Aol et al. BMC Pediatrics(2024) 24:516
https://doi.org/10.1186/s12887-024-04988-5

BMC Pediatrics

RESEARCH

Open Access

Prevalence, patterns, and factors associatedwith abnormal lung function among children
with sickle cell disease in Uganda: a crosssectional study
Pamella Mwa Aol1, Geriga Fahdil2, Felix Bongomin3, Bonny Okello4, Charles Batte5, Bruce J. Kirenga5,
Rebecca Nantanda5* and Hellen Tukamuhebwa Aanyu6
Abstract
Background Pulmonary complications are common among children with sickle cell disease (SCD). However, there islittle literature on associated lung function abnormalities in Uganda. We aimed to determine the prevalence, patterns,
and factors associated with abnormal lung function among children with SCD in a tertiary care hospital in Uganda.
Method A cross-sectional study was conducted among children aged 6 to 18 years at the SCD clinic (SCC) of Mulago
National Super-Specialized Hospital between January 2020 and April 2021. Data on sociodemographic and clinicalcharacteristics was collected using a standardized questionnaire. Laboratory investigations, including a complete
blood count and serum lactate dehydrogenase (LDH), were done. Spirometry was performed following the ATS/ERS
standards. Multivariable modified Poisson regression analysis was performed to determine factors associated withabnormal lung function.
Results A total of 332 participants were enrolled. The mean age was 11.7 ± 3.4 years, and 184 (55.4%) were female.
Overall, 126 (37.9%) participants had abnormal lung function: 67/126 (53.2%) restrictive, 57/126 (45.2%) obstructive,
and 2/126 (1.6%) mixed-ventilatory patterns. Factors associated with abnormal lung function were; serum LDH
level > 600UL (aIRR: 1.89 95% CI: 1.2 — 7.4, p = 0.049), a history of acute chest syndrome (aIRR: 1.55, 95% CI: 1.06–2.25,
p = 0.024), wasting (aIRR: 1.33, 95%CI: 1.02 — 1.72, p = 0.032), and use of charcoal for household cooking (aIRR: 1.49,
95% CI: 1.03–2.15, p = 0.035).
Conclusion More than one-third of children with SCD in Uganda have lung function abnormalities. Strategies
to improve nutrition, reduce exposure to charcoal smoke, and monitoring serum LDH levels may be important inpreventing or managing abnormal lung function in this population. The identification of reversible and irreversible
airway obstruction in children with sickle cell disease also highlights the need for targeted interventions to addressthese specific patterns of abnormal lung function.
Keywords Sickle cell disease, Lung function, Children, Uganda*Correspondence:
Rebecca Nantanda
rnantanda@gmail.com; rebecca.nantanda@mli.mak.ac.ug
Full list of author information is available at the end of the article© The Author(s) 2024. Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0
International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you
give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if you modified thelicensed material. You do not have permission under this licence to share adapted material derived from this article or parts of it. The images orother third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to thematerial. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation
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Aol et al. BMC Pediatrics(2024) 24:516

