Epidemiology

NTM are ubiquitous organisms and can be isolated from soil, house dust, water, food and animals. Transmission is by inhalation, ingestion or direct contact with a contaminated environmental source. Person to person spread is very rare. Hot Topics in Infection and Immunity in Children, edited by Andrew J. Pollard and Adam Finn. Springer, New York, 2006 Clinical syndromes and their causative NTM Syndrome Organisms Time required for growth Clinical syndromes and their causative NTM Syndrome...

Vertical Control Efforts

The new PPPs and IDCs are providing a new generation of products (often referred to as tools) to control the NTDs. However, in the meantime, another group of PPPs, which include the Global Alliance to Eliminate Lymphatic Filariasis (GAELF), the Schistosomiasis Control Initiative (SCI), the International Trachoma Initiative (ITI), the African Programme for Onchocerciasis Control (APOC), and several initiatives focused on leprosy, are directly working to apply existing and new tools to disease...

Prevention and Control Measures 91 Vaccine

A number of strategies have been used for the development of both Lassa and Ebola virus vaccines (Baize et al., 2001 Fisher-Hoch and McCormick, 2004 Sullivan et al., 2000). One novel approach involving immunisation with a DNA priming vaccine followed by a booster immunisation containing recombinant adeno-virus expressing glycoprotein was associated with the development of both humoral and cellular immunity against Ebola virus in Cynomolgus monkeys (Sullivan et al., 2000). Recently, the threat...

Introduction

Neonatal sepsis remains an important cause of morbidity and mortality, particularly in preterm or low birth weight infants. Recognition of infection is difficult because of the non specific nature of presenting signs in most infected neonates. Intravenous antimicrobial therapy should be initiated as soon as possible in neonates with suspected sepsis. Empiric therapy is normally given pending the results of bacterial cultures commonly penicillin and an aminoglycoside. In view of the relative...

CD8 T Cells

CD8 + T cells recognize peptides bound to MHC class I, which is ubiquitously expressed. In most cell types, the peptides bound to MHC class I originate from the cytosol and are derived from either endogenous proteins or viral proteins if the cell is infected. As for na ve CD4 + T cells, myeloid dendritic cells are an important APC for the activation of na ve CD8+ T cells. In contrast to most cell types, myeloid dendritic cells have the ability to load MHC class I with peptides that are derived...

Effects on Medium Term Outcomes

Reducing the proportion of children who develop a chronic effusion (otitis media with effusion) is important clinically, as persistence of the effusion may pre- Review Antibiotics for acute otitis media in children (Version 02) Comparison 01 Antibiotic versus Placebo Outcome 01 Pain 01 Pain at 24 hours vanBuchem 1981b vanBuchem 1981a Burke 1991 Thalin 1985 Le Saux 2005 Subtotal (95 CI) 17 48 13 47 53 112 58 159 82 258 624 10 36 11 40 56 117 58 158 106 254 605 Total events 223 (Treatment), 241...

Recognition and Management of Supected Cases of Viral Haemorrhagic Fever

Comprehensive and detailed guidelines for the recognition and management of patients with suspected VHF are readily available for use in the UK (1996 HPA, 2005b HPA, 2005a), Europe (Eurosurveillance, 2002 Eurosurveillance, 2004) and North America (CDC, 2005b CDC, 2005a). They share a similar approach that emphasises the importance of strict infection control measures including appropriate isolation facilities (see below). They also highlight the importance of minimising 'routine' blood tests....

Therapy

No vaccines, chemotherapeutic agents, or antibodies (monoclonal or polyclo-nal) are currently licensed for use to prevent or treat hMPV infections. However, ribavirin and polyclonal antibody preparations (IVIG), used in the therapy and prevention of hRSV-infections in children, are known to have broad-spectrum activity and can inhibit different viruses. In tissue culture-based assays the antiviral potential of both compounds was assessed and found to have equivalent activity against hMPV and...

Why Prevent Urinary Tract Infections in Children

There are two main reasons for trying to actively prevent UTIs a. To prevent morbidity mortality associated with acute cystitis & pyelonephritis. Young children are especially at risk of severe infections, with 6 of UTIs in the first year of life associated with bacteraemia, 2 requiring fluid resuscitation at diagnosis, and 1 requiring ventilatory support (Craig et al., 1998). The incidence of death from urinary sepsis was as high as 11 during the 1960s, but is now rare. Because UTIs often...

Blood Tests

Once the diagnosis is made, repeat blood films for parasite counts may be useful in following the progress of the disease. However, the paediatrician should be aware that, as quinine acts upon the later stages (schizonts), which are the generally sequestered in the microcirculation and thus not generally visible to the microscopist examining the blood film (that generally examines the circulating younger ring stages), peripheral parasitemia might continue to increase over the first 24 hours. In...

Older Antibiotics

Antibiotic therapy until the most recent decade has focused on beta-lactams (penicillins, cephalosporins, cephamycins, monobactams, and carbapenems), aminoglycosides (gentamicin, tobramycin, amikacin), tetracyclines, glycopeptides (vancomycin, teichoplanin), and lincosamides (clindamycin). Erythromycin antibiotics (the macrolide class) have been available for many decades clarithromycin and azithromycin first became available in the United States 15 years ago, and for purposes of this review...

Factors Pre Disposing to Neonatal Infection

Why should infants be particularly at risk of sepsis, compared to other paediatric populations A number of pre disposing factors that increase the risk of infection can be identified. Broadly, they can be classified as those due to extrinsic and those due to intrinsic factors. Infants on a neonatal unit are subject to frequent breaches of skin and mucous membranes as they regularly undergo cannulation of the vessels, venesection, intubation and nasopharyngeal suction. Fragile skin is also more...

