Our study has four main findings, namely that (1) bronchopneumonia was the most prevalent
lung pathology, (2) comorbidity between non-communicable and communicable diseases
was found in 80 % of children, (3) tuberculosis was detected in 8 % of mortalities,
with 9/10 cases being undiagnosed and untreated ante mortem, and (4) results of molecular
analysis found evidence for MTB in 7/10 histopathologically confirmed TB cases.
The results should be viewed in terms of several limitations. Due to the generic social
and resource limitations of conducting full autopsies in any geographical setting
11], our necropsy study had its focus on the chest cavity and was limited by the small
sample size and the likelihood of the recruited children being older and male. These
biases are difficult to avoid on a consenting autopsy study within a community that
is broadly culturally opposed to mutilation of the deceased 10]. In addition to slightly lower reservations among families over consenting for autopsy
on males and older children, the recruiting clinical officer (CC) felt that families
of lower socioeconomic status were more likely to consent, consistent with our recent
adult autopsy study 14], but we did not collect any socioeconomic indicators such as maternal education status.
Finally, the study was undertaken at a referral centre and so does not include childhood
deaths within the community. It should be noted, however, that within Lusaka, referral
systems are well established and most childhood deaths occur at UTH. The findings
of this study should be interpreted in light of these limitations.
The high prevalence of bacterial lung infections is alarming, as these are supposedly
treatable with the range of antibiotics available at UTH, and more broadly within
Zambia and regionally. In addition, two thirds of pneumonia cases were not diagnosed
ante mortem. These deaths could have been influenced by increasing levels of antibiotic
resistance in common community acquired pneumonia pathogens such as Haemophilius influenzae and Streptococcus pneumoniae18]. Whilst susceptibility of these two community acquired pneumonia pathogens to front
line antibiotics, such as Ampicillin and Amoxicillin, remains quite high in Africa
(70–90 %) 18], a mortality study naturally selects for severe infections that are more likely to
be drug resistant, present late or be complicated by comorbidities. In the absence
of full post mortem we could not determine the relative contribution of lung pathology
with histopathological findings from other tissues, but comparison of lung pathology
findings with clinical data identified possible comorbidity in up to 80 % of cases.
For a minority of cases with severe central nervous system infections or congenital
heart disease, the observed lung pathology may have been secondary, but for the overwhelming
number of cases, including malnourished children, the study pathologists (AS and VM)
considered the lung pathology observed to be the likely primary cause of death. The
observed high levels of comorbidity, in particular with malnutrition, are consistent
with the high levels of malnutrition in Zambia 19]. Severely malnourished children are at increased risk of respiratory infections and
associated mortality 20].
Interstitial pneumonitis is defined as a thickening of the interstitium, which damages
alveoli architecture and function 21]. It can be caused by bacterial, viral or fungal lung infections, and also has a range
of non-infectious aetiologies such as air pollutants. In poor communities in urban
Zambia, most cooking is done on charcoal 22]. As the second most prevalent cause of fatal lung pathology, observed in 17 % (20/121)
of cases, the aetiology of interstitial pneumonitis in African children requires further
definition, possibly through immunocytochemistry or next generation sequencing of
tissue specimens. It is challenging to establish a definitive diagnosis ante mortem,
with chest x-ray manifestations having considerable overlap with other lung diseases
such as TB 7].
Histopathologically confirmed TB (observation of granulomas, caseous necrosis and
Langhans giant cells) was detected in 8 % (10/121) of cases. Molecular analysis confirmed
the presence of M.tb DNA in 7/10 cases, and evidenced possible NTM infection in two cases. A recent national
study determined the prevalence of symptomatic NTM infection in Zambian adults to
be three-fold higher than the national TB prevalence 23], which suggests NTM infections could also be a significant cause of disease in children
as reviewed 24]. M.tb and NTM specific DNA was also commonly detected in the absence of histopathological
evidence of TB infection, possibly indicative of latent infections, including three
cases with rifampicin resistance or comorbidity where less severe TB/NTM infection
was secondary to bronchopneumonia or other causes of death.
These findings seem at odds with Global Burden of Disease estimates, which do not
consider TB as a notable cause of death in African children 25]. However, they are consistent with the views of other leading commentators 26]–28] and our previous paediatric autopsy study (conducted between 1997–2000) which confirmed
TB as a cause of death in 20 % (54/264) of cases, with the point prevalence being
higher among HIV-uninfected children (26 %) than among HIV-infected children (18 %)
12]. Similarly in this study, we found TB in both HIV-infected and uninfected children.
In Zambia, childhood TB notification rates have fallen over the last decade 29], but TB clearly remains an important cause of death. Importantly, only 10 % (1/10)
of TB cases were on TB treatment when they died, illustrating how poor TB diagnostic
services are for children at UTH. Despite significant improvements in HIV prevention,
diagnosis and treatment over the last decade 30], it is the slow pace of improvements in TB diagnostic tools and services for children
31] that has allowed TB to persist as a significant cause of death in children. A recent
modelling study suggested that, for 15 high burden countries, only 35 % of incident
paediatric TB cases are notified globally 26].
Malnutrition was observed in 80 % of histopathologically confirmed TB cases. The mortality
rate on the malnutrition ward within the department of paediatrics and child health
at UTH is 18 %, second highest only to the neonatal intensive care unit (30–50 %)
32]. More active surveillance of TB and bacterial pneumonia may be justified in malnourished
paediatric admissions, and among malnourished children with TB contact, attending
community clinics, at high risk of referral to UTH. There is maybe reservation to
conduct invasive sampling in severely malnourished children, as it may be unpleasant
for the patient. As they are on antibiotics to cover bacterial lung or gut infections
and PCP, the main focus is on addressing their nutritional needs. This might mean
that TB or viral respiratory infections are overlooked. The ideal specimen for TB
diagnosis in young children is induced sputum 33] but spent feeding tubes could be considered as a non-additionally invasive source
of gastric aspirate for TB analysis in severely ill malnourished children 16].
The point prevalence of CMV pneumonia (7 %) and PCP (5 %) were both lower than previously
reported 12], contrary to our previous study where, with a larger sample, we saw a strong association
with HIV infection (CMV?=?22 %, PCP?=?29 %). The previous study was undertaken prior
to paediatric ART roll-out in Zambia and prior to the implementation of cotrimoxazole
prophylaxis in HIV-infected children with pneumonia 12], which may have impacted on reducing CMV and PCP-associated deaths in HIV-infected
children. The previous study also included only respiratory mortalities, had a lower
median age, and used both immunocytochemistry as well as the observation of classic
‘owls eye’ inclusions to define CMV infection 12]. We have shown, in a recent population-based study 34], that early infant CMV infections are linked with impaired development of Zambian
infants and, that among admitted infants, CMV DNAemia is associated with being underweight,
meningitis, and HIV infection 35], suggesting CMV is an important determinant of health in African children. CMV pneumonia
is currently treated with intravenous Ganciclovir at some centres in South Africa
36]–38]. CMV was not considered ante mortem because Ganciclovir is not currently available
at UTH, can cause leukopenia and neutropenia 39], and could be harmful in some HIV-infected children with a low CD4. There is a need
for controlled trials for anti-CMV drugs in the African paediatric setting 36], 40].