Introduction
Sickle cell disease (SCD) is the most prevalent hereditarydisorder affecting millions of people globally [1]. About
300,000 babies are born with SCD annually [2]. The
majority of these births are in sub-Saharan Africa (SSA),
where more than 75% of people with SCD are found; this
proportion projected to increase by 2050 [3]. SCD is an
important public health problem accounting for about
5% of under-five mortality in Africa [4]. In Uganda, about
20,000 babies with SCD are born each year. [5]. About
70–80% of these children die before their fifth birthday
and this contributes 16.2% of all annual deaths amongchildren less than five years in Uganda [6].
Acute and chronic pulmonary complications related to
SCD, including pneumonia, acute chest syndrome (ACS),
chronic hypoxaemia and pulmonary hypertension, aremajor causes of morbidity and mortality, contributing up
to 20–30% of all-cause mortality in people with SCD [7].
Hypoxic-ischemic injuries, and embolisation from bonemarrow infarcts contribute significantly to the pathogenesis of lung disorders in SCD including lung function
abnormalities, interstitial lung disease, and pulmonary
hypertension [8]. Lung function abnormalities such as
lower lung volumes, decreased diffusion lung capacity,
airway hyper-responsiveness, and hypoxemia are common in children with SCD even at a steady state [9].
Although some children with lung function abnormalities are usually asymptomatic, a significant proportion
may have reduced exercise tolerance [10]. A few studies
have elucidated the prevalence and pattern of abnormallung function among children with SCD in Africa [11].
In Nigeria, a prevalence of abnormal lung function of up
to 65.8% was reported [12] while in Malawi, it was 62%[13]. Reversible obstructive airway pattern has been estimated to occur in about 5–35% and restrictive patternin 8–22% of children with SCD [14].The restrictive pattern is generally more common, however, among children less than five years, the obstructive pattern is moreprevalent. Studies have also noted that obstructive patterns are more common in high-income countries while
restrictive type is more prevalent in low and middleincome countries [9, 12, 13, 15]. In African-Americans,the obstructive airway pattern was noted to precede thedevelopment of restrictive airway pattern [16]. There isno data on the burden of the lung function abnormalities
among children with SCD in Uganda. This study aimed
to determine the prevalence, patterns and factors associated with abnormal lung function among children with
SCD at a tertiary care hospital in Uganda.
Methods
Study design

This was a cross-sectional study, conducted at the Sickle
Cell Clinic (SCC) of Mulago National Super-Specialized

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Hospital in Kampala, Uganda, between January 2020 and
April 2021.
Study setting

Mulago Hospital is the largest National Referral hospitalin Uganda. It also serves as a teaching hospital for Makerere University College of Health Sciences and othertraining institutions. The hospital has a total bed capacityof about 1500, and of these, 400 (26.7%) are for the Paediatrics section. The average number of patients seen at
Mulago hospital annually is 480,000. The Department ofPaediatrics and Child Health runs 8 specialized clinics
including the SCC, which had an estimated 14,000 active
patients at the time of the study. The clinic has about
1500 patient visits in a month, and of these, 70 are newly
diagnosed patients with SCD. According to the patientregister, the main reason for patients seeking care at the
SCC are respiratory symptoms contributing up to 250(16.7%) of the monthly visits. Most (75%) of the patients
attending SCC are below 18 years and most come from
Kampala city where the clinic is located and surrounding
districts. The clinic runs from Monday to Friday (8 am –4 pm), with an average of 40 to 70 patients per day. All
patients receive cost-free standard care, including daily
folic acid tablets, monthly sulfadoxine-pyrimethamine,and daily oral Phenoxymethylpenicillin (Penicillin V)
for children less than five years of age. However, patients
have to buy hydroxyurea, and for this reason, only about
2500 ( 17.8%) of the patients regularly get hydroxyurea.
Investigations, including a complete blood count (CBC),
chest radiography and cardiac echocardiogram, are doneat the discretion of the attending clinician.
Study population

The study population were children with a confirmed
diagnosis of SCD based on hemoglobin electrophoresis
who attended the SCC clinic during the study period.
Children who were aged 6 up to18 years and in steadystate were eligible to participate in the study. A steadystate was defined as the absence of emergencies like painful crises, acute chest syndrome, or acute illnesses from
infections like malaria, pneumonia, or septicaemia. We
excluded children with debilitating stroke and those with
contraindications to spirometry.
Sample size estimation

To determine the prevalence of abnormal lung function
among children aged 6 up to 18 years attending Mulago
Hospital Sickle Cell Clinic, we estimated a minimum
sample size of 332 children, based on a study done amongchildren with SCD in Nigeria [12] that estimated that
68.5% of the participants had abnormal lung function.
To determine the prevalence of abnormal lung function

Aol et al. BMC Pediatrics(2024) 24:516

among the participants, we used the KishLesile (1965)
formula for cross sectional studies as shown below.

N=

P (1 − p)Z 2d2

whereby;Z = Standard normal value corresponding to 95% Confidence Interval (1.96).
p = the prevalence of the abnormal lung function which
was 68.5% in the study in Nigeria [12].
d = Absolute error between the estimated and true
value = 0.05 (5%).