Immunoprotection

A major variant surface protein, major outer membrane protein (MOMP) is the principal target of neutralizing antibodies and may be the target of protective immunity. The detailed genetic and immunochemical knowledge of MOMP has stimulated multiple attempts to design an oligopeptide vaccine. Success has been limited in part because of the antigenic variation that the protein exhibits and in part because of the absence of knowledge regarding the three-dimensional structure of the protein. The...

Infections in Females

In women, chlamydial infections may cause pelvic inflammatory disease, tubal infertility, chronic pelvic pain, and ectopic pregnancy. Chlamydial infection may also be linked to cervical cancer (Koskela et al., 2000). Chlamydial and gonococcal infections may increase susceptibility to and transmission of HIV in both men and women (Plummer et al., 1991). Symptoms in females include mild abdominal pain, intermittent bleeding, vaginal discharge, or dysuria-pyuria syndrome. The cervix can appear...

Direct Specific Means to Detect Pneumococci

For a clinical case to be classified as definitely caused by Streptococcus pneumoniae it needs to be confirmed by culture of blood, CSF, pleural or joint fluid or by culture of middle ear fluid after tympanocentesis depending on the clinical suspicion of the focus of infection. Blood is the most commonly collected sample in seriously ill children. The culture method, however, is affected by the previous use of antimicrobials and the volume of blood obtained. Blood culture is very insensitive in...

Which Children are at Risk of Recurrent UTI

Data from a prospective hospital based cohort study in children less than 5 years of age who were identified following their first symptomatic UTI implicates young age and presence of high grade VUR as risk factors for recurrence of UTI (Panaretto et al., 1999). Vesico-ureteric reflux of grade 3 to 5 is an independent risk factor for recurrence (odds ratio 3.5), as is age less than 6 months (OR 2.9). Recurrence of UTI is also a predictor of future recurrence. After 2 UTIs, the risk of...

Carriage of K kingae

Although the niche of the organism was initially unknown, it was suspected that the bacterium was a respiratory tract commensal. This assumption was supported by several lines of evidence 1 other members of the Neisseriaceae family are part of the normal respiratory flora 2 K. kingae has been found in 1 of nasal and throat cultures 3 children with invasive K. kingae infections frequently present with concomitant signs of upper respiratory tract infections 4 K. kingae has been isolated from...

New Glycopeptides

The glycopeptide antibiotics vancomycin and teichoplanin (not approved for use in the US) have been available for many years. With the increasing need for antibiotics with activity against vancomycin-nonsusceptible staphylococci and enterococci, chemical modifications to the basic glycopeptide structure have produced a series of new compounds with altered pharmacokinetics and or enhanced activity against Gram-positive pathogens. Oritavancin (see Figure 13.3), like vancomycin, inhibits both...

Diagnosis

For a virus that is not easily detected by virus isolation in the laboratory, it will be of great importance that rapid, sensitive and reproducible diagnostic tests be developed. The identification of the two hMPV serotypes, A and B, with each serotype divided into genetic sublineages, 1 and 2, has implications for the development of RT-PCR assays and serologic diagnostic tests. Because of the unavailability of rapid antigen detection tests and because its fastidious growth in cell cultures,...

Patients with Familial Disorders

As summarized in Hot topics in infection and immunity in children II (Picard and Casanova, 2005), clinical observation of children with unusual deep-seated or disseminated NTM infections lead to the identification of a defect in up-regulation of TNFa by macrophages in response to interferony (IFNy) (Levin et al., 1995). This defect was subsequently located to point mutation at nucleotide 395 IFNy receptor 1 resulting in a truncated protein (no transmembrane or cytoplasmic domain) (Newport et...

Rhesus Tetravalent Vaccine Rotashield

The rhesus tetravalent rotavirus vaccine became the next major candidate for development. The monovalent rhesus vaccine suffered the same variable efficacy in field trials, as the original RIT borne vaccine, so a tetravalent vaccine was developed. This vaccine was based upon the assumption that animal strains that shared no neutralization epitopes with human strains would need to carry genes encoding these key neutralization targets - principally the VP7 genes of the most common rotavirus...

Beta Lactam Resistance in Streptococcus pneumoniae

Penicillin and cephalosporin resistance in the pneumococcus was first clearly associated with cefotaxime ceftriaxone treatment failure in children with bacterial meningitis caused by these strains (Bradley and Connor, 1991 Sloas et al., 1992), leading to the routine use of combination antimicrobial therapy (vancomycin plus cefotaxime or ceftriaxone) for the therapy of definite or probable pneumococcal meningitis in U.S. children. In Memphis, we also reported two cefotaxime treatment failures in...

Laboratory Diagnosis and Antimicrobial Resistance Testing

Good communication between the clinician and the laboratory is essential to a rapid and accurate diagnosis. More than 50 species of NTM have the potential to cause disease and have been categorized on the basis of colony morphology, growth rate, and pigmentation (Runyon classification) (Saiman, 2004). The growth rate on solid media in particular has proved a practical way to group species within the laboratory. Typically rapid growers require less than 7 days to produce visible colonies, while...

Nonspecific Means to Detect Pneumococcal Involvement

Pneumococcal pneumonia causes a lobar alveolar infiltrate on chest X-ray which is distinguishable from the more widely spread interstitial infiltrates that are considered to typically appear in pneumonia caused by viral pathogens. This view has been challenged by those who maintain that the etiology of pneumonia cannot be interpreted from chest radiograms. The probe method to measure the disease burden of Haemophilus influenzae type b (Hib, see below) suggested that chest radiographs could be...

In the Pipeline

Many candidate antibiotics are being evaluated prior to entering clinical trials. Once a chemical entity is shown to have in vitro activity against Gram-positive pathogens, animal studies on drug handling and toxicology set the stage for human phase 1 clinical trials in adults, in which preliminary dosing parameters and safety are established. Trials then begin to investigate efficacy under well-defined conditions of infection in otherwise healthy adults. As most of the clinical drug...

