1 Instituto de Investigacion Nutricional, AP 18-0191, Lima 18, Peru
2 Public Health Sciences, University of Edinburgh Medical School, Teviot Place, EH8 9AG, Edinburgh, Scotland, UK
3 Department of Epidemiology, School of Public Health 'Andrija Stampar', Rockefellerova 4, 10000 Zagreb, Croatia
4 Child and Adolescent Health and Development, World Health Organization, Avenue Appia, 1211 Geneva 27, Switzerland
5 Vaccines and Biologicals, World Health Organization, Avenue Appia, 1211 Geneva 27, Switzerland
Correspondence: Dr Harry Campbell, Public Health Sciences, University of Edinburgh Medical School, Teviot Place, EH8 9AG, Edinburgh, Scotland, UK. E-mail: Harry.Campbell{at}ed.ac.uk
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Abstract |
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Acute respiratory infections (ARI) are the most important single cause of global burden of disease in young children globally and the largest single cause of mortality.1,2 Prospective community-based surveillance for new episodes of acute lower respiratory infections (ALRI) is necessary for reliable estimates of ALRI incidence to be obtained.3 In addition, community-based surveillance of ALRI episodes is important in the evaluation of the impact of interventions, such as reduction of exposure to indoor air pollution or micronutrient supplementation, seeking to prevent ALRI in young children. Surveillance studies usually employ a combination of interviews asking for recall of the occurrence of respiratory symptoms and signs recognized by the mother and simple assessments by trained field workers to identify ALRI episodes. However, there are numerous important issues relating to the collection and analysis of such data which can compromise the validity or complicate the interpretation of the incidence estimates that are reported. Examples of such issues include the combination of symptoms and signs upon which an ALRI case definition is based, the conditions under which the study was performed, and the degree to which the study population can be considered to be representative of a wider region.36
In the 1980s the WHO programme for the control of acute respiratory infections supported a number of methodological studies aimed at clarifying some of these issues. An expert meeting was convened in January 1990, which reviewed the methods and experiences of these studies and attempted to formulate recommendations on the design and data analysis of prospective studies.6 In 20002003 a Child Health Epidemiology Reference Group (CHERG) was constituted by WHO to provide data to improve the evidence base of burden of disease estimates in children. As part of this effort we completed a review of more than 2000 studies on childhood ALRI published between 1961 and 2001. A database containing selected data from each of 300 studies which reported on ALRI incidence, risk factors, or case fatality ratio was created and has been made available by the WHO Child and Adolescent Health and Development programme at: http://www.who.int/child-adolescent-health/New_Publications/Overview/ari_db.htm in order to support further research on this topic. In this paper, we attempt to define and discuss important issues to consider in designing or conducting an ALRI incidence study or in assessing the quality of published studies and interpreting data and comparing estimates from various studies. The CHERG review identified only 28 studies which were well-designed prospective studies that provided valid ALRI incidence estimates.3 This underscores the need for greater priority to be given to such studies to inform global burden of disease estimates and for guidelines for the proper conduct of these studies.
Acute lower respiratory infections (ALRI) are defined in the International Classification of Diseases as those infections that affect airways below the epiglottis and include acute manifestations of laryngitis, tracheitis, bronchitis, bronchiolitis, lung infections or any combination among them, or with upper respiratory infections, including influenza. The focus of the global burden of disease programme has been on conditions accounting for substantial loss of disability-adjusted life years. Within the WHO CHERG a decision was made to concentrate on pneumonia and bronchiolitis which are considered to be the major components of ALRI accounting for global burden of disease from ARI in young children. This approach is consistent with the WHO approach to case management of ARI and now incorporated in the global Integrated Management of Childhood Illness programmes. These programmes train health workers to identify children with fast breathing, lower chest wall indrawing or selected danger signs (such as cyanosis or inability to drink) in children with respiratory symptoms. For programmatic purposes these are labelled as pneumonia although it is recognized that the children identified in this way include those with pneumonia, bronchiolitis, and a proportion of those with reactive airways disease associated with a respiratory infection. Some authors have used the term clinical pneumonia to describe these conditions but in this review we have used the term ALRI. It is important to recognize that the term ALRI in this context does not include the conditions acute laryngitis, bronchitis, or tracheitis.