N=

0.685(1 − 0.685) ∗ 1.962(0.05)2

N=332
To describe the factors associated with abnormal lungfunction among children with SCDe aged 6 up to 18years
attending Mulago Hospital Sickle cell clinic, we used the
Fleiss formula. assuming a 2-sided confidence level of
95% and 80% power, and based on same study in Nigeria which showed that children with previous ACS were
3.6 times more likely to have impaired lung function thanthose without recurrent ACS [12]. The minimum sample
size was estimated to be 112 participants. Therefore, theoverall sample size to address both objectives was 332.
Data collection

Data was collected using structured, researcher-administered questionnaires(supplementary file.1). Before datacollection, the questionnaires were pre-tested on 10 caregivers of children with SCD to check for understanding
and flow, and the necessary revisions were made. Afterobtaining informed consent from the caregivers andassent for children 8 years and above, the study nurse
and principal investigator administered the questionnaire. The questionnaire included information on sociodemographic characteristics, respiratory symptoms,
the number of hospital admissions in the previous one
year, age at diagnosis of SCD, history of vaso-occlusivecrises and acute chest syndrome, current medication,
history of blood transfusion, history of active and/or
passive tobacco smoking and cooking energy commonlyused in the home. Information on the HIV sero-status
was obtained from the patient’s file. The study doctor
did a physical examination, and this included anthropometric measurements of weight and height. The weight
was measured using the SECA weighing scale while
the height was measured using a stadiometer. Wasting
was defined as zBMI < − 2. The resting peripheral arterial oxygen saturation in room air was measured using

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a finger pulse oximeter with infrared light (Nonin pure
SAT, United State of America).
Spirometry

The spirometry technician screened all participants forcontra-indications to spirometry testing using a structured screening tool. Spirometry was performed in accordance with the American Thoracic Society/European
Respiratory Society [ATS/ESR] standard protocol using
the Vitalograph 6800 Pneumotrac spirometer. Briefly, thespirometer was calibrated every morning before starting
the procedures. The tests were conducted in a quiet andwell-ventilated room. The participants were instructedto blow into the mouthpiece as hard and as fast as they
could and to continue blowing until there was no more
air to exhale. After each blow, the quality of the curves
was quickly assessed by the technician, and a decision was made to accept or reject it. The maneuver was
repeated until three good-quality tests were obtained.
The participants were then given 400 micrograms of
salbutamol inhaler using a spacer, and the spirometry
maneuver was repeated 15–20 min later. A maximum of
8 trials were allowed for each participant, and if a participant could not produce 3 quality tests from the 8attempts, the test differed to another day.
Quality checks and interpretation of the spirograms
was performed by two independent reviewers. All disagreements between the two reviewers were resolved
by a third reviewer. The Global Lung Function Initiative[GLI 2012] reference values were used to interpret the
spirometry results [6]. Spirometry patterns were classified as normal, obstructive, restrictive or mixed as shownin the table below.
Parameter
FEV1/FVC
FEV1
FVC
FEV1/FVC
FEV1
FVC
FEV1/FVC
FEV1
FVC
FEV1/FVC
FEV1
FVC

Percentage predicted
> 70%
> 80%
> 80%
< 70%
< 80%
≥ 80% or < 80%≥ 70%≥ 80% or < 80%
< 80%
< 70%
< 80%
< 80%

Classification
NormalObstructive pattern

Restrictive pattern

Mixed type

The coronavirus disease 2019 (COVID- 19) Standard
Operating Procedures (SOPs) for prevention and control
were observed throughout the data collection processes.
All the participants were screened for signs and symptoms of COVID-19 before spirometry.However, the participants were not tested for COVID-19. This is because
at the time of conducting the study, access to COVID-19

Aol et al. BMC Pediatrics(2024) 24:516

testing in the country was still low and reserved for
symptomatic people and/or travelers.
Laboratory procedure