The Pathogen

Chlamydiae are obligate intracellular parasites that have been classified under the order Chlamydiales with their own family and genus (Chlamydiaceae, Chla-mydia). Molecular sequencing analysis of their ribosomal RNA has shown that chlamydiae are a unique class of bacteria that are closely related to each other and have little relation to other eubacteria (Weisburg et al., 1986). Like other Gramnegative bacteria, chlamydiae have an outer membrane that contains lipopolysac-charide (LPS) and...

Overview of TCell Mediated Immunity

AP-T cells represent more than 90 of all T cells and are defined by their surface expression of antigen-specific, heterodimeric T-cell receptors (TCRs) composed of a TCR-a and TCR-P chain (Chaplin, 2003). aP-T cells are further divided into subsets based on their surface expression of different proteins, which have been assigned cluster of differentiation (CD) numbers. T cells expressing CD4 are called Hot Topics in Infection and Immunity in Children, edited by Andrew J. Pollard and Adam Finn....

Potency Versus Practicality

Selecting the combination for the child depends upon a balance between its potency against the virus and its practicality. Potency is determined both by the characteristics of the virus and the drugs, whereas practicality is determined only by the characteristics of the drugs and depends upon the preferences and circumstances of the child and parents. A drug's characteristics are delineated through in vitro experiments and in vivo practice (mainly from adult experience) and may change...

References

Ahmad, A., Laborada, G., Bussel, J., and Nesin, M. (2002). Comparison of recombinant granulocyte colony-stimulating factor, recombinant human granulocyte-macrophage colony-stimulating factor and placebo for treatment of septic preterm infants. Pediatr Infect Dis J. 21 1061-1065. Baley, J.E., Stork, E.K., Warkentin, P.I., and Shurin, S.B. (1987). Buffy coat transfusions in neutropenic neonates with presumed sepsis a prospective, randomized trial. Pediatrics. 80 712-720. Bedford Russell, A.R.,...

Conclusions

The epidemiology and clinical manifestations associated with hMPV have been found to be reminiscent of those of the hRSV, with most severe RTI occuring in young infants, elderly subjects, and immunocompromised hosts. The seasonal distribution resembles that of hRSV and influenza virus infections, with recurrent epidemics during the winter months. hMPV is the second most important cause, after hRSV, of viral lower RTI in children. hMPV infections account for at least 4 to 8 of the RTI in...

Antenatal Infection and Preterm Delivery

Antenatal infection is a likely candidate to trigger the antenatal inflammatory process. Eighty percent of preterm deliveries occur as a result of spontaneous onset of labour or premature rupture of membranes (Tucker et al., 1991). A large body of evidence now suggests that infection plays a major part in this process. 61 of placentas from infants with preterm labour had one or more organisms isolated, compared to 21 of term placentas (Hillier et al., 1988), whilst other studies have reported...

Generic Approached to Management

The airway must be secured, oxygenation optimised, vascular access established, hypoglycaemia, if present should be corrected (5 ml kg of 10 dextrose). Seizures are common however, in African children with severe malaria around 25 of seizures are subtle or sub-clinical (demonstrated by EEG) (Crawley et al., 1996) The presence of respiratory depression, irregular breathing, drooling, eye deviation or occasionally bizarre posturing should alert the clinician to either the presence of complex...

Ceftobiprole

Beta-lactam antibiotics have compiled an excellent safety profile in pediatrics during the past four decades. Both enzymatic degradation and altered transpeptidase binding sites have resulted in resistance to penicillins, cephalosporins, and carbap-enems. However, with structural modifications of the beta-lactam molecule, both of these mechanisms of resistance in Staphylococcus aureus which produce MRSA have been overcome (see Figure 13.6). Ceftobiprole is stable to the current staphy-lococcal...

Epidemiology of Bacterial Pneumonia in Children

Many episodes of pediatric pneumonia are caused by respiratory viruses, Mycoplasma pneumoniae, or Chlamydia pneumoniae (McIntosh, 2002). More severe or complicated cases of pneumonia are usually caused by pyogenic bacteria, including streptococci and staphylococci, though many studies indicate that clinical or radiological criteria do not reliably differentiate bacterial versus viral versus atypical pneumonias (McIntosh, 2002 Michelow et al., 2004). Lung puncture studies performed in children...

Molecular Epidemiology

Genetic studies on hMPV have demonstrated the presence of 2 distinct hMPV groups each divided in two subgroups (Boivin et al., 2002 Peiris et al., 2003 Madhi et al., 2003 Bastien et al., 2003a van den Hoogen et al., 2004b). Bastien and colleagues (2003a) determined the complete nucleotide sequences of the N, P, M, and F genes of Canadian hMPV isolates. Comparison of the deduced amino acid sequences for the N, M, and F genes of the different isolates revealed that all three genes were well...

Other Virulence Factors

At the time of writing, three signature-tagged mutagenesis screens have been carried out on the pneumococcus which have identified extensive lists of putative virulence factors (Hava and Camilli, 2002 Lau et al., 2001 Polissi et al., 1998). Other proven and potential virulence factors produced by the pneumococcus include a surface-bound enolase that can bind plasmin(ogen) (Bergmann et al., 2003), a superoxide dismutase (Yesilkaya et al., 2000), NADH oxidase (Auzat et al., 1999), hydrogen...

Differential Diagnosis

As a result of the early non-specific features of VHFs, and the multiple and variable subsequent clinical features, the differential diagnosis for VHFs is large. Specific clinical diagnosis is often difficult (Lowenstein, 2004). However, the presence of the combination of fever, pharyngitis, retrosternal chest pain and proteinuria predicted 70 of subsequently laboratory-confirmed Lassa VHF cases in one series (McCormick et al., 1987). Laboratory testing of samples is potentially dangerous for...