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Determinants of study quality |
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Geographical context
Geographical parameters can substantially affect ALRI incidence estimates.3 Thus, altitude, annual rainfall, number and nature of the seasons (wet/dry), average monthly temperatures, and any indicators of outdoor air pollution should be reported.
Socio-cultural context
The population under study should be classified as rural, suburban, or urban. Details of socioeconomic status and/or details of average household income,8,9 and the prevalence of known risk factors for ALRI should be reported. This should include data on crowding,10 maternal age and child care experience,11 breastfeeding practices,12,13 exposure to indoor air pollution,1416 parental smoking,17 and birth order.18,19
Concomitant public health problems
The prevalence of public health problems that are recognized ALRI risk factors should be reported: malnutrition,18,20,21 other concomitant diseases (primarily diarrhoea, AIDS, and malaria),18 low birthweight, and micronutrient deficiency (especially vitamin A and zinc deficiency).2224
Local health care system
Details of the local health care system and the level of access to it should be reported. This should focus particularly on factors which may influence ALRI incidence: immunization coverage against measles,9 pertussis,25 and Hib26 and details of maternal and paediatric care.27 Data on access to health care are available from demographic surveys for regions in over 80 countries from UNICEF at http://www.childinfo.org/eddb/ARI.datbase.htm.
Determinants related to study design (Table 2)
Study duration
The study period should cover all the major periods of annual climate changes (such as wet and dry seasons) and should cover a period of one year or multiples of one year since seasonal factors typically have a major effect on ALRI incidence. Longer study durations may be expected to lead to more robust estimates since any temporary fluctuations in ALRI occurrence will be smoothed to some extent over the longer period of observation.1 Against this, however, it has been shown that conduct of a surveillance study in a community can affect the results of the study, usually by decreasing the estimates over time (the Hawthorne effect). Thus, it is appropriate in longer-term studies to evaluate this effect by reporting the time trends of estimates.
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Site of surveillance
The site of surveillance usually refers to home, field clinic, or hospital, depending on the study design. We have recently shown this to be an important independent determinant of variability in published ALRI incidence estimates, even when correcting for the assessor's experience, case definition, and population type.3 This effect may be due to other factors related to site of surveillance which were not reported.
Surveillance strategy
Recognition of ALRI episodes by the trained field worker during home visits
Field workers should be trained with standard operating procedures to observe and/or measure clinical symptoms and signs to establish a diagnosis of ALRI. It is important to give precise details of how these measurements were made (Table 2). Standardization exercises using an expert as a standard and ideally having field workers and the expert performing observations on the same children are important aspects of training. The methods used to standardize diagnoses and check inter-rater reliability, if more than one field worker participated in the study, should be given and any results described in full.
Diagnosis of ALRI episode by the physician at a field clinic or hospital
Some ALRI studies employ regular home surveillance of a cohort of children by field workers but require confirmation of any ALRI episode by a hospital-based medical doctor. This has the potential to result in a considerably more reliable procedure for ALRI identification. However, the criteria used and the methods for standardization of the diagnosis if more than one physician participated in the study should be described. If a single physician established all diagnoses then details of what provisions were made to validate these diagnoses should be reported.
Since the referral process is a major potential sources of bias it must be described in detail (Table 2). This should include the average length of time between first identification of the episode and the physician examination, and the proportion of suspected cases not seen by the physician. It is important to specify how the repeat visits to the clinic within the same ALRI episode were dealt with: whether data were collected on all attendances or only for new episodes, and if the latter, the criteria for defining a new episode (i.e. how many days without the symptoms or between visits were used to separate two episodes). A description of how many clinical diagnoses were allowed in the same visit and, if more than one, the provisions for ranking the diagnoses and for selecting the ones to be coded should be reported. The procedure for dealing with a case that came initially with one clinical condition or diagnosis but later, in a separate visit within the same clinical episode, had a second diagnosis of ALRI should be made clear.