Two to three milliliters of mls venous blood were drawn
into a vacutainer with clot activator under aseptic technique and transported to the laboratory in a cool box,
within one hour of collection, to be analyzed for serum
lactate dehydrogenase (LDH) level.
In the laboratory, the sample was immediately centrifuged for 10 min at 2000 x g, and serum was separated
from the cells; the serum was then stored at -20 degrees.
It was later defrosted and run in batches of 30 samples
using a Cobas 6000, LDH12 reagent kit.
Data management and analysis

The principal investigator checked all the data fromthe questionnaires, physical examination, and laboratory tests for completeness. The spirometry test results
were evaluated for quality by an independent teamof three clinicians with certified training in spirometry. Data entry was done using Epidata version 3.1 andexported to STATA Version 15 for further cleaning andanalysis. All hard copy data were kept under lock andkey and were accessed by the principal investigator andthe research assistant only. The study computers were
password-protected.
Continuous data were summarized as means with standard deviation for normally distributed data and medianswith and interquartile ranges for skewed data. Categorical variables were summarized as frequencies and percentages. The Chi-Square test was used to compare
proportions between the categorical variables with theoutcome. The Student’s t-test was used to analyze continuous data.
At bivariate analysis, Poisson regression analysis withrobust variance was performed to assess for factors associated with the abnormal lung function. Crude Incidence
Risk Ratios (cIRR) and 95% confidence interval (CI) werereported. Variables with p ≤ 0.2 at bivariate analysis wereentered in a backward stepwise multi-variable Poisson regression analysis. Adjusted Incidence Risk Ratios(aIRRs) and the 95% CIs were reported as measure ofindependent association between the independent variables and abnormal lung function. A p < 0.05 was considered statistically significant. The goodness of fit of themodel was tested using the Akaike information criterion(AIC).
Quality control

Consent and assent forms were translated into Luganda,
the main language spoken in the study area. The research
assistants were trained on the study protocol, data collection tools, data handling and consent process. The

Page 4 of 9questionnaires were crosschecked for completeness andaccuracy daily before entering the data into the database.
The Spirometer was calibrated daily by the spirometry
technician. The SECA weighing scale was calibrated daily
before measurements were made.

Results
Participants

A total of 345 participants were recruited, with 100%
response rate and of these, 184 (55%) were females.
The mean age (SD) was 11.7 ± 3.4 years. The majority
332 (96%) of the participants had valid spirograms. The
details of the study profile and socio-demographics of theparticipants are summarized in Fig. 1 and Table 1
Prevalence and patterns of lung function abnormalities
among children with SCD

A total of 126 (38%, 95% CI, 32.9–43.3) participants had
abnormal lung function; 67 (20%) had restrictive, 57(17%) had obstructive and 2 (0.6%) had mixed ventilator patterns. Of the 57 who had obstructive patterns, 30(53%) had reversible airway obstruction, and 27(47%) had
irreversible airway obstruction. (Fig. 2)
Clinical and laboratory characteristics of the study
participants

Of the 332 participants, 256 (77%) were diagnosed with
SCD before the age of 5 years. Sixty-one (19%) reported
a history of wheezing in the previous 12 months, 26 (8%)
had a history of acute chest syndrome, and 62 (19%) had
low peripheral oxygen saturation (SpO2 < 92%) at thetime of enrolment. Ninety-five (29%) of the participants
had ever been hospitalized with acute respiratory symptoms, 56 (17%) had received a blood transfusion in the 6months prior to enrollment, and 222 (67%) had hydroxyurea at some point during the previous year. Lactate
dehydrogenase was elevated (> 600 IU/litre) in 85(26%)
of the participants. Details of the clinical and laboratory
characteristics of the study participants are summarizedin Table 2, below.
Factors associated with abnormal lung function in children
with SCD

The factors that were significantly associated with abnormal lung function were; wasting (IRR: 1.33, 95% CI: 1.0 —
1.7, p = 0.032), a history of acute chest syndrome (aIRR:
1.55, 95%CI: 1.1 — 2.3, p = 0.024), SpO2 < 92% (aIRR: 1.69,
95% CI: 1.3 — 2.2, p < 0.001), use of charcoal for cooking(IRR: 1.49, 95% CI: 1.1 — 2.1, p = 0.033), moderate serum
LDH levels [between 401 and 600 U/L (aIRR: 1.99, 95%
CI: 1.1 — 3.7, p = 0.029), and high serum LDH levels > 600
U/L (aIRR: 1.89, 95% CI: 1.0 — 3.6, p = 0.049)]. The details
are provided in table 3.