Introduction to Diarrhea in Children

We expect diarrhea to be a problem for children in the developing world where poor hygiene and sanitation, lack of clean water and proper food storage all favor the transmission of a host of different enteric pathogens. In these settings, diarrhea remains the first or second most common cause of hospitalizations and death among children < 5 years. Nonetheless, in the developed world, despite all the improvements made in sanitation and the provision of clean food and water to our population,...

Identification and Management of Shock

Severe falciparum malaria is frequently complicated by features of shock. In a retrospective review of cases presenting to Kilifi District hospital factors associated with a fatal outcome included deep breathing or acidosis (base deficit below -8), hypotension (systolic blood pressure < 80 mmHg), raised plasma creatinine (> 80 imols l), low oxygen saturation (< 90 ), dehydration and hypoglycaemia (< 2.5 mmols L). Shock was present in 212 372 (57 ) children, of whom 37 (17.5 ) died, and...

Other Soft Tissue Infections

Although not common, sporadic cases and outbreaks of cellulitis, soft-tissue abscesses and rarely extra-cutaneous disease associated with rapidly growing NTM have been documented in healthy individuals. These have occurred in both nosocomial (contaminated surgical or clinical devices contaminated with water) and community settings (contamination of traumatic wounds with soil or water). Recently, outbreaks of cutaneous NTM infection in older children and adults have been linked to nail salon...

Immunopathogenesis

Most individuals with chlamydial infection spontaneously heal without disease sequelae. Individuals with severe forms of chlamydial disease often display immune responses to a common chlamydial heat shock protein 60 (hsp60) antigen. Because the protein shares nearly 50 sequence identity with the human homolog, it is speculated that molecular mimicry may result in autoimmune inflammatory damage that in turn causes chlamydial disease sequelae. Because hsp60 immune responses are genetically...

Prophylactic Growth Factors for the Prevention of Neonatal Sepsis

In order to resolve the clinical conundrums posed above, it may be possible to prevent sepsis by the use of prophylactic treatment with growth factors, rather than treating possible septic episodes. Three studies have been analysed and reported in a Cochrane Review looking at a total of 359 infants who received prophylactic growth factors (Carr et al., 2003). All infants received GM-CSF although 2 different preparations were used and there were 4 different dosages used over 2 dosage schedules...

Risk Factors for AOM

AOM occurs most frequently in winter months, and is usually preceded by a viral upper respiratory tract infection (Henderson et al., 1982 Arola et al., 1990). Apart from young age (< 2 years), and a history of a previous episode of AOM, other risk factors for AOM include the risk factors for viral upper respiratory infections attending day care outside the home, exposure to cigarette smoke, having at least one sibling, and possibly use of a dummy (pacifier) (Uhari et al., 1996 Owen et al.,...

The Overall Protective Effect of Pneumococcal Vaccines

Pneumococcal disease can be prevented by a) the direct protective effect of the vaccine on vaccinated individuals (both PPV and PCV) and or b) an indirect protective effect via reduced transmission of the pathogen to susceptible, nonvacci-nated individuals (PCV only, since the mucosal protection provided by PPV is insignificant). The public health benefit arising from both is enforced by the reduction of the incidence of vaccine preventable strains resistant to antimicrobials. Also, the...

Clinical Manifestations

Most studies report that 25 of men and 70 of women infected with C. trachomatis are asymptomatic or minimally symptomatic. The National Longitudinal Study of Adolescent Health Study collected data prospectively from 14,322 U.S adolescents and followed them into adulthood (Miller et al., 2004). Of the participants that tested positive for chlamydial infection, 95 did not report symptoms in the 24 hours preceding specimen collection. Among men with chlamydial infection, the prevalences of...

Risks of Motherto ChildTransmission of HIV1

The timing and transmission of HIV-1 from Mother-to Infant is shown in the Table 17.1 (Cock et al., 2000). Transmission takes place in utero, intrapartum, and postnatally through breastfeeding. The in utero rate is 5-10 , intrapartum rate is 10-20 , and the postnatal (breastfeeding) rates vary according to the duration of breastfeeding. Avoidance of breastfeeding which works well in richer populations, is not a realistic option for developing countries because the dangers of formula feeding...

Giant cell formation

Genetic defects and susceptibility to mycobacterial infection. Contact with intracellular pathogens (e.g., NTM) cause antigen presenting cells (APC) such as macrophages to secrete IL12. This leads to the release of interferon (IFNy) which activates the APC to kill the pathogen. Persistent macrophage activation results in differentiation into epithelioid cells and the formation of giant cells. Mutations in the IL12 p40 subunit, the IL12 receptor (IL12R), the INFy receptor (INFyR)...

Long Term Side Effects

Long-term side effects cannot all be known. Some side effects are known to be associated with specific drugs or classes of drugs and some of these side effects are potentially irreversible. Because of the need for long-term suppressive therapy for HIV and because it is envisaged that children will need to take these medications for longer than infected adults, the issue of abnormal lipid metabolism is extremely important. There are two main abnormalities, lipodystrophy (both lipoatrophy and...

Future Directions

In summary, Streptococcus pneumoniae is a more common causative agent of childhood morbidity and mortality both in rich and resource poor countries than can be demonstrated by the best available data. PCV provides a powerful tool in the prevention of this morbidity and mortality globally. The fact that only one manufacturer presently produces the rather expensive 7-valent PCV is a cause for concern, especially since it is not ideally designed to match the pneumococcal serotypes causing majority...

