Lung function in HIV-infected children and adolescents
Githinji et al. Pneumonia
Lung function in HIV-infected children and adolescents
Leah N. Githinji 0
Diane M. Gray 0
Heather J. Zar 0
0 Department of Paediatrics and Child Health, Red Cross War Memorial Children's Hospital and MRC Research Unit on Child and Adolescent Health, University of Cape Town , Rondebosch, Klipfontein Road 7700, Cape Town , South Africa
Background: The advent of antiretroviral therapy has led to the improved survival of human immunodeficiency virus (HIV)-infected children to adulthood and to HIV becoming a chronic disease in older children and adolescents. Chronic lung disease is common among HIV-infected adolescents. Lung function measurement may help to delineate the spectrum, pathophysiology and guide therapy for HIV-related chronic lung disease. Aim: The aim of this study was to review the available data on the spectrum and determinants of lung function abnormalities and the impact of antiretroviral therapy on lung function in perinatally HIV-infected children and adolescents. Methods: Electronic databases “PUBMED”, “African wide” and “CINAHL” via EBSCO Host, using the MeSH terms “Respiratory function” AND “HIV” OR “Acquired Immunodeficiency Syndrome” AND “Children” OR “Adolescents”, were searched for relevant articles on lung function in HIV-infected children and adolescents. The search was limited to English language articles published between January 1984 and September 2017. Results: Eighteen articles were identified, which included studies from Africa, the United States of America (USA) and Italy, representing 2051 HIV-infected children and adolescents, 68% on antiretroviral therapy, aged from 50 days to 24 years. Lung function abnormalities showed HIV-infected participants had increased irreversible lower airway expiratory obstruction and reduced functional aerobic impairment on exercise, compared to HIV-uninfected participants. Mosaic attenuation, extent of bronchiectasis, history of previous pulmonary tuberculosis or previous lower respiratory tract infection and cough for more than 1 month were associated with low lung function. Pulmonary function tests in children established on antiretroviral therapy did not show aerobic impairment and had less severe airway obstruction. Conclusion: There is increasing evidence that HIV-infected children and adolescents have high prevalence of lung function impairment, predominantly irreversible lower airway obstruction and reduced aerobic function.
HIV; Lung function; Children; Adolescents
Improved survival of perinatally human
immunodeficiency virus (HIV)-infected children to adolescence has
occurred with the scale-up of pediatric antiretroviral
therapy (ART) and prevention of mother-to-child
transmission (PMTCT) programs. This has led to a large
cohort of youth living with vertically transmitted HIV in
sub-Saharan Africa [
]. Of the 2.3 million children living
with HIV globally, 43% are on ART [
]. In 2016, 7
million people were reported to be living with HIV in
South Africa, of which 350,000 were between 10 and
19 years old .
HIV-related chronic lung disease (CLD) is a major
cause of morbidity and mortality [
]. In the post-ART
era, the spectrum of CLD has changed from lymphocytic
interstitial pneumonitis (LIP) being most predominant
to bronchiolitis obliterans and bronchiectasis being more
prevalent patterns [
]. The spectrum of chronic lung
disease in HIV infection has broad clinical phenotypes.
For example, bronchiolitis obliterans may present as an
obstructive pattern on spirometry [
], while chronic
Pneumocystis jirovecii pneumonia (PCP), pulmonary
tuberculosis (TB), bronchiectasis or LIP have a restrictive
or mixed pattern spirometry. Interstitial pneumonitis,
LIP and PCP are likely to lead to a reduced diffusion
capacity for carbon monoxide (DLCO).
Comprehensive lung function measures are therefore
needed to delineate the spectrum of CLD, monitor
progression, and guide therapy and treatment response.
These include measurements of lung capacities and flow,
such as spirometry and bronchodilator response testing;
measurement of lung volumes with plethysmography;
measurement of resistance and compliance with tests
such as the forced oscillation technique (FOT),
interrupter technique or single-breath occlusion technique;
measurement of gas diffusion with single-breath carbon
monoxide lung diffusion test to assess alveolar-capillary
membrane function; measurement of ventilation
distribution with multiple breath nitrogen wash-out test
(MBW); and cardiopulmonary functional assessment
with the six-minute walk test (6MWT) and exercise
The aim of this study was to review the available data
on the spectrum and determinants of lung function
abnormalities in perinatally HIV-infected children and
A review of published literature was performed by
searching “PUBMED”, “African wide” and “CINAHL” via
EBSCO Host using the MeSH terms “Respiratory
function” AND “HIV” OR “Acquired Immunodeficiency
Syndrome” AND “Children” OR “Adolescents”; full search
terms are shown in Table 1. The search was limited to
English language articles with a publication date between
January 1984 and September 2017. Articles involving
infants, children, adolescents or youth, HIV-infected or
exposed, and lung function testing were included. Articles
on adult studies or healthy populations were excluded.