Aol et al. BMC Pediatrics(2024) 24:516

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Fig. 1 Study profile

Table 1 Socio-demographic characteristics of the participants (N = 332
Variables

Normal(n = 206)(Frequency, %)Obstructive(n = 57)(Frequency, %)Restrictive(n = 67)(Frequency, %)Mixed(n = 2)(Frequency, %)Age (years) 6–10
11–14
15–18
Sex Male
FemaleResidence RuralUrban

89(43.2)
77(37.4)40(19.4)
94(45.6)
112(54.4)54(26.2)
152(73.8)24(42.1)
20(35.1)
13(22.8)21(36.8)36(63.2)
19(33.3)
38(66.7)

20(29.9)23(34.3)
24(35.8
33(49.3)
34(50.8)21(31.3)
46(68.7)1(50.0)0(00)1(50.0)0(00)2(100)
1(50.0)1(50.0)Discussion
The prevalence of abnormal lung function among children with SCD was high. More than half of the lungfunction abnormalities showed a, with half of restrictive pattern. This is different from findings in developed
countries that reported higher prevalence of obstructive
ventilatory pattern [16]. However, our findings are similar to studies done in Africa which showed higher prevalence of restrictive ventilatory pattern in children with
SCD [8, 9, 13]. This difference may suggest more severelung disease in children in sub–Saharan Africa comparedto their counterparts in high-income countries. The exact

Total(n = 332)(Frequency,%)
134(40.4)
120(36.1)
78(23.5)
148(44.6)
184(55.4)95(28.6)
237(71.4)

cause of lung abnormalities and disease in SCD is notclear. However, there some evidence suggesting that these
could be due to increased pulmonary capillary blood
volume associated with anemia [17]. Some studies haveindicated that abnormal lung function could be related tothe inflammation which is part of the pathophysiology of
SCD, in which several cytokines like TNF, IP-10 and IL-4
are released. [18]. It is also possible that lung function
abnormalities are a result of the destruction of erythrocytes freeing up haem [19], which uses nitric oxide,significantly increasing vasodilation. The subsequent
compromised blood flow induces obstruction in the lung

Aol et al. BMC Pediatrics(2024) 24:516

Page 6 of 9function among children with SCD may indicate that asignificant proportion of children with SCD will suffera wide range of pulmonary complications throughout
their life course. Early detection through screening may
be associated with a reduction in the risk of chronic lungdiseases and subsequent associated mortality amongchildren with SCD.
Patterns of ventilatory abnormalities in children with SCD

Fig. 2 Study profile

blood vessels, leading to acute chest syndrome and, insome cases, producing emboli [20]. Abnormal lung function in childhood is associated with an increased risk ofchronic lung diseases like asthma and Chronic Obstructive Pulmonary Disease [21]. For children with sickle celldisease who already have a high risk of pulmonary complications like Acute Chest Syndrome, chronic hypoxaemia and pulmonary hypertension, the presence of lungfunction abnormalities indicates the potential likelihoodof suffering from a wide range of chronic lung diseases[22]. Therefore, a high prevalence of abnormal lung