The Different Pneumococcal Structures and Vaccines Directed Against Them

Pneumococci consist of a family of Gram positive bacteria with over 90 different types of capsular polysaccharide. The capsule is a virulence factor for the bacterium, which alters opsonisation by phagocytes. The capsular polysaccharides are T-cell independent, and only weekly immunogenic immunity to them develops gradually during childhood. Antibodies against the capsular polysaccharides are protective and prevent pneumococcal disease. The classification of Streptococcus pneumoniae into...

The Pathogens

Staphylococcus aureus has long been associated with infections in children, both community-associated and hospital acquired. Penicillin-resistance which is beta-lactamase mediated, has been widespread for many years. Nosocomial methicillin-resistance (MRSA) caused by altered transpeptidase binding sites was Hot Topics in Infection and Immunity in Children, edited by Andrew J. Pollard and Adam Finn. Springer, New York, 2006 first reported 30 years ago. However, these nosocomial strains of MRSA...

Lassa Fever

Most infections with Lassa virus are mild and or subclinical. Zoological studies in Guinea, Nigeria and Sierra Leone suggest that up to half the population have previously been exposed to this virus. Hospitalised cases therefore represent only the tip of the iceberg and severe symptomatic disease is said to occur in approximately 20 of infected individuals. In Sierra Leone infection rates of up to 20 of the population each year have been documented and it has been shown that up to 20 of febrile...

Adverse Effects of Antibiotics

Children who received antibiotics in the studies reviewed in the Cochrane review were significantly more likely to experience vomiting, diarrhoea or rash (16.6 in antibiotic group vs. 10.5 in placebo group). However in the more recent LeSaux study, there were no statistically significant differences in the occurrence of diarrhoea, rash or vomiting between children in the placebo and control groups. This may be because the majority of children in this latter study had moderate AOM, and hence...

FollowUp Appointments

Follow-up appointments for those on therapy should always include discussion of adherence in a non-confrontational way and display a genuine appreciation of how difficult it is to keep taking these drugs. Where there are admitted difficulties, children should be praised for being honest about these difficulties and ways to help the child and family should be explored. Maintaining treatment requires dose adjustments in a growing child. For some anti-HIV medications whether this adjustment is...

Principles and Practicality

Starting treatment is never an urgent requirement and clinical benefit is seen only after several weeks. It is important to optimise the chance of adequate absorption and tolerance of these drugs. It is usually wrong to initiate treatment in a very ill child with a life threatening illness where gastrointestinal function may be compromised and the child is receiving many other concomitant medications. One should also consider the duration of other treatments (e.g., for tuberculosis) and delay...

Effects on Short Term Outcomes

Most evidence on the effects of antibiotics for acute AOM address their effects on short-term outcomes. A 1994 metaanalysis of 33 randomized, controlled trials involving 5400 children (Rosenfeld et al., 1994) found that antibiotics increased complete clinical resolution within 7-14 days after the start of treatment by 13.7 (95 CI 8.2-19.2 ). Rosenfeld's metaanalysis included studies which used various outcomes, not all of which would be directly relevant to patients or their caregivers. A...

CD4 T Cells

The TCRs of CD4+ T cells recognize peptides bound in a molecular complex to major histocompatibility complex (MHC) class II proteins on the surface of specialized antigen presenting cells (APCs), such as myeloid dendritic cells (Figure 6.1A) (Watts, 2004). MHC class II peptides are mainly derived from extracellular proteins or pathogens that have entered into lipid bilayer bound compartments in the APC, such as endosomes, by phagocytosis, pinocytosis, or internalization of the cell membrane....

Sustainable Development

The direct effects of war attract a disproportionate amount of attention. Although it is a tragedy that an average of 0.2 million children die every year as a result of war (Machel, 2000), this is only a small proportion of the total of 10.1 million unnecessary deaths amongst children aged less than 5 years. Most of the 10.1 million deaths are caused by common childhood infections, such as pneumonia and diarrhoea, in communities that are not involved in war. It is important to provide urgent...

Clinical Epidemiology

HMPV has circulated in humans for at least 50 years a 100 seroprevalence was found in 72 serum samples obtained from individuals 8 to 99 years old, collected in 1958 in the Netherlands van den Hoogen, 2001 . The few seroprevalence studies available indicate that virtually all children are infected in early childhood. Since the first description of hMPV infection in children by van den Hoogen et al. 2001 , hMPV has been found in most parts of the world (Table 21.1) North America, Europe, Asia,...

Some Good News Costa Rica

Costa Rica provides an extraordinary example of the effects of disarmament. In 1948, the presidential election was won by Otilio Ulate, but the incumbent refused to recognise the result. The resulting civil war was won by forces led by Jose Figueres Ferrer, who disbanded the army and then handed over power to Ulate in 1949. Infant mortality was almost 100 per 1000 live births. Since that time, Costa Rica has spent less than 0.05 of its GNI on military expenditure, and has concentrated on public...

What can be Done

It will be very difficult to achieve real reductions in military activity and eradicate poverty (Table 1.4). Arms expenditure has increased in the last 20 years, development aid has decreased, and there has been little improvement in trade opportunities for developing countries. To reduce military activity, the United Nations Security Council urgently needs radical reform, the UN Convention on the Rights of the Child must be enforced, and we need an effective arms trade treaty - such as the one...

Epidemiological Considerations

The resurgence of malaria in most tropical countries equates with an increased risk to travellers. Throughout the world, many countries are reporting an increasing number of cases of imported malaria. There are four species of malaria parasite known to naturally infect man. In the UK, other European countries and America there has been a steady rise in the number and proportion of the potentially lethal falciparum malaria. In the UK over two thousand cases of malaria are imported Hot Topics in...

