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Original Articles Indian Pediatrics 2001; 38: 827-838 |
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Improving Antibiotic and Bronchodilator Prescription in Children Presenting With Difficult Breathing: Experience From an Urban Hospital in India |
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Acute respiratory infections (ARI) constitute one of the principal causes of morbidity and mortality in children less than five years of age in developing countries. It is estimated that 3.9 million children die annually from ARI, most of them in developing countries(1). The strategy for dealing with ARI, therefore, forms a critical component of the global child survival programs(2,3). The current World Health Organization (WHO) strategy for the control of mortality due to ARI relies heavily on standardized case management for preventing pneumonia deaths-(2-4). As most cases of fatal pneumonia are bacterial (S. pneumoniae or H. influenzae) in etiology(5), the central component of this approach is early diagnosis and antibiotic treat-ment of pneumonia by paramedical workers in the community, based on simple clinical signs. The WHO guidelines are also intended to rationalize referral and the use of antimicrobials so that children who may benefit receive them sooner and also there is less over prescribing of antibiotics to those who do not need them. The utility of these guidelines has been validated in several field trials in developing countries(6). Despite the proven benefit of this strategy, the need for improving these guidelines is increasingly becoming apparent. The major clinical guidelines for the diagnosis of pneumonia pertain to fast breathing and other features of respiratory distress like chest indrawing, central cyanosis or inability to drink. An identical clinical presentation may occur in several other potentially fatal condi-tions that necessitate different therapeutic modalities. These include acute exacerbation of asthma, congestive cardiac failure, metabolic acidosis and raised intracranial pressure. At the time of conception of these simple guidelines(2) in early 1980s, pneumonia could have been the predominant condition with this clinical presentation. However, it is possible that with the passage of time, the epidemiology of various conditions presenting with fast breathing and other features of respiratory distress may have considerably altered. Amongst the above mentioned other causes of rapid breathing, there is now enough data globally to prove that the prevalence and severity of asthma is increasing in all age groups(7-12). In this context, it is also important to appreciate that asthma related fatalities do occur and can be largely prevented by an accurate diagnosis and early institution of appropriate therapy including broncho-dilators(13,14). For logistic reasons, the WHO recom-mended case management(2,3) is structured towards treatment as pneumonia in preference to acute asthma. It is warned that wheezing can occur during pneumonia and therefore, care must be taken when treating wheezing not to miss treating pneumonia with an antibiotic(2). Further, the need for bronchodilator therapy is guided by the presence of a wheeze which for paramedical personnel pertains to only an estimated one-third(15) episodes in which the wheeze may be audible without the aid of a stethoscope. Thus, according to the current guidelines, in a child with cough and rapid breathing, there is a predilection for over-treatment for pneumonia with antibiotics and for under-treatment for asthma with broncho-dilators. There is thus an urgent need for refining the available algorithm for case management to reliably differentiate pneumonia from acute asthma. The present investigation was therefore designed to: (i) evaluate the relative frequency of other conditions that share a clinical overlap with pneumonia as defined by the WHO case management algorithm(2); and (ii) determine the possibility of refining the antibiotic and bronchodilator prescription in the WHO case management algorithm(2), especially on the basis of simple clinical features which can reliably diagnose acute asthma and differentiate it from pneumonia. Subjects and Methods Selection Criteria The study was conducted in a tertiary level hospital in New Delhi during the months of September to April, which include the local peak season for respiratory illnesses. Children in the age group of 6 months to 5 years were enrolled in this investigation. The lower limit of 6 months was used since a diagnosis of acute asthma below this age is uncommon. All subjects fulfilling the entry criteria on a fixed day of the week during the study period were recruited. The study was approved by the Institutional Committee. Informed verbal con-sent for participation was taken from the parents or relatives prior to recruitment in the trial. Subjects presenting to the Pediatric Emergency Services with an acute attack of less than 5 days duration of cough or difficult breathing (rapid breathing with or without chest indrawing) comprised the initial filter. Rapid breathing was defined as 50 breaths per minute or more in a child in the age group 6 months - 1 year and 40 breaths per minute or more in a child 1-5 years old(2). Subsequent exclusion criteria comprised either: (i) stridor, (ii) severe undernutrition (<50% weight for age), or (iii) no evidence of difficult breathing as per the WHO recommended algorithm for the management of pneumonia in the hospital(2). Clinical and Investigative Evaluation The detailed clinical evaluation of these subjects, undertaken by a single observer (SCM), was recorded on a pre-tested proforma. Special emphasis was given to symptoms like cough, fever, nasal discharge, tachypnea, chest indrawing, refusal of feeds, history of previous attacks and family history of allergic disorders and asthma. On physical examination, the following were specially looked for: (i) Toxic look (investigator’s impression); (ii) Tempera-ture: axillary temperature was recorded for 60 seconds; (iii) Pulse rate: counted by palpating radial pulse for 60 seconds; (iv) Respiratory rate: counted by observing the movement of chest and abdomen for 60 seconds in an awake but quiet child; (v) Chest indrawing: by observing the inward movement of the bony structure of the lower chest wall with respiration when the child was at rest for 60 seconds; (vi) Nasal discharge: if present was classified into watery, mucopurulent or purulent; (vii) Chest examina-tion: especially percussion, breath sounds and added sounds like crepitations and wheeze. For wheeze, it was also ascertained prior to aus-cultation whether the sound was audible without the stethoscope; (viii) Abdomen: liver and spleen size were noted; and (ix) Other systemic examination was also conducted. Investigations performed in all subjects included chest roent-genogram and peripheral blood smear differ-ential leukocyte count with special attention to band forms. Other investigations were based on clinical presentation including hemoglobin, lumbar puncture, CT scan, acid base status, electrocardiogram, echocardiography, etc. Treatment Treatment was instituted on the basis of clinical features and investigations. This included bronchodilators (aerosolized beta-2 agonist, oral or parenteral beta-2 agonist, theo-phyllines - oral or parenteral) and/or steroids for patients with acute exacerbation of asthma and antibiotics for patients with pneumonia (refer to later text for definitions). A combination of both was instituted if the two conditions co-existed. In conformity with the treating Unit’s routine policy, bronchodilators were also administered for bronchiolitis. Other supportive measures included intravenous fluid and oxygenation, if required. Specific treatment for other conditions was instituted according to the diagnosis and included decongestive therapy, blood trans-fusion, etc. Depending upon the response to initial therapy, the subjects were either admitted or kept under observation. The children were kept under observation until the breathing difficulty had subsided (rapid normalization of respiratory rate as per WHO algorithm(2) and simultaneous marked resolution of bronchospasm, if present). The observation period usually ranged from 4 to 16 hours. These subjects were instructed to come for follow up immediately in case of a recurrence or within one week. Diagnostic Definitions No universally acceptable criteria are available to objectively define either pneumonia or acute asthma(16). Pneumonia is known to occur without cough, respiratory distress or obvious radiological abnormalities while conversely infiltrative changes in the X-ray are possible even in bronchiolitis or asthma(16). Since the WHO guidelines are intended to rationalize case management in a simplified manner for paramedical personnel, the diag-nostic capabilities of trained Pediatricians with access to investigative facilities could reason-ably be considered as the "gold standard" for this purpose. In this context, the following operational definitions of pneumonia and acute asthma were resorted to. A diagnosis of only pneumonia was made if there was pulmonary infiltration on x-ray with or without associated crepitations and/or signs of consolidation on auscultation. Pneumonia was further categorized as bronchopneumonia on the basis of clinical profile and radiology. The patient was diagnosed to have only acute asthma if there was (i) wheeze; (ii) absence of pulmonary infiltration on X-ray; (iii) absence of polymorphonuclear leukocytosis or bandemia on peripheral smear. A poly-morphic response was defined as >70% poly-morphonuclear leukocytes(17) and bandemia as >10% band cells(18) on a peripheral smear; and (iv) rapid clinical improvement (difficult breathing and wheeze) on bronchodilator therapy without antibiotics. Wherever required, the response to bronchodilator therapy was assessed before considering institution of antibiotics. The WHO defines recurrent wheeze at any age as asthma(19) without specifying the number of attacks. This definition was also adhered to provided the conditions (i) to (iv) outlined above were satisfied. The first attack of wheeze after 1 year of age fulfilling the above four criteria was labeled as possible asthma. A co-existence of these two entities (acute asthma and pneumonia) was defined if there was an overlap in the two definitions outlined earlier. The terminology pneumonia with spasm or bronchopneumonia with spasm was used in such cases. These subjects, in addition to pulmonary infiltrates on X-ray or polymorpho-nuclear response/bandemia on peripheral smear also had wheeze