Clinical case review: A method to improve identification of true clinical and radiographic pneumonia in children meeting the World Health Organization definition for pneumonia

The World Health Organization (WHO) has developed standard case management guidelines to reduce the two million deaths, or 20 percent of all child deaths, caused by pneumonia through early diagnosis and treatment [1]. A meta-analysis showed that these guidelines, if effectively implemented, result in significant reduction in mortality: 24% (95% CI 14–33%) in total mortality and 36% (95% CI 20–48%) in pneumonia-related mortality in children aged 0 to 4 years in developing countries with infant mortality over 90 per 1,000 live births [2]. Many countries have now adapted these guidelines as part of national acute respiratory infections control and Integrated Management of Childhood Illnesses (IMCI) programs.

The WHO guidelines define pneumonia as an acute disease episode with cough or difficult breathing combined with fast breathing with age specific cut-off values for increased respiratory rate. Children with lower chest wall indrawing classified as severe pneumonia are referred for evaluation and possible in-patient care. While it is estimated that these criteria detect over 80 percent of children that require antibiotic treatment for probable bacterial pneumonia or hospital care for severe disease, 20 to 30 percent of children fulfilling the criteria receive unnecessary antimicrobials for non-severe viral respiratory infection [3]. This is especially true for children with expiratory wheezing due to asthma, bronchiolitis or other viral respiratory infections who are often misclassified as pneumonia requiring antimicrobial treatment and referred for in-patient care [4].

Another problem of the low specificity of the WHO definition for pneumonia is its use as study enrolment criteria or one of the study endpoints in disease burden and intervention studies. For example, studies evaluating the efficacy of new conjugated vaccines against Streptococcus pneumoniae show these vaccines are effective in reducing invasive pneumococcal disease and radiographic pneumonia, but the efficacy is low for the WHO-defined clinical pneumonia [5, 6].

We carried out a randomised, double-blinded, placebo-controlled study to evaluate the efficacy of an investigational 11-valent pneumococcal conjugate vaccine against childhood pneumonia in the Philippines. We used the WHO definition for pneumonia as entry criteria for clinical data collection from study subjects hospitalised and as a secondary endpoint for vaccine efficacy analysis. This report describes, without un-blinding the study randomisation code, results of a retrospective review of clinical, laboratory and radiological data from study subjects hospitalised with an illness that on admission fulfilled the WHO definition for pneumonia. Our aim was to describe the clinical methods used in our vaccine study and evaluate the use of WHO definition for clinical pneumonia in a South East Asian paediatric hospital setting. We attempted to improve the specificity of diagnosis of WHO defined clinical pneumonia by classifying the disease episodes into International Classification of Diseases, version 10 (ICD-10)-classification system categories for pneumonia which then could be used to analyse the vaccine efficacy. The results are discussed in light of possible different diagnostic approaches for respiratory infections, which could be utilised in pneumococcal or other vaccine and disease burden studies.

The planned cohort of 12,194 infants was enrolled the vaccine efficacy study by December 2003 (78% of the total birth cohort, 92% of the non-transient population eligible for the study). Overall, 98.7% of the enrolled subjects received 3 doses of study vaccine. The median age at vaccination was 1.8, 2.9 and 3.9 months for first, second and third dose, respectively. Vaccine and placebo groups did not differ in key baseline socio-economic indicators (data not shown). The data on all hospital admissions and other important medical events were collected until study termination visit at 23 months of age (N = 8,780) or end of study follow up at the end of December 2004 (N = 2,366). Altogether 64 children died and 984 children were lost to follow up due to migration or were withdrawn from the study for various reasons.

This analysis covers 1,195 disease episodes fulfilling the WHO criteria for pneumonia among 821 children (60% boys) who were hospitalised at the Bohol Regional Hospital. The age distribution is shown in Table 1 [see Additional file 1]. According to the WHO pneumonia severity classification algorithm, 290 episodes (24%) were non-severe pneumonia i.e. without chest indrawing or other danger signs, 785 (66%) were severe pneumonia presenting with chest indrawing and 120 (10%) were very severe pneumonia with either inability to drink or central cyanosis. A blood culture was obtained in 90% of episodes. We detected 13 (1.1% of episodes) invasive bacterial infections. The most common bacterial pathogens included Staphylococcus aureus, Streptococcus pneumoniae and Salmonella Typhi. Chest radiographs from 182 (15.2%) episodes showed abnormal findings which met the WHO criteria for probable bacterial pneumonia (Primary endpoint consolidation). The mean duration of hospitalisation was 3.2 days (Range 0 to 32 days). Altogether 19 patients died while in hospital or within 14 days from discharge (Case fatality rate 1.6%).