Infection Control

Isolation and strict barrier nursing of patients with suspected VHF are critical in all settings. Strict disinfection procedures for all items that come in contact with patients are mandatory. Additional measures should ideally include the use of gloves, gowns, masks, shoe covers and eye face protection. Where available resources permit they may also involve the use of airborne precautions such as HEPA-filtered masks or respirators, negative pressure isolation rooms and positive pressure...

The Natural History of the Disease

The epidemiology and natural history of rotavirus seems quite straightforward. All children are infected in their first few years of life, these first infections are usually symptomatic, and subsequent infections are silent, rarely causing symptoms and associated with very little if any viral shedding. Humans appear to be the main reservoir of infection but rare or novel strains can creep into humans, often representing strains from animals. In temperate climates, rotavirus has a winter peak...

Use of Growth Factors in Neonatal Sepsis

Granulocyte - macrophage colony stimulating factor (GM-CSF) and granulocyte colony stimulating factor (G-CSF) are naturally occurring cytokines used routinely to accelerate neutrophil recovery during the aplastic stage of bone marrow transplantation. When used in this clinical setting there are no adverse side effects. Their use as a treatment to increase circulating neutrophils in septic neutropenic infants may be of benefit because the neutrophil precursor storage pool should readily respond...

Antenatal Inflammation

Chorioamnionitis, the histological inflammation of the placenta, is common in mothers who deliver prematurely (Goldenberg et al., 2000). The presence of chorioamnionitis has been reported to be protective against the development of RDS (Hannaford et al., 1999). Despite not developing RDS, infants born to mothers with chorioamnionitis have an increased risk of developing CLD and also of cerebral palsy (Nelson et al., 1998). Thirty percent of preterm infants with RDS have histological evidence of...

Industrialized Countries

The experience in industrialized countries had previously shown that there is a gradient in transmission rates determined by the number of ARVs provided in those given no drugs the MTCT rate was 20 with monotherapy it was 8 -10.4 dual therapy gave a rate of 3.8 and with combination ARVs (> 2 ARVs) and Highly Active Antiretroviral Therapy (HAART) the figure was down to 1.2 -3 (Cooper et al., 2002 Peters et al., 2003). The landmark PACTG 076 trial with an efficacy of 68 had established the...

S There Any Harm Associated with the Long Term Use of Antibiotic Prophylaxis

Antibiotic prophylaxis is not always a benign intervention. The presence of E. coli resistant to trimethoprim has been demonstrated in up to 66 of children on antibiotic prophylaxis following breakthrough infection, suggesting that prophylaxis may play a role in inducing the emergence of antibiotic-resistant organisms (Braendstrup et al., 1990). Moreover, there is an 8-10 risk of adverse reactions with antimicrobial prophylaxis (Uhari et al., 1996). Trimethoprim-sulfamethoxazole has been...

Specific Side Effects

A low threshold should be exercised for seeing the child at the first signs of a rash particularly if the child's combination contains drugs with a known serious side effect of rash such as nevirapine (Stevens Johnson) and abacavir (Hypersensitivity). The rash may be trivial (an intercurrent illness is very likely to be the cause) but could be the beginning of a serious reaction. If the child is taking nevirapine and a rash develops, antihistamines can help, steroids may be of benefit but if...

Lung Development

Classical CLD has been described histologically as having variable areas of atelectasis and hyperinflation, smooth muscle hyperplasia and extensive fibroprolif-eration (Northway et al., 1967). The more recent pattern that is seen in extremely preterm infants is quite different with a decreased number of large, over simplified alveoli and significantly less fibrosis than seen previously (Coalson, 2003). This is felt to represent an aberration of normal lung development. Newborn preterm infant...

Growth Factors To Treat Neonatal Sepsis

A meta-analysis on 7 randomised controlled trials using growth factors to treat infants with suspected or proven bacterial sepsis and neutropenia (Table 7.1) has been published as a Cochrane Review (Carr et al., 2003). Four different definitions of neutropenia were used between the studies and the definition of sepsis varied between a clinical or clinical and culture proven episode. Five studies used G-CSF as treatment, one used GM-CSF and one used either GM-CSF or GCSF. Six different dosage...

Aims of Therapy

The aims of therapy are to preserve or restore health, to enable normal somatic and neurological development of the child and to prevent the occurrence of encepha-lopathy. This is achieved through suppression of HIV replication leading to immune preservation or restoration. HIV is a rapidly mutating virus and a number of basic principles need to be borne in mind. It is necessary to maintain drug levels sufficient to prevent the development of viral resistance. Past experience indicates that at...

The Goal for Rotavirus Vaccines

The goal for rotavirus vaccines remains the prevention of rotavirus diarrhea in children worldwide. In each country, this goal should be measurable within several years of the vaccine's introduction and will differ in the developed and developing world. In industrialized countries, a rotavirus vaccine program should decrease hospitalizations and clinic visits for diarrhea in children by 30-50 within 2-3 years of the vaccine's introduction. This would lead to substantial economic savings in...

Preface

This book is based on the course Infection and Immunity in Children 2005 which was held at St Catherine's College Oxford, UK in June 2005. This is the third book in this series covering topics in infection and immunity during childhood and based on the Oxford courses. These courses, and their companion books, are aimed at encouraging excellence in clinical practice and raising the profile of paediatric infectious disease with a particular eye on the needs of trainees in the specialty. At the...

Role of Exchange Transfusion

Exchange transfusion has been advocated for hyper-parasitaemia (> 10 ) in adult ICU settings, despite no evidence to suggest that it confers a better outcome (Riddle et al., 2002). Even when parasitaemia exceeds 25 , the vast majority of children respond rapidly to the treatments outlined above. In those with persistent acidosis, and multi-organ impairment not responsive to the resuscitation treatments outlined above, exchange transfusion may be considered as a means of rapidly reducing the...

