Trial in Childhood Pneumonia With Malnutrition
Condition: Malnutrition; Pneumonia
MeSH terms: Pneumonia; Malnutrition
Study type: Interventional
Phase: Phase 4

Summary: 
      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.
    

Detailed description: 
      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.
    

Intervention name(s): Day-care clinic; Hospital Management
Intervention type(s): Other; Other
Intervention description(s): Inj. Ceftriaxone and other micronutrients will be given to children at the day-care clinic from 8:00 a.m. to 5:00 p.m. daily.; Inj. Ceftriaxone and other micronutrients will be given to children at the hospital from admission till discharge.
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Severe and very severe pneumonia; severe malnutrition; children; day-care management; hospital management