Trial in Childhood Pneumonia With Malnutrition
Trial in Childhood Pneumonia With Malnutrition
The impetus for this study came from the findings of the investigators' recently published
 study entitled "Day-care management of severe and very severe pneumonia, without associated
 co-morbidities such as severe malnutrition, in an urban health clinic in Dhaka, Bangladesh".
 If day-care management is found to have comparable efficacy to that of hospital management of
 severe and very severe pneumonia in children then they could be managed at outpatient,
 day-care set ups reducing hospitalization and thus freeing beds for management of other
 children who need hospital care. Such management could also be implemented in rural areas of
 Bangladesh and potentially to other developing countries. Additionally, availability of the
 treatment facility in community set-ups will be cost and time saving for the population. But,
 as patients with severe malnutrition were excluded from the pilot study for ethical reasons,
 the peer reviewers of the manuscript felt that the study findings cannot be applied to the
 treatment of severe and very severe pneumonia in general. Similarly, management of severely
 malnourished children with associated complications relies on hospital-based treatment. In
 another study, a day-care clinic approach by providing antibiotics, micronutrients, diet and
 supportive care to severely malnourished children showed that they could be successfully
 managed at existing day-care clinics using a protocolized approach. Therefore, after the
 successful conduction and publication of these two study results in international journals
 with severe and very severe pneumonia as well as severe malnutrition at the day-care clinic,
 it is mandatory to perform the final study where the investigators will include severe
 malnutrition as well as associated co-morbidities to be applied to the treatment of severe
 and severe pneumonia in children in general to make the treatment approach more widely
 applicable.
Acute lower respiratory infections particulary pneumonia, are the leading cause of childhood
 morbidity and death in the developing countries such as Bangladesh [3]. Acute respiratory
 tract infection causes more than 2 million child deaths worldwide each year, mostly from
 pneumonia and 90% of them occur in less-developed countries [4-6]. Recent estimates suggest
 that 1.9 million (95% CI 1.6 million to 2.2 million) children died from acute respiratory
 tract infection throughout the world in 2000, and 70% of them occurred in Africa and
 Southeast Asia [7]. ARI is also a major cause of visits to the outpatient and emergency
 departments as well as admissions to the hospitals. Although bronchiolitis, tracheobronchitis
 and pneumonia, each accounts for about one-third of ALRI cases, pneumonia is responsible for
 most ALRI deaths. Three studies that reported diagnoses in children who died of ALRI revealed
 that a median of 89% (range 71% to 100%) of ALRI deaths was associated with pneumonia [8-10].
 In Bangladesh, acute lower respiratory tract infections account for 25% of deaths in the
 under-5 age group and 40% of all infantile deaths [11]. A study conducted at the Dhaka
 Hospital of ICDDR,B in 1986-88 in 401 under-5 children with ALRI has documented that
 pneumonia was most common among them and a respiratory pathogen (both bacterial and viral)
 was identified in 30% cases. The case fatality rates were 14% in bacterial pneumonia and 3%
 in viral pneumonia [12]. Bacterial infections play a major role in childhood pneumonia in
 developing countries. Pooled data from lung aspiration studies, mostly from developing
 countries, reported bacterial isolation rates of 52-62% [13, 14]. The case-fatality rate in
 severe ALRI in children aged 1-4 years was reported to be 10-15 times higher in the
 developing than in the developed countries [15, 16]. It is usually not possible to determine
 the specific cause of pneumonia by either clinical or chest X-ray features. In children,
 Streptococcus pneumoniae and Haemophilus influenzae are the two most important bacterial
 pathogens [17, 18]. Respiratory Syncytial Virus (RSV) is also an important cause of ARI among
 preschool children [12, 18]. Emerging evidence suggests that Mycoplasma pneumoniae and
 Chlamydia pneumoniae may cause pneumonia among older children. Available data also suggests
 that mixed viral and bacterial infections are common in children in developing countries
 [12], which require antimicrobial therapy. The WHO recommendations for treatment of pneumonia
 are based on data that Streptococcus pneumoniae and Haemophilus influenzae are the most
 common causes of bacterial pneumonia in developing countries [9].