Low perceived quality of health care or cultural factors can prevent care takers from presenting children at health facilities. It is therefore important that studies adopt active surveillance in which each cohort child is examined regularly. ALRI incidence estimates from passive surveillance (in which children with ALRI are identified when they present to a health facility) may be strongly influenced by the level of care seeking and access to health facilities and have been shown to decline with distance from and cost of reaching the health facility.28
Cohort structure and size
Large age-related and sex-related differences in ALRI incidence (and mortality) exist throughout childhood. In our recent review we found that when the incidence in the first year of life is set to 1.0, the mean ratios of age-specific incidence were 1.000.580.350.220.15 over the first 5 years of life.3 In addition, it has been shown consistently that incidence in male children is greater than in female children. It is important, therefore, to give details of the age and sex structure of the cohort or to report age-specific ALRI incidence rates for each year of age over the 04 year range. We identified only five published studies which had reported these age-specific rates.3
Study size should be guided by the required precision of the ALRI estimate in observational studies or size of difference in ALRI incidence considered to be important in intervention studies. Cohort sizes meeting quality criteria in our recent review varied from <300 (6 studies), 3001000 (12 studies) to >1000 (10 studies).3 The total number of enrolled children over the entire study period and mean number of children under surveillance each month should be reported. It should be clear whether enrolment was continuous or a fixed cohort design was employed. If the cohort was fixed, the replacement of losses of follow-up should be described.
Case definition
We have recently reported the effect of case definition on ALRI incidence estimates.3 Almost all published studies can be classified into one of the two broad groups. The first group used some modification of the original WHO/ARI classification of acute respiratory infections into mild, moderate, and severe based on simple clinical signs (with ALRI episodes falling into the moderate and severe categories) (see below). In the second group of studies, ALRI cases were diagnosed based on physician's own assessment and experience including use of auscultatory findings. We have shown that requiring auscultatory findings, such as crepitations or rales, to be present in the case definition tends to decrease the reported ALRI incidence estimate.3 Thus, it is important to give a clear description of the exact case definition employed (Table 2). Since most studies have reported estimates based on the presence of fast breathing (see below) or lower chest wall indrawing then separate reporting of these findings would facilitate comparisons of estimates across published studies. Ideally, the data should be reported in a way that ALRI incidence based on a number of differing case definitions can be obtained.
ALRI case definitions based on clinical signs
Shann, on the basis of a study in Papua New Guinea, proposed a simple clinical method for the assessment of ARI in children.29 A WHO Working Group on Case Management of Acute Respiratory Infections reached a consensus that three signs related well to acute respiratory infection severity: rapid breathing, chest indrawing, and too sick to feed.30,31 The increased respiratory rate associated with pneumonia or bronchiolitis is a patho-physiological response by the body to compensate for the reduction in gas exchange capacity in the lung due to the lung pathology caused by the infection and the resultant ventilationperfusion imbalance. This results in a respiratory rate which is continuously raised over a period of time. This is quite different to the transient rise in respiratory rate that can occur in infants and young children in response to a stressful event (as when being examined). The mean respiratory rate is influenced by body temperature rising by about 2.5 breaths per minute for every 1°C rise.31
A simple classification of ARI into three categories according to severity was proposed.
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Classification of children with wheeze
Wheezing in young children is now considered to be a broad category of bronchospastic airways disease including bronchiolitis, other associated viral infections, and asthma. Most published ALRI studies from developing countries have either commented that wheeze was not a common finding or excluded children with wheeze from their case definition of ALRI. We have recently shown that inclusion of wheeze in diagnostic criteria for ALRI will tend to inflate the ALRI incidence, as expected.3 It is important, therefore, to give details of how children with both ALRI and wheeze were recorded.
We recommend that exact definitions of wheeze be given since the nomenclature is this area is confusing. For example, British textbooks tend to refer to (sibilant) rhonchi whereas those from the US refer to wheezes. It should be noted whether the wheeze was audible and/or heard by auscultation. It is difficult to clearly distinguish between wheezing disorders such as bronchiolitis and pneumonia, as crepitations on auscultation and segmental or lobar changes on chest X-ray can be found in both conditions36 so the criteria used to diagnose bronchiolitis, asthma or other wheezing disorders should be recorded. Where attempts were made to identify infection with respiratory syncytial virus (RSV) the proportion of children with wheeze who were positive for RSV (by ELISA, immunofluorescence, PCR testing, or culture) should be given.