that responded to broncho-dilator therapy. This operational definition was utilized since it indicated the need for both antibiotic and bronchodilator therapy. According to the WHO guidelines, the first attack of wheeze in the first year of life is regarded as bronchiolitis(19). This definition of bronchiolitis was utilized irrespective of radio-logical findings if the peripheral smear failed to reveal a polymorphonuclear response or bandemia. Other diagnoses were made on the basis of clinical presentation and investigations. Additional Radiological Evaluation After completion of the study, an additional independent evaluation of the chest X-rays was done by a radiologist (AG) who was unaware of the clinical diagnoses and therapy instituted. A diagnosis based on the definitions enumerated above in which the clinician’s interpretation of chest X-ray had been substituted with the radiologist’s assessment was referred to as radiologist aided diagnosis. Sample Size The prime aim for the purpose of sample size calculation was the possibility of refining the WHO algorithm for case management, particularly in relation to bronchodilator under-use. Guesstimates from earlier experience(15) had indicated that bronchodilator under-utiliza-tion with WHO algorithm may be about 35%. The estimated sample size (EpiInfo Version 6 - unmatched cohort and cross sectional studies) to reliably comment upon an improvement of 15% (from a baseline of 35%) with 95% confidence level and 90% power was 197 subjects eva-luated by two alternative algorithms. Similar calculations for evaluating a relative risk of 3 (from a baseline of 35%) for a pair matched case control study(20) yielded a sample size of 199 subjects. The study, therefore, was conducted on 200 children. Statistical Analysis Algorithm differences (and 95% confidence intervals) for appropriateness of antibiotic and bronchodilator prescription in comparison to "gold standard" were computed by paired proportion test with exact two sided p value by Arcus Quickstat software(21,22). Results Of the 200 recruited subjects, 129 (65%) were boys and 71 (35%) girls. Their age distribution was as follows: 6 mo to 11 mo - 45 (22.5%), 12 mo to 23 mo - 52 (26%) and >24 mo - 103 (51.5%). The subjects could not be recruited on three pre-decided days due to unavoidable circumstances. In two children, chest radiographs could not be performed as these subjects expired within a short time of hospitalization. In them, the etiologic diagnosis was made clinically without the aid of radiology. The relative frequency of the etiologic diagnoses, both clinicians and radiologist aided, are depicted in Table I. It is evident that asthma (acute and possible) was the predominant diagnosis (46% or 54%). Since bronchospasm also coexisted with pneumonia, the need for bronchodilator therapy (excluding bronchiolitis) was defined in almost two thirds of the cases (68% or 69%, respectively). A sole diagnosis of pneumonia was made in <10% of the cases. Pneumonia in association with other conditions, namely, spasm and congestive cardiac failure, was documented more frequently. Thus, pneu-monia alone or in association with other conditions was seen in 35% (clinicians diag-nosis) or 27% (radiologist aided diagnosis) cases. Surprisingly, diagnoses other than those in relation to the respiratory system were documented in a substantial proportion of subjects (18% or 17%). In this group, acidosis with gastroenteritis and increased intracranial pressure were the two important categories. All the children in whom a history of preceding cough was not elicited had non-respiratory illnesses, namely, acidosis with gastroenteritis or increased intracranial pressure or drowning (20 subjects for clinicians diagnosis and 18 cases for radiologist aided diagnosis). Thus, the inclusion of cough as a mandatory criteria in the entry point of the current algorithm (cough and difficult breathing instead of cough or difficult breathing) would exclude 71% (20/28) of subjects with nonrespiratory illnesses while missing none with a respiratory condition. An audible wheeze was appreciated in only 44 of the 150 cases (29.3%) with an auscultable wheeze. Amongst the clinical criteria evaluated, a history of previous similar attack of cough and difficult breathing had the best predictive value for the diagnosis of auscultable wheeze (sensitivity - 77%, specificity - 80%). An important objective of the study was to explore the possibility of refining the antibiotic and bronchodilator prescription in the WHO case management algorithm(2) on the basis of simple clinical features which can reliably diagnose acute asthma and differentiate it from pneumonia. However, we encountered several other diagnoses apart from pneumonia and acute asthma including a co-existence of both conditions in a substantial proportion of subjects. It was, therefore decided to identify reliable predictors (sensitivity >70% and specificity >70%) of antibiotic and bronchodilator pres-cription irrespective of the exact diagnostic category. Subsequently, various modifications of the WHO case management algorithm(2) were attempted with incorporation of these potential predictors, either singly or in combina-tion. Finally, two viable modifications emerged which are depicted in Figs.1 and 2. TABLE I – Relative Frequency of Etiologic Diagnosis.