The distribution of key clinical, laboratory and radiology findings in each of the WHO pneumonia severity categories is shown in Table 1 [see Additional file 1]. In episodes of severe, but not very severe pneumonia, 51% of children presented with expiratory wheeze compared to 9.3% in the non-severe and 40.8% in the very severe pneumonia categories. Very severe pneumonia was associated with highest probability for abnormal radiograph and hypoxemia, as well as the highest case fatality rate: 9.2% compared to 0.3% in non-severe pneumonia and 0.5% in severe pneumonia categories.

The WHO classifications of severe and very severe pneumonia identified acute lower respiratory infection very well (95% and 85% respectively) whereas the non-severe pneumonia classification identified only 49% of subjects with ALRI. According to the retrospective review of clinical, laboratory and radiographic data, 402 episodes (33.6%) had radiographically confirmed pneumonia as the major cause of hospitalisation (Table 2) [see Additional file 1]. Bacteriologically confirmed bacterial pneumonia or probable bacterial pneumonia was the diagnosis in 8.6%, 11.5% and 15.9% of episodes in non-severe, severe and very severe WHO pneumonia categories, respectively. Viral lower respiratory infection i.e. viral pneumonia or bronchiolitis was most common in the severe pneumonia category: 37.5% compared to 14.5% and 25.9% in non-severe and very severe pneumonia categories, respectively.

A total of 203 episodes (17.0%) were evaluated as not having a lower respiratory infection as the main reason for hospitalisation. Non-respiratory diseases, of which acute gastroenteritis was the most common, accounted for 12.7% of hospitalisations. The other non-respiratory diagnoses included a broad range of paediatric diseases such as acute febrile infections with seizures, skin infections, urinary tract infections and 9 cases of central nervous system infections.

Episodes which fulfilled the WHO criteria for non-severe pneumonia had the highest likelihood for having a non-respiratory disease as the main diagnosis. However, in 15 of the 37 episodes of acute gasteroenteritis the child had also signs of lower respiratory infection (3 with radiographic abnormalities). In total, seven of the 290 (2.4%) of episodes were diagnosed as sepsis or meningitis. In the severe pneumonia group, other than lower respiratory infection diagnoses were rare. The 12 episodes of gasteroenteritis included one episode, in which the patient also had a diagnosis of viral pneumonia. The 11 other episodes presented with chest indrawing on admission, but this could have been due to dehydration or simultaneous lower respiratory infection which did not show any radiographic abnormalities. Only in two episodes, the final diagnosis was meningitis or sepsis without pneumonia. The other diagnoses in the very severe pneumonia group included five episodes of sepsis, four episodes of central nervous system infections and three episodes of acute gastroenteritis. One episode was classified as an upper respiratory infection.

In order to ensure the reproducibility of the review, 111 episodes (9.3%) were re-evaluated several months later by the same review team who were blinded to the results of the first review round. The team assigned the same ICD-10 coded diagnosis in 79 of the 111 episodes evaluated (71.2%). Additional 21 episodes (18%) had diagnosis in the same disease group, but the ICD-10 coding differed (e.g. J22 non-specified lower respiratory infection vs. J21.9 bronchiolitis). A total of 37 episodes were assigned a pneumonia group diagnosis in the first review compared to 44 in the second review (Kappa coefficient 0.79). According to both reviews 93 episodes had a diagnosis belonging to any of lower respiratory tract infection categories (Kappa 0.87).

Our study demonstrates that in this population of Filipino children the WHO definition of clinical pneumonia captures a broad spectrum of respiratory infections varying from mild upper respiratory infections to severe bacterial pneumonia. In total, one third of episodes showed radiographic evidence of pneumonia and one third of these (11.2% of the total) were classified by the group of paediatricians as definitive or probable bacterial pneumonia. The severity of the disease correlated well with the WHO pneumonia severity algorithm. The non-severe pneumonia group had a higher probability for upper respiratory and non-respiratory group diagnoses than the severe or very severe pneumonia groups which identified very well the lower respiratory and other severe infections.

The findings of this study are in conformity with other studies conducted in the Philippines [14, 15] and in other Asian countries [4] reporting a similar clinical picture in patients with a WHO-defined pneumonia. The case fatality rate of 0.5% observed in the severe pneumonia group was similar to that in a recent multi-centre study evaluating antimicrobial treatment alternatives for WHO-defined severe pneumonia [16], but lower than the 2.1% and 12% mortality described in Bohol, the Philippines during 1990's and in Lombok, Indonesia among children hospitalised for acute lower respiratory infection, respectively [17, 18]. This may reflect the different patterns in care seeking behaviour and access to care.