Indicators of severity of the ALRI episode
A severe episode is usually defined as one that results in higher mortality or one that requires hospital treatment or has the presence of a sign used to define a severe episode. The need to receive hospital care is a severity indicator associated with a variety of clinical indications including need for parenteral antibiotics, oxygen therapy, help with feeding difficulties, or when the care giver cannot be relied upon to give oral antibiotic treatment at home. Need for hospital treatment is the most useful definition of severe ALRI for burden of disease studies. This outcome has a meaning that is readily understood and one that can be used directly for planning of health services and when performing cost-benefit analyses of potential interventions to reduce ALRI incidence. However, the study surveillance system usually affects the management of ALRI cases, aborting the need for hospitalization and so this important severity indicator is seldom available from these studies or is underestimated.
The WHO case management algorithm utilizes the presence of lower chest wall indrawing as the main sign indicating severity. However, this is also problematic as it is one of the most difficult clinical signs to teach and standardize and studies have employed different definitions. This has resulted in a very wide range of reported prevalence of chest indrawing. This indicator is also influenced by the prevalence of wheezing disorders in the study population since bronchospastic airways diseases are commonly associated with indrawing.
The signs most often considered in the assessment of severity are given in Table 2.37 Other indicators such as data on hypoxaemia from pulse oximeters are used where the data are available. In the four published community-based studies that separately reported the incidence of severe ALRI and the incidence of all ALRI, the proportion of severe cases (defined as requiring hospital inpatient treatment) was consistently between 6% and 12%.3 A more objective way of defining severity of ALRI may be by pulse oximetry. Oximetry measurements of oxygen saturation need to be adjusted for altitude, but at sea level, a cut-off of 90% has been used to denote severe ALRI requiring oxygen.38
Radiological recognition of pneumonia
Chest X-rays can often be performed even in community-based studies in developing countries. They can permit a permanent record to be made of the illness episode that allows future review of the study. If a standard procedure for taking and reading the chest X-rays is employed then ALRI estimates between studies can be compared. In addition, if these same procedures are adopted in vaccine intervention trials then an estimate of the vaccine preventable burden of ALRI disease can be obtained by extrapolating impact estimates from intervention trials to local ALRI incidence (burden of disease) data.
The relationship between clinical and radiological assessment depends on the criteria and definitions used. In several Hib and pneumococcal vaccine trials where the radiological criteria have been used for the diagnosis of pneumonia, between 1020% of cases who meet the WHO clinical criteria for severe episodes of ALRI have evidence of alveolar consolidation or pleural effusion and, therefore, are categorized as primary end point pneumonia for these trials by the standardized WHO radiological criteria (WHO Pneumonia Vaccine Trialists Groupunpublished data). It is important give details of the procedures and definitions adopted in any study (Table 2).
Since the clinical criteria for the recognition of ALRI may vary among studies, the use of radiological criteria have been proposed for defining ALRI episodes that are likely to be due to bacterial agents since chest X-rays are considered more specific than clinical criteria. In addition, data from a number of studies can be later evaluated together using a common protocol thus allowing direct comparison of ALRI case definitions. In order to maintain a reasonably high level of inter-observer agreement, the interpretation of radiographs needs be simplified. The WHO Pneumonia Vaccine Trialists Group39 classify cases of suspected ALRI into one of three categories (rather than attempting aetiological or pathological diagnosis based on the detailed description of the radiological findings). A computer-based training program has been developed by the WHO Vaccines and Biologicals Programme (VAB) to ensure optimal interpretation. The categories are:
End point consolidation: A dense opacity that may be a fluffy consolidation of a portion or whole of a lobe or of the entire lung, often containing air-bronchograms and sometimes associated with pleural effusion.
Other (non-endpoint) infiltrate: linear and patchy densities (interstitial infiltrate) in a lacy pattern involving both lungs, featuring peribronchial thickening and multiple areas of atelectasis. Lung inflation is normal to increased. It also includes minor patchy infiltrates that are not of sufficient magnitude to constitute primary endpoint consolidation, and small areas of atelectasis which in children may be difficult to distinguish from consolidation.
Pleural effusion: The presence of fluid in the lateral pleural space between the lung and chest wall. In most cases this will be seen at the costo-phrenic angle or as a layer of fluid adjacent to the lateral chest wall. This does not include fluid seen in the horizontal or oblique fissures. Pleural effusion was considered as primary end point if it was in the lateral pleural space (and not just in the minor or oblique fissure) and was spatially associated with a pulmonary parenchymal infiltrate (including other infiltrate) OR if the effusion obliterated enough of the hemithorax to obscure an opacity.
