Clinical Trial Details
— Status: Completed
Administrative data
| NCT number |
NCT00968370 |
| Other study ID # |
2008-009 |
| Secondary ID |
|
| Status |
Completed |
| Phase |
Phase 4
|
| First received |
August 28, 2009 |
| Last updated |
July 14, 2013 |
| Start date |
November 2008 |
| Est. completion date |
June 2013 |
Study information
| Verified date |
August 2009 |
| Source |
International Centre for Diarrhoeal Disease Research, Bangladesh |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
Bangladesh: Ethical Review Committee |
| Study type |
Interventional
|
Clinical Trial 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.
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.