The microbial aetiology of respiratory infection is difficult to determine, as the sensitivity of tests, especially bacterial cultures, is low, and mixed bacterial and viral infections are common. The chest radiograph and non-specific laboratory markers such as C-reactive protein, procalcitonin and white blood cell count provide some guidance, but the results overlap significantly in viral and bacterial pneumonia [19, 20]. In this study the WHO classification of non-severe, severe and very severe pneumonia appeared to correlate with disease severity, but poorly with the probability of definitive or probable bacterial aetiology for infection. The distributions of C-reactive protein concentration and blood leukocyte count did not suggest major differences in proportions of episodes with bacterial aetiology in the different severity categories of pneumonia. Despite special attention to laboratory techniques the ratio of positive blood culture findings was low in all pneumonia severity categories. This may be partly explained by Hib vaccination provided to all study participants and pre-hospital antimicrobial treatment, which was, according to a parental questionnaire, 35% in our previous epidemiologic study conducted in Bohol during 1995–99 [9]. Nevertheless the overall ratio of invasive pneumococcal infections is far lower than those seen in studies in Africa [21]. In this study 15.2% of episodes showed a primary endpoint consolidation in chest radiograph. The frequency of chest radiograph findings increased with the pneumonia severity. The Gambian pneumococcal study, which used similar WHO criteria for case ascertainment, reported a primary endpoint radiographic finding in 18.1% of hospitalized children [5]. However, in the Gambian study, 4.2% of hospitalized patients had a blood culture or CSF positive for Streptococcus pneumonia compared to 0.3% in this study population.

Other studies have reported 65% to 90% specificity of the WHO pneumonia criteria for lower respiratory infection [3, 12, 13, 21]. In our study, the retrospective clinical review demonstrated that in 17% of episodes the child showed signs and symptoms of WHO-defined pneumonia, but the main condition prompting the decision to admit the patient for hospital care was not the acute lower respiratory infection. Largely this consists of patients with non-severe pneumonia, of which over half had another concomitant disease that was the main reason for hospitalisation. According to the WHO guidelines the children with non-severe pneumonia should not be referred for hospital care, but provided with oral antibiotics for acute respiratory infection. Among children with severe pneumonia presenting with chest indrawing, the frequency of concomitant disease prompting the decision for admission was low (< 5%). The episodes of very severe pneumonia included, in addition to lower respiratory infections, also other severe infections. This finding supports the current practise of including these patients to the IMCI guidelines category of severe disease needing urgent referral to hospital care.

We noted expiratory wheeze in half of episodes of WHO defined severe pneumonia. This finding emphasises the importance of including the management of wheeze to the current pneumonia management guidelines. It is not known whether all children with wheeze, presumable caused by a viral infection, require antimicrobial therapy and, if not, which additional clinical findings would support withholding antibiotics [3, 4]. The WHO currently recommends that children without previous history of wheeze who develop a lower respiratory infection with wheeze and tachypnoea may have a bacterial or mixed bacterial-viral infection, and should always be treated with antibiotics for suspected bacterial pneumonia [23]. The findings from the South African pneumococcal study, which reported 31% efficacy of the vaccine against pneumonia associated to respiratory viruses support this strategy [24]. The situation may, however, be different in many Asian countries where the incidences of wheezing diseases and paediatric asthma have increased and mortality attributable to severe respiratory infections has decreased [3, 25, 26].

A limitation of this study is the uncertainty of the role of the pneumococcal conjugate vaccine in modifying the clinical picture of respiratory infections. Other pneumococcal vaccine efficacy studies suggest that the vaccine may prevent 20–36% of radiographic pneumonia [5, 6]. It is thus possible that viral respiratory infections are enriched in this patient population. We assumed that in 5% of episodes where a chest radiograph was not obtained the clinical review diagnosis was not pneumonia. While probably missed some infiltrates we do not believe that the overall interpretation of the data would have changed significantly. The diagnostic procedures conducted in this study represent practices available in many hospitals in South East Asian countries. The results of this study are not, however, directly applicable to other health care settings, in which the clinical picture of WHO-defined clinical pneumonia may be different. The reproducibility of our clinical case review process was high in our own study settings, but it is difficult to know if this process, based primarily on clinicians' best judgement, could be repeated in similar manner elsewhere. Whether the classification according to probable aetiology of infection was successful can be evaluated once we analyse the vaccine efficacy in different ICD-10 categories of respiratory infections and complete the on-going testing of respiratory viruses from nasopharyngeal samples collected from hospitalized study children.

The WHO case management algorithm for pneumonia provides an important tool for managing respiratory infection in resource poor settings. It also provides a tool to compare the total burden of respiratory infections in different communities, but should not, without additional microbiological evidence, be used to compare the burden attributable to specific respiratory pathogens. This study suggests that the category of WHO-defined severe pneumonia is very specific for lower respiratory infections whereas the non-severe pneumonia category includes, at least in hospital settings, a large proportion of other diseases.

The WHO definition for clinical pneumonia captures a broad spectrum of different paediatric respiratory diseases. The WHO classification of non-severe, severe and very severe pneumonia correlated well with disease severity, but poorly with the probability of definitive or probable bacterial aetiology for infection. The category of severe pneumonia presenting with chest indrawing showed high specificity for lower respiratory infection, and could be used when comparing the burden of respiratory infections in resource poor countries.