Based on the above findings a case is categorized into one of three groups:
Primary endpoint pneumonia: The presence of end point consolidation (as defined above) or pleural effusion that meets criteria for primary end point (as defined above).
Other consolidation/infiltrate: The presence of other (non-end point) infiltrate as defined above in the absence of a pleural effusion.
No consolidation/infiltrate/effusion: Absence of end point consolidation, other infiltrate, or pleural effusion.
These criteria are designed for epidemiological studies and may not be suitable for patient care decisions. They are currently being used and evaluated in Haemophilus influenzae type b and Streptococcus pneumoniae conjugate vaccine trials, pneumonia burden studies, and antibiotic intervention trials. The use of common standardized radiological criteria should facilitate comparability of results and easy application of the data from intervention studies to disease burden studies.
Use of other laboratory investigations
Other laboratory investigations are not generally helpful in establishing a diagnosis of ALRI. Certain laboratory tests are known to be associated more often with bacterial infection and if used in conjunction with radiological criteria may increase the specificity of the diagnosis of bacterial pneumonia. These include total leucocyte and granulocyte counts, erythrocyte sedimentation rate, C-reactive protein, and serum procalcitonin. However, in practice their usefulness is limited by their weak predictive power and the requirement for testing early in the course of the infection. Details of any investigations made should be given together with a report of any biological specimen (such as blood, pharyngeal smear, or lung aspirate) analysed. A note should be made of which laboratory tests were used to identify bacterial and viral aetiological agents, and in what percentage the isolate was successful.
While the specificity of high leucocyte and granulocyte counts in diagnosing bacterial pneumonia is reasonably high depending on the breakpoint chosen, the sensitivity is low.40 The erythrocyte sedimentation rate is higher in children who have pneumonia with alveolar consolidation compared with those with interstitial pneumonia.41,42 C-reactive protein has been shown to be significantly higher in patients with bacterial pneumonia, compared with those with non-bacterial pneumonia.41 Circulating levels of calcitonin precursors are known to increase several thousand-fold with microbial infections and various forms of severe systemic inflammation.43 Serum procalcitonin has been shown to be helpful in predicting the presence of serious bacterial infections in patients with fever without localizing signs. In pneumonia there is a significant difference between the levels of procalcitonin in those with bacterial and viral pneumonia. Using a cut-off value of 1 ng/l serum procalcitonin demonstrated a sensitivity and specificity of 0.86 and 0.88 respectively in one study.44 However, malaria may substantially increase serum procalcitonin levels and this may limit the use of this test in malaria endemic populations given the overlap of clinical manifestations of pneumonia and malaria.
Recording of maternally reported signs or symptoms
Local concepts and words used for describing ALRI signs and symptoms and illness categories should be identified prior to surveillance. The most important signs and symptoms relate to the terms used for cough, difficulty breathing, fast breathing, chest indrawing, noisy breathing, phlegm, nasal discharge, not looking well (maternal perception that child is ill), changes in appetite, and reported fever. For each of these signs and symptoms a record should be kept of the study definition used, whether the reported symptom was prompted or not, whether there were any attempts made to classify these symptoms according to severity (e.g. mild, moderate, or severe) and how this was done. When reporting breathing difficulties, blocked nose as a single symptom should not be included in the ALRI definition.6 The day on which the recalled information was obtained should be recorded since prevalence estimates are strongly influenced by recall period. This effect tends to be greater for milder/commoner signs and symptoms of illness. Because of this effect, home surveillance studies should ideally be done with visits that are no less frequent than weekly.
Frequency of monitoring
There is a general concern that the ALRI incidence estimates will increase with a greater frequency of monitoring in community-based studies. However, our recent review3 did not find any strong correlation between frequency of monitoring and reported ALRI incidence when the interval between monitoring was not longer than 2 weeks. We recommend that frequency of monitoring should ideally be once a week and not greater than every 2 weeks.
Level of experience of assessors
Assessors can range from lay reporters, trained field workers, medical students, nurses, physicians, to paediatricians or combinations of the above. It has been shown that assessors with higher qualifications are generally associated with lower reported ALRI incidence estimates.3 This is, at least in part, because they are likely to apply case definitions which have higher specificity for the recognition of ALRI. The exact qualification of the assessor and details of any training for the study should therefore be described.