 Depending on clinical presentation, pneumonia can be classified as very severe, severe or
 non-severe, with specific treatment guidelines available for each [8, 16, 19, 20]. The WHO
 defines very severe pneumonia as clinical symptoms and signs of pneumonia (cough or
 difficulty breathing with one or more danger signs like cyanosis, convulsions, drowsiness,
 stridor in calm child or inability to drink, all signifying hypoxaemia or severe respiratory
 distress) and severe clinical malnutrition [8, 16, 19, 20]. Severe pneumonia is defined as
 cough or difficulty breathing with lower chest wall in drawing with or without fast breathing
 defined as the respiratory rate ³ 50 breaths per minute for children aged 2-11 months and ³
 40 breaths per minute for children aged 12-59 months [8, 16, 19, 20]. Lower chest wall in
 drawing is defined as inward movement of the bony structures of the lower chest wall with
 inspiration, observed while the child is at rest [21]. Finally, non-severe pneumonia is
 defined as cough or difficulty breathing with fast breathing as defined earlier [8, 16, 19,
 20]. Antibiotic therapy is indicated irrespective of the severity of pneumonia. Proper
 management of children presenting in health centres and hospitals with respiratory symptoms
 is the cornerstone of acute respiratory infection control. To address the high mortality
 associated with ALRI, WHO launched a programme for control of ARI with the major objective to
 reduce the child mortality and to promote rational use of antibiotic. Current standard ARI
 case management recommends ambulatory treatment of children with cough and normal breathing
 without antibiotics assuming viral infection or mild bacterial infections; treatment of those
 with rapid respiration (tachypnoea) indicating lower respiratory infection or pneumonia with
 an antibiotic (non-severe pneumonia); and hospitalisation of those with lower chest wall in
 drawing (indicative of severe pneumonia) and treatment with parenteral antibiotics and
 supportive cares [22, 23]. Vaccination against measles, pertussis, Haemophilus influenzae
 type b (Hib) and Streptococcus pneumoniae can help decrease the incidence and/or lessen the
 severity of respiratory infections. However, newer vaccines against respiratory infections
 such as Hib and pneumococcal conjugate vaccines are not widely available in developing
 countries. Under-5 children with respiratory symptoms are brought to the general
 practitioners as well as to primary health care facilities for treatment and health care
 providers are required to differentiate between acute upper respiratory infections (AURI) and
 acute lower respiratory infections (ALRI)/pneumonia, categorize severity of pneumonia taking
 into consideration the nutritional status of the patients, and provide either ambulatory
 therapy or refer patients for hospitalization, as appropriate.