* Includes two cases in whom chest radiology could not be performed. The relative utility of these two alternative algorithms in comparison to the existing WHO case management algorithm is depicted in Table II. The following assumptions were made while deriving these comparative figures: (i) For the WHO case management algorithm, antibiotic or bronchodilator usage was identified as appro-priate or otherwise irrespective of the fact that the illness was respiratory or not; and (ii) For the alternative algorithms, a correct identification as a "non respiratory" illness (n = 20 and n = 18 for clinical and radiologist aided diagnoses, respectively) was considered to be appropriate antibiotic and bronchodilator usage. Amongst the remaining cases, like the WHO case man-agement algorithm, antibiotic or bronchodilator usage was identified as appropriate or otherwise irrespective of the fact that the illness was respiratory or not. The two alternatives represent a significant improvement over the WHO algorithm (Table II) preventing inappropriate usage of both antibiotics and bronchodilators, primarily by restricting over-prescription of the former (14% and 26.5% for proposed algorithms 1 and 2, respectively) and under-utilization of the latter (40%). The performance of the alternative algorithms for the radiologist-aided diagnosis was marginally better for over-prescription of antibiotics (16.2% and 30.9% for proposed algorithms 1 and 2, respectively). The penalty evaluated as under-prescription of antibiotics (2% and 0.5% for clinicians and radiologist aided diagnosis, respectively) and over-utilization of bronchodilator (5%) was relatively negligible. Of the two proposed alternatives, algorithm 2 was significantly better for restrict-ing over-prescription of antibiotics [p = 0.0001; OR - 1.72 (95% CI - 1.12, 2.66)] while both were equally effective for preventing under-utilization of bronchodilators. Thus amongst the three evaluated algorithms, proposed alternative 2 had the best performance. Of the 126 cases hospitalized (63%), 5 expired (intracranial pathology in 3, severe anemia with congestive cardiac failure with pneumonia in 1 and pneumonia in 1). Five subjects left the hospital after significant improvement but before complete recovery (1 child was referred to another institution for removal of foreign body, and 3 cases with acute asthma and 1 subject with severe anemia with congestive cardiac failure with pneumonia went home on treatment due to social reasons). Of the 74 subjects (37%) sent home after the initial period of observation, 44 reporting for follow-up had completely recovered. Thus, follow-up information was available in 170 (85%) cases.