The study showed that more than half of the children
with lung abnormalities had restrictive ventilatory patterns. A significant proportion had obstructive patterns,
and very few had a mixed type of ventilatory defect.
These findings are similar to those from and study among
adults with SCD in Lagos Nigeria in which more thanhalf of the abnormal lung function were of restrictive pattern [23]. In this study, the mean forced vital capacity was
reduced, inferring poor ventilation [23].A significant proportion of participants with abnormal lung function had
the obstructive type, and this phenotype is thought to be
due to cellular endothelial adhesion following rigidity of
the cell membrane [18].
In this study, wasting increased the risk of abnormallung function by nearly 2-folds. This observation is consistent with studies in Nigeria and the Central African
Republic, which found that wasting was associated witha 2.3-4-fold increased risk of abnormal lung function [9,11]. [24] Wasting affects the chest dimensions and thestrength of the expiratory muscle, leading to poor expiratory effort. Wasting could also be a result of increased
metabolic demands due to a more severe lung disease[11]. Wasting among children with SCD has also been
associated with frequent and prolonged hospitalizations

Table 2 Clinical and laboratory characteristics of the participants
Variables

Body Mass Index Z-score
NormalWasting
History of blood transfusion within 6 months prior toenrolment
Use of Hydroxyurea
History of acute chest syndrome
History of wheezing in the previous 12 months
Presence of enlarged tonsils and/or nasal turbinates
Low peripheral oxygen saturation (SpO2) < 92%
Serum lactate Dehydrogenase U/L
135–225 (normal)
226–400 (mild)
401–600 (moderate)> 600 (severe)
Underweight(wasting) < -2SD, median BMI 16.12(IOR 14.92–17.86)

Normal(n = 206)(frequency, %)Obstructive(n = 57)(Frequency, %)Restrictive(n = 67)(frequency, %)

Mixed
Total
(n = 2)(n = 332)(frequency, %) (Frequency, %)154(74.8)52(25.2)
35(16.9)44(77.2)
13(22.8)4(7.0)

31(46.3)
36(53.7)
17(25.4)

1(50.0)1(50.0)0(00)230(69.3)
102(30.7)56(16.9)133(64.6)11(5.3)30(14.6)
76(36.9)27(13.1)

40(70.2)
6(10.5)12(21.1)
24(42.1)
13(22.8)48(71.6)9(13.4)19(28.4)
23)34.3)
22(32.8)1(50.0)
0(00)
0(00)
0(00)
0(00)

222(66.9)26(7.8)61(18.4)
123(37.1)
62(18.7)

31(15.0)65(31.6)65(31.6)45(21.8)4(7.0)
17(29.8)24(42.1)
12(21.1)

4(5.1)
8(11.9)27(40.3)
28(41.7)0(00)1(50.0)1(50.0)0(00)39(11.7)
91(27.4)
117(35.2)
85(25.6)

Aol et al. BMC Pediatrics(2024) 24:516

Page 7 of 9

Table 3 Factors associated with abnormal lung function among children with SCD (N = 332)
Variables

Age of the child (years)
BMI
History of recurrent Wheezing
History of Acute chest syndrome
HIV infection/positive
Serum LDH (IU/L)

Use of charcoal for cooking
SpO2 (%)

Category

NormalWasting
No
Yes
No
Yes
No
Yes
135–225
126–400
401–600
> 600
No
Yes
< 92(abnormal)> 92(normal)

Lung function (N = 332)
Normal (n = 206) ,% Abnormal(n = 126) %11.4 ± 3.3
12.3 ± 3.4
154(74.8)76(60.3)
52(25.2)
50(39.7)
176(85.4)95(75.4)30(14.6)
31(24.6)
195(94.7)
111(88.1)
11(5.3)15(11.9)204(99.1)120(95.2)2(0.9)
6(4.8)
31(15.1)8(6.4)
65(31.6)
26(20.6)
65 [5, 31]
52(41.3)45(21.8)40(31.8)54(26.2)
105(83.2)
152(73.9)21(16.7)
27(13.1)
35(27.8)
179(86.9)91(72.2)

Crude
IRR (95% CI)

p value

Adjusted
IRR (95% CI)

p-value

1.05 (1.01,1.09)
1.00
1.48(1.13,1.94)
1.00
1.44(1.08,1.94)
1.00
1.59(1.11,2.28)
1.00
2.03(1.32,3.09)
1.00
1.39(0.69,2.80)
2.17(1.13,4.16)
2.29(1.19,4.43)
1.00
1.46(0.98,2.16)
1.0
1.67(1.27,2.21)