 Management of severe and very severe pneumonia in children relies on hospital-based
 treatment, but practical barriers often prevent children in areas with highest rates from
 receiving hospital care. It is recommended that children with severe or very severe pneumonia
 be hospitalised [8, 16, 19, 20] for supportive treatment, including suction, oxygen therapy
 for hypoxemia, fluid and nutritional management, and close monitoring [8, 16, 19, 20]. In
 Bangladesh, there are not enough hospital beds for admission of all severe and very severe
 cases of pneumonia. In addition, hospitalization may not be possible because of the inability
 of parents to visit the hospital. Reliable demographic information on this issue is not
 available in most hospitals in Bangladesh due to poor record keeping system. However, we have
 reviewed data for a 2-month period (May and June 2007) from the Institute of Child Health and
 Shishu Sasthya Foundation Hospital (ICHSH), Mirpur, Dhaka, and observed that only 52/120
 (43%) children with severe and very severe pneumonia were admitted into the hospital, and the
 majority (57%) could not be admitted due to the lack of beds and most of them were sent home
 after some supportive therapy and parenteral antibiotics from the outpatient department of
 the hospital. It is therefore important to provide institutional care for children who cannot
 be hospitalised. A prospective observational study was conducted to examine the feasibility
 of day-care-facility-based, modified primary care as an alternative for children denied
 hospital admission who would otherwise be sent home. We developed and prospectively evaluated
 a day-care clinic approach of management by providing antibiotics, feeding and supportive
 care during stay at the clinic, and continuation of care at home by parents as an effective
 alternative to hospitalization for such children. We have recently published the study
 results as "Day-care management of severe and very severe pneumonia, without associated
 co-morbidities such as severe malnutrition, in an urban health clinic in Dhaka, Bangladesh
 [1]". From June 2003 to May 2005, 251 children with severe and very severe pneumonia were
 enrolled at the Radda Clinic. The mean±SD age of the children was 7 ±7 months, and 143/251
 (57%) of them were hypoxemic with mean ± SD oxygen saturation of 93 ± 4% that increased to 98
 ± 3% on oxygen therapy. The mean ± SD day-care period was 7 ± 2 days. Day-care management of
 severe and very severe pneumonia was assessed successful in 234/251 [93% (95% CI, 89-96%)]
 children, and the management was assessed to have failed in the remaining 17/251 [7% (95% CI,
 4.3-10.6%)] children of whom 11/251 [4.4% (95% CI, 2.5-7.7%)] had to be referred to hospital
 and 6/251 [2.4% (95% CI 1.1-5.1%)] discontinued treatment. There were no deaths during the
 day-care study period; however, 4/251 [1.6% (95% CI 0.6%-4%)] children died during the
 3-month follow-up period, and another 11/251 [4.4% (95% CI, 2.5-7.7%)] required hospital
 admission during the 3-months' follow-up period. The results of the study indicate that
 children with severe and very severe pneumonia without associated co-morbidities such as
 severe malnutrition can be successfully managed at day-care clinics [1]. If the day-care
 management is found to have comparable efficacy to that of hospitalized management of severe
 and very severe pneumonia in children then they could be managed at day-care set ups on an
 outpatient basis, reducing hospitalization and thus freeing up of beds for management of
 other children with greater need for hospital care. Additionally, availability of the
 treatment facility in community set-ups will be both time-and cost-savings for the
 population. But, as patients with severe malnutrition were excluded from the pilot study for
 ethical reasons, the peer journal reviewers [1] correctly commented that the study findings
 cannot be generalised and applied to the treatment of severe and very severe pneumonia.

 Similarly, the case-fatality from severe malnutrition has been as high as 60% in the 1990's
 primarily due to faulty case management [24-26]. The management of severely malnourished
 children with associated complications relies on hospital-based treatment. In Bangladesh,
 only a few hospitals have beds dedicated for the management of severely malnourished
 children. Hospitalization may not also be possible as a result of the inability of the
 parents to visit a hospital either due to distance or financial reason (s), even after
 appropriate referral. It is, however, important to provide institutional care to such
 children, at least until stabilization of their acute conditions. If such children are sent
 home with antibiotics, it would be important to establish an expensive, home follow up
 system, without which a significant proportion of them could be reasonably expected to have a
 fatal outcome. With the implementation of a protocolised management at the Dhaka Hospital,
 ICDDR,B, the case-fatality of such children reduced from 19% to 5% [27, 28]. In another
 study, we evaluated a day-care clinic approach of management of severely malnourished
 children by providing antibiotics, micronutrients, diet, and supportive care during stay at
 an established day-care centers, followed by continuation of care by parents at home as an
 effective alternative to hospitalization. From February 2001 to November 2003, 264 severely
 malnourished children were enrolled at the Radda Clinic, where they received protocolized
 management with antibiotics, micronutrients and milk-based diet from 08:00 to 17:00 daily,
 while their mothers were educated on continuation of supportive care at home at night. They
 were transitioned to the day-care nutrition rehabilitation unit (NRU) of the Radda Clinic
 following resolution of acute illness, received NRU diets daily until attainment of 80%
 weight-for-length. Fifty-two percent of the children were boys, and 78%, 21% and 1% of all
 children had marasmus, marasmus-kwashiorkor and kwashiorkor, respectively. Only 13% had
 severe malnutrition alone, while 35% had pneumonia, 35% had diarrhoea and 17% had both
 pneumonia and diarrhoea. The mean ± SD duration of acute and NRU phases were 8 ± 4 and 14 ±
 13 days respectively. The mean ± SD weight gain (g/kg) of the children was more rapid during
 acute (10 ± 7) than the NRU phase (6 ± 5). The day-care management of severe malnutrition was
 assessed successful in 216/264 [82% (95% CI, 77-86%)] children, and failure in the remaining
 48/264 [18% (95% CI, 14-23%)] children of whom 17/264 [6% (95% CI, 4-10%)] had to be referred
 to hospital and 31/264 [12% (95% CI, 8-16%)] discontinued treatment. The results clearly
 demonstrated that severely malnourished children could be successfully managed at existing
 day-care clinics using a protocolized approach [2].

