These data could provide a foundation for assessing the impact on mortality of future health initiatives such as the introduction of a universal pneumococcal vaccination programme in England and Wales.     

Clinical features, aetiology and outcome of empyema in children in the north east of England

BACKGROUND: The incidence of empyema in children in the UK is increasing. The reason for this is unclear. A prospective study was undertaken to investigate the clinical features, aetiology, and outcome of cases of empyema and parapneumonic effusion presenting to a tertiary paediatric respiratory centre between February 1997 and August 2001. METHOD: Routine bacterial culture of blood and pleural fluid was performed for 47 cases. Forty three pleural fluid specimens, culture negative for pneumococcus, were analysed for pneumococccal DNA by real time polymerase chain reaction (PCR). Penicillin susceptibility was determined for DNA positive specimens using complementary PCR assay. Capsular serotype specific antigen detection was by enzyme immunoassay (EIA) using monoclonal antibodies to serotypes 1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F, and 23F. Clinical data were obtained from patient notes, supplemented by a postal questionnaire. RESULTS: The median (range) age of the patients was 5.6 (0.6-16.9) years and 70% were male. The median (range) duration of illness before referral to hospital was 5 (0-25) days. Forty five (96%) had received antibiotics before referral; 32 (68%) required decortication and eight (21%) thoracocentesis. Median postoperative stay was 4 days (2-8). Thirty two (75%) pneumococcal culture negative specimens were pneumococcal DNA positive; 17 (53%) of these were serotype 1. All were penicillin sensitive. CONCLUSIONS: Pneumococcus is the major pathogen in childhood empyema and serotype 1 is the prevalent serotype. This has implications for vaccine development and immunisation strategy as the current 7-valent pneumococcal conjugate vaccine does not protect against serotype 1.     

Community-Acquired Pneumonia Among Smokers

Recent studies have left absolutely no doubt that tobacco increases susceptibility to bacterial lung infection, even in passive smokers. This relationship also shows a dose-response effect, since the risk reduces spectacularly 10 years after giving up smoking, returning to the level of non-smokers.Streptococcus pneumoniae is the causative microorganism responsible for community-acquired pneumonia (CAP) most frequently associated with smoking, particularly in invasive pneumococcal disease and septic shock.It is not clear how it acts on the progress of pneumonia, but there is evidence to suggest that the prognosis for pneumococcal pneumonia is worse.In CAP caused by Legionella pneumophila, it has also been observed that smoking is the most important risk factor, with the risk rising 121% for each pack of cigarettes smoked a day.Tobacco use may also favor diseases that are also known risk factors for CAP, such as periodontal disease and upper respiratory viral infections.By way of prevention, while giving up smoking should always be proposed, the use of the pneumococcal vaccine is also recommended, regardless of the presence of other comorbidities.     

Missed opportunities for measles immunisation in selected western Cape hospitals

Measles is still a major cause of childhood mortality and morbidity in South Africa. The World Health Organisation (WHO) has recently recommended that greater attention be paid to opportunities for immunisation in the curative sector. This study quantified the extent of missed opportunities for measles immunisation in children attending primary, secondary and tertiary level curative hospitals in the western Cape. Exit interviews of 1,068 carers of children aged between 6 and 59 months inclusive showed that 2.4-40.7% of carers had been requested to produce a Road-to-Health card, and that 4.8-43.1% of carers had a card available. The proportion of children with documented evidence of measles immunisation available ranged from 4.8% to 40.0% between facilities. The study demonstrated that a considerable number of potential opportunities to immunise children against measles are currently being missed in children attending hospitals and day hospitals in the western Cape. The study documents the effect of a fragmented approach to health care, and indicates a need for rapid integration of preventive and curative components of health care into a metropolitan-based primary health care service.     

Acute respiratory infections as an important cause of childhood deaths in South Africa

Compared with other major preventable childhood diseases, such as diarrhoea, acute respiratory infections (ARI) have received comparatively little attention as an important cause of death in children. In this study of mortality from ARI in South Africa, national data was examined for the period 1968-1985, and data for Greater Cape Town for 1987. Almost 90% of ARI deaths were attributable to pneumonia and large inter-group differences were found that favoured whites and Asians over blacks and coloureds. For example, during 1980-1985 the mortality rate for pneumonia in coloured infants under 1 year of age was 11 times that observed in whites (88 v. 981/100,000). Pneumonia accounted for 14.5% of coloured and 12.7% of black deaths under 1 year of age during this period, compared with 6.7% of white and Asian deaths. The mortality rates from pneumonia declined substantially (50%) over the 18-year period in whites, coloureds and Asians. Sequential data for blacks is not available. There was a marked seasonality of deaths among coloured and Asian infants, with rates peaking in winter months. In Cape Town, pneumonia is now a more important cause of death among white and coloured children than diarrhoea, while it ranks with diarrhoea as a cause of death in black children. In all population groups, death rates from ARI are from 7 times to 270 times greater than those recorded in Western European countries. Studies are urgently required to discover why South African children suffer such a high mortality from ARI and how these deaths can be prevented.     