Definition of an episode
There is no clear consensus on the definition of the start and end of a discrete ALRI episode. This will influence estimates of ALRI duration but also of ALRI incidence. We recommend that an episode begins with the first day of cough and rapid breathing (reported or measured), and ends with the last day of the same combination. However, a minimum of 14 days free of these combined symptoms should be required between the end of one episode and the beginning of the next. If symptoms recur within a period of less than 14 days, these days of symptoms, as well as the intervening symptom-free days, should be considered part of the immediately preceding episode. Some episodes may start with days of cough before rapid breathing/raised respiratory rate develops. Children with bronchospastic airways disease may be particularly prone to cough for prolonged periods of time and pneumonia may occur with this clinical background in these children. These cough-only days should not be included in the episode of ALRI. Similarly, cough alone after rapid breathing ceases to be reported or respiratory rates return to normal levels should not be considered part of the ALRI episode.6 Clearly, this definition will be affected by the frequency of home or clinic visits at which the respiratory rate was counted.
Duration of ALRI signs and symptoms during an episode
If duration of ALRI episodes is an important study endpoint then the mean, median, and range of duration of episodes and of symptoms and signs associated with the episode should be calculated. If there are interruptions within the episode, two periods of symptoms should not be counted, but instead the mean and duration calculated for the whole period.6
Determinants related to statistical analysis
The specific method of dealing with the occurrence of multiple episodes of illness within the same child and the methods of calculating prevalence and incidence estimates are important to consider.
Prevalence of ALRI symptoms
Reporting the prevalence of ALRI signs and symptoms in all studies might help understand differences in reported ALRI incidence rates. Prevalence estimates may be based on data on the presence or absence of symptoms for each day under surveillance, or only on observations made on the day of the home visit. Days with missing data, such as due to temporary study absences, should be excluded from the denominator in these estimates. It would be useful to report prevalence rates by age, sex, season, and study year.
In addition, it would be useful to examine the mean respiratory rate and the prevalence of elevated respiratory rates in children without reported or observed cough, or any symptoms and signs of ALRI. This would not be possible in all studies, as some are designed to measure breathing rates only for children with respiratory symptoms or signs.
Where data are available, the prevalence of fast breathing should be available, using the cut-off points described above. The prevalence of an elevated respiratory rate could further be investigated separately for first and second count (to explore the benefit of two consecutive counts).
Incidence of ALRI
Most studies use child-weeks of follow-up (number of weeks each child was under surveillance) as the denominator to calculate the incidence rate of ALRI. These should include all weeks when the child was seen by the field-worker, as well as the weeks when the child was temporarily absent from the home, but should not include periods of time when the child had moved away from the study area. We recommend weeks of illness should not be subtracted from the total weeks of follow-up. Some studies may use child-days of follow up instead, but for ALRI surveillance, child-weeks may be more appropriate.
Some issues requiring further research
Sensitivity and specificity of ALRI symptoms and signs
The WHO criteria were developed to serve as a diagnostic test in health facilities with poor access to properly trained physicians or other health workers rather than for use in epidemiological studies. In this context high sensitivity is the dominant test attribute. However, there is a need to consider further the most appropriate respiratory rate thresholds for research purposes where high specificity is relatively more important. For example, misclassification of cough and cold episodes as ALRI (due to low test specificity) will act to reduce the true power of an intervention study to detect a difference in ALRI incidence among intervention groups. The criterion reference or gold standard for the assessment of sensitivity and specificity of any clinical sign or symptom could be the assessment of a trained paediatrician on the same child or the assessment of the WHO panel of radiologists (or other panel using the WHO criteria). One area of particular importance for future research is to identify clinical, radiological, or laboratory criteria that can reliably distinguish between ALRI and bronchospastic airways diseases in children who present have audible and/or auscultatory signs of wheeze.
