Date Published: April 22, 2008
Publisher: Public Library of Science
Author(s): J. Anthony G Scott, Mike English
Abstract: The authors look to the future and imagine the implications of a successful vaccination campaign againstH. influenzae type b and pneumococcus.
Partial Text: Pneumonia is the single commonest cause of death in children under five years old, accounting for 2 million out of 10 million childhood deaths worldwide . Severe pneumonia is an important diagnostic syndrome within the World Health Organization (WHO)/UNICEF system for triage and clinical management in developing countries, the Integrated Management of Childhood Illness (IMCI). The objective of IMCI is early recognition of disease and timely access to effective therapy; for severe pneumonia, this means referral to hospital and treatment with lifesaving antibiotics directed against the principal etiological agents, Streptococcus pneumoniae and Haemophilus influenzae type b (Hib) .
The World Health Organization pneumonia classification system was designed to be used at first point of contact, where a few reproducible signs could be elicited by health workers with only basic training. Bacteria account for the majority of fatal cases of pneumonia and, as treatment with antibiotics may be lifesaving and the adverse consequences of overtreatment are not significant, the case definition emphasizes sensitivity over specificity. Thus, pneumonia is diagnosed simply by counting breaths per minute with different rate thresholds at different ages in children with a history of cough or difficulty breathing. Severe pneumonia is classified by the presence of lower chest wall indrawing and very severe pneumonia by signs of hypoxia or mental changes .
The WHO case management strategy, formulated in 1991, is rational and evidence-based . A review of all etiology studies in developing countries using blood and lung aspirate cultures concluded that 55% of cases of hospitalized pneumonia were caused by bacteria, and approximately 70% of these cases were attributable to just two organisms, S. pneumoniae and H. influenzae type b . Given the insensitivity of culture techniques , it is reasonable to assume that more than half of all cases are attributable to just two agents, and empiric treatment guidelines were designed to target these pathogens specifically. WHO supported a series of community-based controlled trials of this case management strategy, and in a meta-analysis of seven of these trials the estimated reduction in pneumonia mortality attributable to the intervention was 24% . As WHO extended its empiric management guidelines to all the major syndromes of childhood, the pneumonia case management strategy became formalized within IMCI . The two pathogens upon which the strategy is founded are precisely those whose decline we now anticipate.
Beyond Hib and pneumococcus, the limited evidence we have from children 2–59 months old suggests that the remaining pathogens are more equally distributed [17–23]. These include the bacteria Staphylococcus aureus, Moraxella catarrhalis, viridans group streptococci, Klebsiella pneumoniae, Escherichia coli, Acinetobacter species, non-typhi Salmonellae, Bordetella pertussis, non-typeable H. influenzae, and Mycobacterium tuberculosis; the viruses RSV (respiratory syncytial virus), influenza A, influenza B, parainfluenza, adenovirus, human metapneumovirus, and rhinovirus; and the atypical organisms Mycoplasma pneumoniae, Chlamydia pneumoniae, and Chlamydia trachomatis. Pneumocystis jiroveci pneumonia (PCP) occurs primarily in immunosuppressed infants and children [23–25]. With a broad and even diversity of pathogens, the old strategy for empiric therapy of “picking the winners” may not have a significant clinical impact.
The sensitive WHO clinical definitions of pneumonia encompass a wide variety of lung diseases, not all of which have the typical lung consolidation of pneumonia. Furthermore, etiology studies tend to overemphasize infectious causes of respiratory disease, and it is not until the lung is examined at postmortem that the full breadth of noninfectious causes becomes apparent. Among 84 HIV-negative children who died of respiratory disease in Zambia, half had acute pyogenic pneumonia at necropsy and 7% had PCP, while 18% had interstitial pneumonitis and 11% had pulmonary edema . Anemia, malaria, congenital heart disease, acute interstitial pneumonitis, eosinophilic pneumonia (secondary to helminthiasis or schistosomiasis), and poisoning, especially with kerosene , may all present with difficulty breathing or cough and a raised respiratory rate.
Among children with HIV infection, tuberculosis is a common cause of respiratory disease. For example, among 242 children admitted to hospital in Durban with WHO-defined severe pneumonia, 38 (16%) had culture-proven tuberculosis and 85% of these had a history of illness lasting less than two weeks . In the necropsy study in Zambia, tuberculosis was diagnosed in 32 (18%) of 180 HIV-infected children dying with respiratory disease . In both these studies the prevalence of tuberculosis was equally high in HIV-uninfected children. If half of all present cases of severe pneumonia were prevented by antibacterial vaccines, tuberculosis would account for one third of future pneumonia cases in areas like these with a high prevalence of HIV. The insensitivity of diagnostic tests makes it difficult to estimate the role and prominence of M. tuberculosis in childhood pneumonia, and a “trial of treatment” in patients who are unresponsive to penicillin or chloramphenicol is a blunt diagnostic tool with significant toxic potential.