 Therefore, after the successful conduction and publication of results of these two studies on
 management of severe and very severe pneumonia [1] and severe malnutrition [2] at the
 day-care clinic, it is prudent to perform the final study in which we will assess if
 treatment of children with severe and very severe pneumonia in association with severe
 malnutrition will be possible on a day-care basis. If successful, this treatment approach
 could be more widely applicable. In the proposed study, we would identify under-5 children
 with severe and very severe pneumonia with severe malnutrition with/without associated
 co-morbidities attending the outpatient department of the Radda Clinic and the outpatient and
 emergency departments of ICHSH and randomize them, in equal numbers, for management either at
 the day-care centre (Radda Clinic) or hospital (ICHSH), subject to the consent of respective
 parents/guardians. About 3000 children with pneumonia visit the Radda Clinic each year, and
 we estimate that about 200 of them will have severe and very severe pneumonia with severe
 malnutrition requiring hospitalization. Similarly, about 700 children with severe and very
 severe pneumonia with severe malnutrition visit the outpatient and emergency departments of
 the ICHSH each year. Our study patients will be selected from these children population of
 the Radda Clinic and ICHSH, and we hope to complete enrolment of the requisite 440 (220/site)
 children during 3-year period of the study.

 Rationale

 Malnutrition and severe malnutrition are prevalent and ALRI/pneumonia is the leading cause of
 under-5 morbidity and deaths in Bangladesh. Hospital management is recommended for children
 with either or both of these problems. However, there simply is not enough beds to
 hospitalise every child with these problems. It is often not possible to provide appropriate
 treatment and supportive care at home to children refused admission to a hospital. With a few
 exceptions, childhood malnutrition is a problem of the poor, and thus parents of children
 with severe malnutrition and/or pneumonia are often unable to provide private care to their
 children, and some times unable to take their children to a hospital far off from their
 community. What happens to such children remains largely unknown; however, many can be
 expected to have a fatal outcome. Successful management of such children at a day-care clinic
 in their community would provide better access to their treatment and care and affordable to
 the parents. Proved effective, this management could also be implemented in Bangladesh and
 potentially to other developing countries. The day-care based management is expected to be
 cost effective intervention and contribute significantly to reduction of under-5 child
 mortality due to severe and very severe pneumonia as well as severe malnutrition.
Inclusion Criteria:

 -  Age: 2 to 59 months

 -  Sex: Both boys and girls

 -  Severe and very severe pneumonia

 -  Severe malnutrition (defined as < - 3 weight-for-height Z-score)

 -  Attending Radda Clinic or ICHSH between 8:00 to 16:00

 -  Written informed consent by respective parents/guardians

 Exclusion Criteria:

 -  Non-severe pneumonia

 -  Nosocomial pneumonia

 -  Bronchiolitis

 -  Bronchial asthma

 -  Living long distance (>5 km) from the Radda Clinic and ICHSH

 -  Visits during late hours of the day (after 16:00)

 -  Parents/guardians not consenting for enrolment of children in the study