Conclusion

Whilst the concept of replacing the neonatal immunological deficit to prevent or treat systemic sepsis is theoretically attractive, the results from clinical trials performed to date are perhaps less dramatic than expected. The reasons for this are likely to be multifactorial, but include the recruitment of low risk infants who are not septic or neutropenic, and use of inappropriate immunoglobulin preparations that contains little or no antibody effective against pathogens causing neonatal...

Lassa Fever in Pregnancy and Children

Lassa VHF is associated with particularly severe disease in pregnant women and their infants and is associated with high levels of viraemia. Infection during the third trimester of pregnancy is associated with maternal mortality greater than 30 and increased foetal and neonatal mortality (greater than 85 ). Delivery improves the mother's chance of survival. Lassa virus infection is a significant cause of paediatric admissions in some areas of West Africa and the clinical features can be more...

Seasonal Distribution of Invasive K kingae Infections

Examination of the monthly distribution of the 96 cases of invasive disease diagnosed in southern Israel since 1988 shows that K. kingae infections are significantly more common in the second half of the year (69.8 ) of all cases. To elucidate the relationship between seasonal carriage of K. kingae and occurrence of invasive infection, the prevalence of the organism in the pharynx was determined in children and adults between the months of February and May (when invasive diseases are rare), and...

Military Expenditure

The marked inequality between rich and poor countries is very dangerous. Widespread, severe poverty contributes to overpopulation, and threatens the environment. It breeds anger, promotion of violence, and greatly increases the risk of world pandemics of infectious diseases. Both humanitarian considerations and the self-interest of developed countries demand that poverty be reduced. World military expenditure totalled US 1035 billion in 2004 (SIPRI, 2005). The annual budget for the World Health...

Summary Conclusions and Recommendations

Two trends threaten the efficacy of empiric therapy of pediatric pneumonia with cefotaxime or ceftriaxone alone. (A) Increasing penicillin and cephalosporin resistance amongst pneumococci may result in cefotaxime ceftriaxone treatment failure of pneumococcal pneumonia, but this appears to be rare and may only apply to infections caused by isolates with unusually high cefotaxime ceftriaxone MICs. Less than one percent of pneumo-cocci isolated from U.S. patients with invasive disease have...

Future Vaccines in the Pipeline

It is unlikely that vaccines produced by these two multinationals will be able to satisfy the global need for rotavirus vaccines at an affordable cost. A number of other candidate vaccines are in the pipeline and all are likely to be produced by emerging manufacturers in the developing world. In China, a rotavirus vaccine based on a single strain of lamb rotavirus and produced by the Lanzhou Institute of Biological Products has been licensed and is currently being sold. The efficacy of this...

Choice of Drugs

With potency and practicality in mind the clinician must select a combination which should best suit the child. There are three main classes of antiretroviral medications, NRTIs (nucleoside reverse transcriptase inhibitors), NNRTIs (non-nucleoside reverse transcriptase inhibitors) and PIs (protease inhibitors). Some of these medications come in a combined form (usually two drugs) enabling reduction of pill burden and greater convenience. At the time of writing, widely-used first line...

Direct Effects of

It is estimated that, on average, guns, bombs, mines and chemicals kill 0.2 million children and disable 0.5 million children every year (Machel, 2000). In addition, at any given time, 300,000 children less than 18 years of age are fighting as soldiers (Machel, 2000) - many are forced to fight against their will, and many are brutalized and tortured. Land mines are still found in 105 countries. They are estimated to kill 1000 children every year, and cause serious injury to 20,000 children...

Use of Granulocyte Infusions in the Treatment of Neonatal Sepsis

Because neutropenia is associated with poor outcome in neonatal sepsis, and the neutrophil pool is depleted in such patients, the use of granulocyte infusions to treat these patients has been considered for more than twenty years (Christensen et al., 1982a). A number of small studies have looked at the use of granulocyte infusion for the treatment of neonatal sepsis. A meta-analysis of some of these have been published by the Cochrane Review (Mohan and Brocklehurst, 2003). Three small...

The Earliest Vaccine

To date, all of the vaccines against rotavirus that have entered clinical trials have been live attenuated rotavirus strains that have been administered orally with buffers. Attenuation has been achieved either through the repeated passaging of human rotavirus strains or the natural attenuation of animal strains administered to humans. The first candidate rotavirus vaccine was a bovine strain of rotavirus, RIT 4237 prepared by SmithKline Rixensart, that was administered to infants just before...

Duration and Type of Antibiotics Used in AOM

The effect of the type and length of course of antibiotics on outcomes of AOM as well as rates of adverse effects have been explored with both a systematic review and a later Cochrane review (Kozyrskyj et al., 1998 Kozyrskyj et al., 2000). Most studies have compared antibiotic courses of 5 days (short course), to those of 8-10 days (long course). In the 12 trials that reported outcomes at 1 month or less, the summary odds ratio (OR) for treatment failure in 1549 children treated for 5 days...

Development of Resistance To Nevirapine

One of the main problems with the use of ARVs in the prevention of mother-to-child-transmission of HIV-1 is that drugs used in these regimens can induce the development of drug resistant strains. In resource-limited settings, the simplest and safest ARV regimen conferring the most efficacious outcome is the sdNVP intra-partum postpartum regimen (Guay et al., 1999 Jackson et al., 2003). Resistance to NVP may compromise the subsequent use of NVP-containing pMTCT, and HAART regimens in women or...

Pathogenesis

An experimental infection model in cynomolgus macaques (Macaca Fasicu-laris) has confirmed that hMPV is a primary pathogen of the respiratory tract in primates Kuiken, 2004 . The hMPV-infected macaques showed mild clinical signs of rhinorrhea corresponding with a suppurative rhinitis at pathological examination. In addition, mild erosive and inflammatory changes in the mucosa and submucosa of conducting airways, and an increased number of alveolar macrophages in Table 21.1. Incidence of hMPV...