0.016

1.02(0.98,1.07)
1.00
1.33(1.02,1.72)
1.00
1.32(0.98,1.77)
1.00
1.55(1.06,2.25)
1.00
1.39(0.81,2.40)
1.00
1.48(0.76,2.40)
1.99(1.07,3.73)
1.89(1.00,3.56)
1.00
1.49(1.02,214)
1.0
1.69(1.29,2.22)

0.196

0.004
0.014
0.012
0.001
0.353
0.020
0.013
0.059
< 0.001

0.032
0.065
0.024
0.228
0.246
0.029
0.049
0.035
< 0.001

IRR: incidence risk ratio, CI: confidence interval, BMI: body Mass Indexduring which nutritional intake is limited, coupled withincreased stress [25].
[25].
Children with SCD who have high LDH had almost
2-fold higher risk of having abnormal lung function compared with those with normal levels. A study done in the
USA showed a weak association between high LDH andabnormal lung function, especially obstructive patterns[26]. The high levels of LDH could be due to tissue damage following haemolysis [27] which causes the releaseof free haem, which in turn consumes NO (nitric oxide),
reducing endothelial NO bioavailability and impairing
vascular functions. Lysed erythrocytes also release arginase that destroys L-arginine (converts to L-ornithineand urea). This reduces arginine availability for NO
production via nitric oxide synthase (NOS). The hemolysis-induced mechanisms of NO-arginine pathway dysfunction and allergen sensitisation, in combination withinnate genotypic susceptibilities, may promote interplay
between the above factors in modifying SCD lung inflammation and downstream effects [28].
Children with a history of acute chest syndrome weremore likely to have abnormal lung function comparedto those without a history of acute chest syndrome. Thisis similar to a study in Nigeria, which showed that a history of ACS had 2-fold higher odds of having abnormallung function. However, a study in the USA found noassociation between ACS and abnormal lung functions[16]. This variation could be that children in high-income
countries have better health care than the ones in lowincome countries. This may be due to poor health-seeking behavior and poverty, which hinders access to basic

health care and routine medications required by a childwith sickle cell disease. ACS is a common cause of acutelung disease in children with SCD [29]. The etiology of
ACS is often multifactorial. The development of ACS
represents a vicious cycle of lung infarction, inflammation, and atelectasis leading to ventilation–perfusion
mismatch, hypoxemia, and acute increases in the pulmonary artery and right ventricular pressures [29]. At
the cellular level, in the presence of low alveolar oxygen
tension, abnormal rheology of the sickled red blood cells(sRBCs) facilitate adhesion to each other, leukocytes,
and the vascular endothelium, resulting in vaso-occlusion and tissue hypoxia. These interactions also cause
the release of inflammatory cytokines, which promote
acute and chronic inflammation in the airways by beingnear the vasculature [29]. Patients suffering from repetitive episodes of ACS can develop scattered areas of lungfibrosis, predominantly observed in the lung bases [27].
Pulmonary fibrosis is linked to restrictive lung patterns
on spirometry evaluation. This is a common findingin adults with SCD, possibly as a result of longstanding
chronic inflammation of the small airways from recurrent ACS, infections, vascular infarction and extra-pulmonary restriction [30].
The study results showed that using charcoal as a cooking fuel source increases the risk of abnormal lung function. Studies show that exposure to smoke from use of
charcoal during cooking is associated with systemic andpulmonary inflammation, leading to an increase in neutrophils in the broncho-alveolar fluid and blood [31]. Thiseffect might be exaggerated in SCD due to the chronicAol et al. BMC Pediatrics(2024) 24:516

inflammatory state and its impact on the lung and otherorgans.
Low peripheral oxygen saturation (SpO2 < 92%)
increased the risk of abnormal lung function by nearly
2-folds. This could be explained by the fact that children
with SCD already have compromised lungs, and hypoxemia is just a manifestation of lung disease. This may also
be confounded by the fact that hypoxemia is prevalentin patients with SCD during steady state, in the absenceof overt cardiopulmonary illness, and during ACS or
VOC crises [32]. Oxyhaemoglobin desaturation triggers
HbS polymerisation, the first chain of events culminating in SCD complications [33]. Moreover, in the presence of Sleep- disordered breathing the repeated cycles
of hypoxia and re-oxygenation enhances the oxidative
stress and pro-inflammatory signalling pathways that
contribute to SCD-related acute and chronic manifestations [34].
Strengths and limitations of the study