The decline of pneumococcus and Hib will raise two therapeutic problems. Firstly, if an antibiotic is required at all it will have to cover a significant proportion of the bacteria listed above in section 3, which, in practice, suggests a third-generation cephalosporin, a macrolide, or a quinolone. These drug classes are substantially more expensive than the present developing world pharmacopoeia of benzyl penicillin, amoxicillin, gentamicin, and chloramphenicol. Although newer drugs are widely available in Asia, their cost is likely to create inequities in health care on a local scale and also between continents as they are less accessible in Africa. Furthermore, the potentially massive scale of their use in childhood pneumonia may lead to widespread antibiotic resistance, compromising the treatment of other important infectious diseases such as typhoid, bacterial meningitis, nosocomial infections, and tuberculosis.
In the past, microbiological studies have rarely defined the etiology of more than two-thirds of all cases of pneumonia [17–20,22]. It is assumed that the undiagnosed fraction has roughly the same distribution of causes as the diagnosed fraction and that the division is accounted for by the poor sensitivity of the diagnostic assays used, such as blood cultures and complement fixation tests. Molecular diagnostics, using multiplex PCR assays, MassTag PCR, and microarrays, will provide a wealth of data to re-evaluate this undiagnosed group [31–33]. However, existing studies, using traditional insensitive techniques, have frequently found evidence of two or more pathogenic agents within the same patient with pneumonia [17,23]. Highly sensitive molecular techniques are likely to lead to an explosion of “multiple etiologies.” Although the interaction between different agents in pneumonia pathogenesis is an interesting and convincing biological phenomenon, the likelihood is that the majority of agents identified in these patients will be either false laboratory positives or, more likely, false etiological positives—meaning that they are truly present but not involved critically in the development of disease. This tends to occur especially when the material under assay comes from the upper respiratory tract.
Inevitably, without one or two dominant causes common to all types of patients, we will use the matrix of etiologies against patient and geographical risk factors to focus treatments to best effect. The single convenient and globally applicable treatment algorithm for “pneumonia” will be replaced by a complex branched algorithm. The full matrix will only become apparent through further etiological studies, but some divisions are well established, and WHO has already differentiated its guidelines on treatment of HIV-positive and malnourished children. Pneumonia is more likely to be bacterial in young infants than it is in older children, and the causative bacteria are different; “adult” pneumococcal serotypes, which are not covered by present vaccines, group A streptococcus, group B streptococcus, and E. coli all occur with relatively greater frequency in the first two months of life [34–36]. Gram-negative bacteria are considerably more common among malnourished children than well-nourished children . PCP, salmonellosis, and lymphoid interstitial pneumonitis are all more frequent among children with HIV . In all children, contact with a case of tuberculosis may be a risk factor well worth determining. Nosocomial infections represent a large potential risk that has been little studied in developing world settings. Geography too may play a significant part in the distribution of likely causes, separating for example Asia from Africa but also differentiating at country level. The prior probabilities of several etiologies, such as RSV, also vary considerably with season .
One solution to the changing epidemiology of pneumonia is the development of a new bedside diagnostic test using modern molecular technology. However, given the scenario envisaged above, the point-of-care diagnostics that will be most useful in the specific management of pneumonia will be an HIV test with CD4 lymphocyte count, a generic marker of invasive bacterial disease, and a sensitive and rapid test for tuberculosis. Indications for supportive therapy are unlikely to change in the post-vaccine era and will rely heavily on the availability of oximetry to guide oxygen therapy. Radiographic classification of respiratory disease has evolved little in the developing world, though many district hospitals that lack relatively basic tools are equipped with X-ray machines. There may be considerable additional gains in extending the WHO radiological classification of pneumonia to define simple reproducible signs for lung disease caused by other etiologies.
It may seem rash even to contemplate the decline of S. pneumoniae, which has evolved as a varied, adaptable, and enduring human parasite. However, the operational success of PCV immunization in America does prompt this very consideration. If the initiative of the GAVI Alliance to introduce effective vaccines against Hib and pneumococcus throughout the developing world succeeds in reducing these diseases significantly, our present approach to the management of pneumonia will abruptly become irrelevant.