Treatment and outcome of Shiga-toxin-associated hemolytic uremic syndrome (HUS)

Hemolytic uremic syndrome (HUS) is the most common cause of acute renal failure in childhood and the reason for chronic renal replacement therapy. It leads to significant morbidity and mortality during the acute phase. In addition to acute morbidity and mortality, long-term renal and extrarenal complications can occur in a substantial number of children years after the acute episode of HUS. The most common infectious agents causing HUS are enterohemorrhagic Escherichia coli (EHEC)-producing Shiga toxin (and belonging to the serotype O157:H7) and several non-O157:H7 serotypes. D(+) HUS is an acute disease characterized by prodromal diarrhea followed by acute renal failure. The classic clinical features of HUS include the triad of microangiopathic hemolytic anemia, thrombocytopenia, and acute renal failure. HUS mortality is reported to be between 3% and 5%, and death due to HUS is nearly always associated with severe extrarenal disease, including severe central nervous system (CNS) involvement. Approximately two thirds of children with HUS require dialysis therapy, and about one third have milder renal involvement without the need for dialysis therapy. General management of acute renal failure includes appropriate fluid and electrolyte management, antihypertensive therapy if necessary, and initiation of renal replacement therapy when appropriate. The prognosis of HUS depends on several contributing factors. In general "classic" HUS, induced by EHEC, has an overall better outcome. Totally different is the prognosis in patients with atypical and particularly recurrent HUS. However, patients with severe disease should be screened for genetic disorders of the complement system or other underlying diseases.     

Battling COVID-19: critical care and peri-operative healthcare resource management strategies in a tertiary academic medical centre in Singapore

In December 2019, a cluster of atypical pneumonia cases were reported in Wuhan, China, and a novel coronavirus elucidated as the aetiologic agent. Although most initial cases occurred in China, the disease, termed coronavirus disease 2019, has become a pandemic and continues to spread rapidly with human-to-human transmission in many countries. This is the third novel coronavirus outbreak in the last two decades and presents an ensuing healthcare resource burden that threatens to overwhelm available healthcare resources. A study of the initial Chinese response has shown that there is a significant positive association between coronavirus disease 2019 mortality and healthcare resource burden. Based on the Chinese experience, some 19% of coronavirus disease 2019 cases develop severe or critical disease. This results in a need for adequate preparation and mobilisation of critical care resources to anticipate and adapt to a surge in coronavirus disease 2019 case-load in order to mitigate morbidity and mortality. In this article, we discuss some of the peri-operative and critical care resource planning considerations and management strategies employed in a tertiary academic medical centre in Singapore in response to the coronavirus disease 2019 outbreak.     

Clinical experience with pneumococcal conjugate vaccines in infants and children

Streptococcus pneumoniae is a leading cause of morbidity and mortality in pediatric patients, particularly in infants and children younger than 2 years. Each year, S pneumoniae is responsible for significant morbidity and mortality in the United States. During the past several decades, the emergence of penicillin-nonsusceptible and multidrug-resistant pneumococcal isolates has become a major cause for concern, with the overuse or inappropriate use of antibiotics playing a significant role in the increase of resistance. Because the resistance of S pneumoniae to antibiotics has complicated the treatment of pneumococcal infections, attention has focused on the need to prevent disease through vaccination. The objective of this article is to describe the rationale for the development of pneumococcal conjugate vaccines and to summarize the clinical experience to date with these vaccines in infants and children.     

A 20-year history of childhood HIV-associated nephropathy

In 1984, physicians in New York and Miami reported HIV-infected adult patients with heavy proteinuria and rapid progression to end-stage renal disease. These patients showed large edematous kidneys with a combination of focal segmental glomerulosclerosis (FSGS) and tubulointerstitial lesions. This renal syndrome, named HIV-associated nephropathy (HIVAN), was found predominantly in African Americans. Subsequent studies confirmed the presence of HIVAN in children, who frequently develop nephrotic syndrome in association with FSGS and/or mesangial hyperplasia with microcystic tubular dilatation. Since then, substantial progress has been made in our understanding of the etiology and pathogenesis of HIVAN. This article reviews 20 years of research into the pathogenesis of HIVAN and discusses how these concepts could be applied to the treatment of children with HIVAN. HIV-1 infection plays a direct role in the pathogenesis of childhood HIVAN, at least partially by affecting the growth and differentiation of glomerular and tubular epithelial cells and enhancing the renal recruitment of infiltrating mononuclear cells and cytokines. An up-regulation of renal heparan sulfate proteoglycans seems to play a relevant role in this process, by increasing the recruitment of heparin-binding growth factors (i.e., FGF-2), chemokines, HIV-infected cells, and viral proteins (i.e., gp120, Tat). These changes enhance the infectivity of HIV-1 in the kidney and induce injury and proliferation of intrinsic renal cells. Highly active anti-retroviral therapy (HAART) appears to be the most promising treatment to prevent the progression of childhood HIVAN. Hopefully, in the near future, better education, prevention, and treatment programs will lead to the eradication of this fatal childhood disease.     

Increased risk of pneumococcal infections in cardiac transplant recipients

We observed 5 episodes of pneumococcal infection among 129 cardiac transplant patients between March 1985 and December 1987, giving an estimated incidence of 36 cases per 1000 patient-years. Infections occurred a mean of 58 days after transplantation and included bacteremia with empyema, bacteremia alone, and pneumonia. All patients recovered from their infections. There was no correlation between infection and age, sex, immunosuppression, or rejection episodes. We also measured antibody levels to 12 pneumococcal antigens in 6 unvaccinated, uninfected patients before and after cardiac transplantation, to see if baseline antibody levels decreased. Protective levels of antibody were defined as greater than or equal to 300 ng of anticapsular antibody nitrogen per milliliter serum. Before transplantation patients had protective antibody levels to a mean of 8.7 +/- 1.2 pneumococcal serotypes; after transplantation, the number of presumably protective antibody levels decreased to 6.5 +/- 1.4 (P = 0.021). One of these patients subsequently developed pneumococcal pneumonia. Cardiac transplant patients are at increased risk of pneumococcal infections. Vaccinating transplant candidates prior to transplantation may provide protection after transplantation.