Serology

Antibodies to Chlamydia spp. are best detected with a microimmunofluores-cent (MIF) assay, but these assays are not widely available. Serologic screening is of very little value in uncomplicated genital infections but may be useful for population studies. Patients who have LGV infections demonstrate elevated specific IgG and IgM antibody levels compared to those with other chlamydial infections. The MIF is species-specific and sensitive but is available only at a limited number of clinical...

Role of Prophylactic Intravenous Immunoglobulin Infusions in the Prevention of Neonatal Sepsis

Would the prophylactic administration of pooled human immunoglobulin help to preterm or low birth-weight infants help prevent systemic infection A Cochrane Review has analysed 19 trials that randomised 5000 preterm or low birth weight infants to prophylactic intravenous immunoglobulin infusions or placebo (Ohlsson and Lacy, 2004b). Eight different IVIG preparations were used and there were 7 dosage variables. In 4 trials, infants received a single dose of intravenous immuno-globulin, and in the...

Tim J Mitchell 1 Introduction

Streptococcus pneumoniae (the pneumococcus) is a major human pathogen, causing diseases such as pneumonia, meningitis and otitis media. The organism is also carried asymptomatically in a large proportion of the population. The primary niche of the pneumococcus is the human nasopharynx where it exists asymptomati-cally as a commensal. Colonisation can occur within hours of birth and by twelve days post-birth the carriage rates are similar to that of the babies' mothers (Gray et al., 1980)....

Treatment

The most widely used treatments for uncomplicated oculogenital infections caused by C. trachomatis in nonpregnant adolescents and adults are doxycycline (100 mg orally twice daily) for 7 days or azithromycin (1 g orally) in a single dose. In populations with poor compliance with treatment, azithromycin may be more cost-effective because it provides single-dose, directly observed therapy (Martin et al., 1992). Doxycycline costs less than azithromycin, and it has been used extensively for a...

Prevention of AOM

Preventive approaches include reducing environmental risk factors, vaccination, antibiotic prophylaxis, tympanostomy tubes and adenoidectomy (Giebink, 2001). Prevention of frequent recurrences of AOM includes the possible use of daily antibiotic prophylaxis. The effects of this may be limited, and are associated with emergence of resistant bacteria, adverse drug reactions and suppression of symptoms without affecting the actual disease process (Williams et al., 1993). The addition of the...

Nonculture Tests for C trachomatis

The previous gold standard of cell culture is being outperformed by more sensitive molecular techniques confirmatory studies of discrepant test results frequently find true positives that were negative by cell culture. Amplification tests based on the detection of chlamydial DNA or specific chlamydial ribosomal RNA are now available. Both detect C. trachomatis in urine or in self-administered vaginal swab specimens, with sensitivity comparable to that obtained with urogenital swab specimens,...

Do Nonantibiotic Interventions Have a Role in Preventing Recurrent Urinary Tract Infections

Cranberry juice has been examined as a UTI prophylactic in a Cochrane meta-analysis. No difference in incidence of bacteriuria between treatment and control groups was found, although small numbers may have underestimated any treatment effect (Jepson et al., 2004). The authors concluded that this safe intervention requires larger trials to evaluate its efficacy. Addressing voiding dysfunction with bladder training programs with or without the additional use of anticholinergic agents may be an...

Ebola and Marburg Viruses

Ebola and Marburg viruses are filamentous or bacillus form with a uniform diameter of 80 nanometres but a variable length between 860 and 1086 nanometres that can help distinguish Marburg and the different subtypes of Ebola viruses. These viruses contain non-segmented negative-strand RNA with a 19 kb genome that encodes 7 structural (and in the case of Ebola also one non-structural) proteins. Ebola and Marburg viruses have 55 nucleotide homology. The viruses are coated with an envelope that...

Diagnosis of AOM

Accurately diagnosing AOM is challenging as young children have limited ability to describe symptoms, and physical examination may be limited by narrow external auditory canals and poor cooperation. Doctors may be uncertain of their diagnosis of AOM in up to 40 of cases (Rosenfeld et al., 2002 Karma et al., 1989). This can lead to over-diagnosis of AOM, resulting in potential iatrogenic harm due to increased use of antibiotics or referral to ENT specialists (in the case of recurrent...

Limitations of Current Evidence

The Cochrane review by Glasziou et al. used reduction in pain at any point between 2 and 7 days after the onset of treatment as the primary outcome. Since most children with AOM will have recovered spontaneously by 7 days regardless of treatment used, it is possible that such a wide range may mask effects on treatment of children at the lower end of this timescale. There is some evidence that the findings of the Cochrane and other reviews may not apply equally to children of different ages, or...

The Pneumococcal Cell Surface

One of the main virulence factors of the pneumococcus is the polysaccharide capsule, which is believed to be anti-phagocytic (Jonsson et al., 1985). Over 90 different serotypes of the pneumococcus have been identified based on the antigeni-cally distinct polysaccharide capsule (Kalin, 1998). As well as the capsule the pneumococcus produces a range of other molecules on its cell surface that are associated with pathogenesis including components of the cell wall itself and cell-surface proteins...

The NTDs as the Ancient Afflictions of Stigma and Poverty

The NTDs are caused by parasitic worms, protozoa, and the bacterial agents of leprosy, Buruli ulcer, and trachoma (Table 3.1). Unlike the well-publicized newly emerging infections, such as Ebola, West Nile fever, or avian influenza, the NTDs have burdened humanity since the beginning of recorded history (WHO, 2003). Descriptions of leprosy, schistosomiasis, guinea worm, hookworm, trachoma and other NTDs are found in the Bible (Dirckx, 1985 Hulse, 1971 Ceccarelli, 1994), the Talmud (Ostrer,...