Fig 1. Proposed Algorithm 1
Fig. 2. Proposed Algorithm 2.0 Discussion The results of this urban tertiary care center based study suggest that amongst 6 months to 5 year old children presenting with difficult breathing, acute asthma is the predominant condition (46% or 54%), pneumonia alone is rare (10%), co-existence of pneumonia with wheeze (bronchospasm) is more frequent (22% or 15%) and often diagnoses not related to the respiratory system are documented (18% or 17%). It is feasible to amalgamate simple clinical features (history of: (i) previous similar episode of cough and difficult breathing, and (ii) fever) in the HO case management algorithm(2) to significantly refine the antibiotic (95% CI range 7% to 33%) and bronchodilator (35%; 95% CI 27% to 43%) prescription. It would be prudent to examine the potential biases and limitations which could influence the extrapolation of results: (i) Recruitment age: The study was deliberately conducted in children above 6 months old since a diagnosis of acute asthma below this age is rare and an important objective of the investigation was to determine the possibility of refining the antibiotic and bronchodilator prescription in the WHO case management algorithm(2), especially on the basis of simple clinical features which can reliably diagnose acute asthma and differentiate it from pneumonia(15). This would have resulted in an over-representation of acute asthma. (ii) Recruitment site: The possibility that children with relatively milder recruitment criteria (difficult breathing) were sent away directly from the outpatient services is unlikely, since as a routine and especially during the period of the study, the staff had instructions to refer all children with difficult breathing to the Emergency Room for appropriate management decision by the Senior Resident. Emergency room setting of an urban tertiary hospital in a polluted city is certainly not representative of the community scenario and probably not representative of a similar site in a less polluted city of India or other developing countries. Children brought to the Emergency Room are sicker and in this study too, 63% of the subjects had to be hospitalized. There is some evidence that children with acute asthma develop severer and faster respiratory distress than pneu-monia(15) and also the prevalence of asthma in an urban setting is higher than rural regions. A site bias for recruitment of acute asthma is therefore possible. (iii) Season: The requisite sample size was achieved before completion of a full calendar year but the peak period for respiratory illnesses was included. However, the period excluded the peak diarrheal season, which could have led to an under-representation of this condition. (iv) Investigator: The possibility that the data collector (SCM) may have been biased towards recruiting acute asthma requiring bronchodilator therapy is not corroborated by the radiologist aided diagnosis in which pneumonia in combination with spasm was lower and acute asthma was higher. A paramedical person is expected to have lower skills than a pediatric resident for recognizing audible wheeze and eliciting relevant history. (v) Appropriateness of "gold standard": Bacteriological and virological isolations were not a part of the protocol and all pneumonias were considered to be bacterial in origin as is the case with the WHO algorithm(2). In the absence of any uniform definitions for asthma and pneumonia, the diagnostic and prescriptive capabilities of trained Pediatricians with access to other investigative facilities could reasonably be considered as the "gold standard" for the study objectives. Presence of auscultable wheeze was considered to be indicative of bron-chospasm and the need for prescribing broncho-dilators. However, the use of bronchodilators in bronchiolitis is controversial. A recent meta-analysis on this subject concluded that bron-chodilators do produce modest short term improvement in clinical scores but cautioned against their routine use(23). Clinical response to therapy in bronchospasm associated with pneumonia justified bronchodilator prescription. However, the quantum of benefit in subjects with viral pneumonia associated wheeze is debatable. (vi) Follow-up information: This was available in 85% of the subjects and an analysis restricted to those with complete follow-up information yielded similar results. From the aforementioned appraisal, it is apparent that the current study design has the potential bias for minor over-representation of asthma or wheez-ing illness and over-prescription of broncho-dilators.
This study offers the possibility of refining the current algorithm by incorporating simple features that have the potential for application by para-medical personnel. The proposed modi-fications do not lead to major restructuring of the earlier algorithm. Amongst the two proposed algorithms, there is no difference in appro-priateness of bronchodilator usage whereas the antibiotic prescription is better in algorithm 2. However, algorithm 2 leads to 8% (95% CI 4% to 13%) under-use of antibiotics, which are actually required. In view of the risk of mortality due to this antibiotic under-use, algorithm 2 may be difficult to implement. This possibility is considerably reduced in algorithm 1 (clinician’s diagnosis: 2%, 95% CI -0.2 to 5% and radio-logist-aided diagnosis: 0.5%, 95% CI -1.4 to 2.8%), making it an attractive option. Our study indicates the need for initiating multi-centric trials in diverse settings to confirm or refute the findings. A confirmation has practical implications for refining the current case management of a child presenting with difficult breathing. Improved bronchodilator prescription can reduce the morbidity and possibly mortality in children with acute asthma(13,14). In this context, the feasibility of simplified delivery of aerosolized broncho-dilator therapy through a metered dose inhaler and spacer (holding chamber) merits explora-tion(24). Preventing over-use of antibiotics has obvious economic advantages and may also restrict emergence of antibiotic resistant strains of bacteria. Over the years an increasing trend of resistance to the commonly used antibiotics for the treatment of pneumonia has been shown(25-27), which can be partly ascribed to inappro-priate use of antibiotics(28-30). Contributors: HPSS designed the study, analyzed and interpreted the data, and drafted the manuscript; he will act as the guarantor for the manuscript. SCM collected the data and helped in analysis and drafting. AG interpreted the radiological findings and helped in analysis. Funding: None. Competing interests: None declared.
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