Aetiology-specific ALRI incidence and prevalence
It has recently been estimated that approximately 165 million episodes of ALRI occur globally each year in children aged 04 years, resulting in 2.1 million deaths.3 Current published data suggest that after excluding measles and pertussis-related deaths, the remaining deaths, attributed collectively to ALRI, are in large part due to Streptococcus pneumoniae, Haemophilus influenzae, and respiratory syncytial virus.26 A future goal will be to improve the estimates of the proportion of ALRI morbidity which can be assigned to specific aetiologic agents. This would be important for health planning and the assessment of the likely impact of aetiology-specific interventions such as immunization against Haemophilus influenzae type b, Streptococcus pneumoniae and respiratory syncytial virus. However, the other agents, such as Staphylococcus aureus, might have a greater role than generally thought, especially in particular locations of the world.
It has been proposed that the preferred approach to investigate the proportion of new cases/deaths attributable to each agent is to study the decrease in incidence or mortality associated with the introduction of a new vaccinethe so-called probe study design. This has already been successfully performed with Hib vaccine in the Gambia,26 and several other intervention trials using conjugate pneumococcal vaccines are underway.
However, until the completion of these studies, a review of hospital-based studies which investigate the aetiology of ALRI using reasonably sensitive methods (lung aspirate and naso-pharyngeal aspirate studies employing recommended bacterial and viral isolation and identification methods in centres with proven ability to study these microbiological agents) can be performed. The validity of this approach, however, is restricted by concerns about bias in the referral of cases to hospital, selection bias in the hospital cases which are studied and the generally low and differential sensitivity (across different aetiological agentse.g. 8090% for RSV by immunofluorescence or polymerase chain reaction but only 1020% for bacterial agents by blood culture) of currently available methods.36
Other medical conditions that may affect the diagnosis of ALRI
The influence of (co-existing) medical conditions on the diagnosis of ALRI require further study. Malaria, which can present with fast breathing due to high fever, severe anaemia, acidosis or pulmonary sequestration of parasites, may thus be classified as an ALRI episode. A recent study3 investigated this problem and concluded that, generally, the risk of malaria at the study site was not correlated with ALRI incidence estimates in published studies. Severe anaemia may also result in fast breathing which may be classified incorrectly as ALRI but this has not been studied formally. The effect of (severe) malnutrition on the performance of fast breathing and lower chest wall indrawing as a predictor of ALRI and on ALRI incidence estimates45 also merits further study.
Clustering of ALRI
Some published studies suggest that the majority of episodes of ALRI may be clustered among a small (20%) group of children. The degree of clustering will be an important consideration to take into account when discussing the optimal approach to the analysis of these data. Further thought is required about how to handle data from children with multiple episodes since these are clearly not independent of each other. Incidence studies should report ALRI incidence with and without controlling for repeat episodes.6 A substantial proportion of children with recurrent ALRI in some settings may have wheeze and may be classified as asthma.46
Recall of ALRI signs and symptoms by informant type
There are few studies reporting data on the ability of informants to recall individual ARI signs or symptoms (which could help inform the definition of the optimal recall period for surveillance and thus the best frequency of home visits). Examination of this issue would require recording of the day on which the information was obtained and ideally the type of informant that provided the information about the child on each visit, as mentioned above.6 The reliability of future recall by the care-taker of ALRI symptoms and signs in the child could then be assessed in comparison with direct observations and reports on the day of examination.
Effects of the environment and climate
The effects of climate on ALRI incidence, such as altitude, average temperature, annual rainfall, and number and duration of wet and dry seasons have not been investigated in detail. Our recent review has identified annual rainfall as a significant independent determinant of ALRI variation across 28 published studies, possibly reflecting an effect on RSV or other respiratory virus activity.3
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Conclusion |
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There is therefore a need for further ALRI surveillance studies to be conducted to improve the global estimates and to explore the extent to which true national and regional variations exist. Since a large number of factors can affect ALRI incidence estimates in longitudinal community-based studies it is essential that study design measure these factors. Furthermore, in order to permit valid comparisons of ALRI incidence across studies it is important that a minimum dataset related to study setting, study methods, and statistical analysis is reported in all publications. In this paper, we attempt to identify and describe many of these factors and propose how these data should be reported. It would be helpful if international agencies who fund such studies make available on the Internet any essential data that were not accepted for inclusion in the publication but which might be of interest to the wider research and public health policy community. Finally, we highlight several issues that warrant further research to provide better understanding of determinants of ALRI incidence in developing country settings. Giving priority to this research agenda would result in improved understanding of published data and improved estimates of the global burden of disease from ALRI in young children in developing countries.
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Acknowledgments |
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References |
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