This study provides valuable insights into the prevalence,patterns, and associated factors of abnormal lung function in children with SCD, shedding light on an important aspect of their health. The large sample size gives ita high power. Additionally, the identification of reversible
and irreversible airway obstruction patterns contributes
to a deeper understanding of respiratory health in children with sickle cell disease.
However, the study had some limitations. This study
had a cross-sectional design, which limits the ability toestablish causality between the identified factors andabnormal lung function. Additionally, the study was carried out in an urban setting, which may limit the generalizability of the findings to other regions or populations
in rural areas. Furthermore, the reliance on self-reported
data for certain factors such as cooking practices and history of acute chest syndrome may introduce recall bias
and affect the accuracy of the results.

Conclusion
The study showed a high prevalence of abnormal lungfunction among children with SCD, and this was associated with wasting, high serum LDH levels, and use of
charcoal for household cooking. Strategies to improve
nutrition, reduce exposure to charcoal smoke, and monitor serum LDH levels may be important in preventing
or managing abnormal lung function in this population.
The identification of reversible and irreversible airway
obstruction in children with sickle cell disease also highlights the need for targeted interventions to address these
specific patterns of abnormal lung function.
Acknowledgements
Special thanks to the children and their parents/guardians who participatedin the study. We appreciate the research team members; Sr. Beatrice Amoit,

Page 8 of 9

Sr. Margret Grace Amul and, Sr. Hope Mandhawun Ongu. We acknowledge
the support from the head of sickle cell clinic Mulago National Referral
Hospital, Dr. Phillip Kasirye and all the staff in the clinic for their cooperation
during data collection. Many thanks to St, Mary’s hospital, Lacor for providing
tuition for the residency program of Pamella Mwa Aol. This study was fundedby the National Institute of Health through the Makerere University NonCommunicable Diseases Research Training Program ( MakNCD).
.
Author contributions
Study conception and design: P.A.M; Data acquisition, Analysis andinterpretation: P.A.M; H.T. A: R. N: G. F, C. B, B. O, F. B, B. K. Initial draft of thearticle: P. A. M; critical revision for important intellectualcontent: all authors;
final approval of the version to be published: all authors; guarantor of thearticle: P. A. M.
Funding
This study was funded by the Fogarty International Center of the National
Institutes of Health under Award Number D43TW011401. The content is solely
the authors’ responsibility and does not necessarily represent the official viewsof the National Institutes of Health.
Data availability
The datasets used and/or analysed during the current study available from thecorresponding author on reasonable request.

Declarations
Ethics approval and consent to participate
Ethical approval was obtained from the Makerere University School of
Medicine Research and Ethics Committee (Number SOMREC 2019 − 160).
Administrative clearance was obtained from Mulago National SuperSpecialized Hospital. Informed written consent was obtained from theparents/guardians, and informed written assent was obtained from all children
aged 8 years and above.
Consent for publication
Not applicable.
Competing interests
The authors declare no competing interests.
Disclosures
None.
Author details
1
Department of Paediatrics and Child Health, St. Mary’s Hospital Lacor,
Gulu, Uganda
2
Uganda Cancer Institute, Mulago National Referral Hospital, Kampala,
Uganda3
Department of Medical Microbiology and Immunology, Faculty of
Medicine, Gulu University, Gulu, Uganda
4
Department of Planning, Kwania District Local Government, Kwania,
Uganda5
College of Health Sciences, Makerere University Lung Institute, Makerere
University Kampala, Kampala, Uganda
6
Department of Paediatrics and Child Health, Mulago National Referral
Hospital, Kampala, Uganda
Received: 23 August 2023 / Accepted: 1 August 2024

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