Where full articles could not be retrieved on Endnote,
the full article was requested from the corresponding
author by email. In addition to database searches, other
relevant references from previous original articles were
searched manually through Google Scholar. Data
regarding patient characteristics, lung function test used and
outcome were abstracted and summarized in table
The process of the literature search is shown in Fig. 1.
After combining all the search terms, 146 articles were
found; 8 additional articles were obtained by a manual
search, (Fig. 1). One hundred and thirty-six studies were
excluded because they were unrelated to lung function,
or were not related to the population of interest, or only
a conference abstract was available. Eighteen full-text
articles were found and included in this review (Table 2).
All included studies were published between July 1997
and September 2017. Of the 18 included studies, 11
were from Africa, 6 from the United States of America
(USA) and 1 from Italy. Three studies focused on infants
(two of which also included HIV-exposed uninfected
], two focused on children < 8 years [
and 13 focused on adolescents and youth (9–24 years),
(Table 2). Eleven studies had a comparator group
(control) (Table 2). All the HIV-infected participants were
Baseline characteristics of participants differed among
studies with median age ranging from 50 days to 24 years.
The number of participants in each study ranged from
100 to 600, with a total of 2051 HIV-infected participants
pooled from all studies. Severity of disease differed;
Ferrand et al. [
] reported 66% had chronic cough, McHugh
et al. [
] reported 54% had chronic cough. Githinji et al.
] reported 3.5% had clubbing while Mwalukomo [
reported 22% with digital clubbing.
Participants were reported to have been on ART in 75%
of the studies (Table 2). The duration of ART was
reported in 5 studies and ranged from 2 to 8 years [
]. In 3 studies, no participant was on ART (Table 2); 2
of these studies took place in sub-Saharan Africa [
and 1 in Italy in the pre-ART era [
Lung function measures reported were spirometry
with bronchodilator response testing and exercise testing
(with treadmill or incremental shuttle walk test or
6MWT). One study included comprehensive lung
function testing including FOT and MBW tests [
Spirometry testing was standardized in all studies as per
American Thoracic Society (ATS)/European Respiratory
Society (ERS) criteria [
]. The definition of restrictive
pattern spirometry varied across studies with most
reporting reduced forced vital capacity (FVC) as a spirometry
pattern. The definition of obstructive pattern also varied
across studies, with some studies using the lower limit of
normal of forced expiratory volume in 1 s/forced vital
capacity (FEV1/FVC), as per the global lung initiative
] and others using FEV1/FVC < 80%. Shearer et al.
] had broad inclusion criteria of obstructive spirometry
pattern including FEF25–75 < 65% or FEV1/FVC < 80%.
Assessment and definition of bronchodilator
responsiveness varied among the studies. Criteria for
bronchodilator responsiveness (BDR) in most studies was change
in FEV1 > 12%. Shearer et al. [
] used albuterol and a
change of ≥10% in FEV1. Three studies used 2.5 mg
nebulized salbutamol [
1, 13, 16
] while the rest used 400 μg
Of the 10 studies reporting spirometry findings (Table 2),
9 reported obstructive spirometry pattern, 6 of which
demonstrated low rates of bronchodilator reversibility. In 5
studies with a comparator group, this rate of irreversible
obstruction spirometry was higher in the HIV-infected.
Rylance et al. [
] reported 11 (35%) out of 31
e m )s d m
iru ro tn ire ro
d e u d
q n c
c y s q yn :
““((((A scyen leodA ““((((cA iscyen rtySob
ND iifc R D ifc s
A e )O N e te
)))tse uond iirtca )))tsA uond aeno
t m ed te m n
io im ap n im O
tc d R ito d )s
c e r
fun ire O n ir e
u ) g
c fu uq a
ng cq irt g c 8 n
lu A ia n A :14 tee
lu R :5
R RO edp
R O 8 R
)tseO I)SD RO )tsO I)SD ,095 )tsO
tn RA )ren te RA ”,]6 fan
ifrtycuno i)rsyvuO li((((((hdC 6 iftcunon i)rsvuO lcaveeen li)eRnpO
a c (( :1 rya cyn :[ry o
n n ( 8 e
o ie D :5 on iie b p
lm ifc N 80 c rt g
u e A , lm fe o n
6 u d S u
Rp ond )))) 4 o
1 Rp uno ))e y
d 7 e
ireu :804 rom
q , d
c 2 n
A 5 y
O 2 c
) 4 n
S , e
IAD ”]ce iifc
R an d
O ve o
)s lre un
iv :y m
y b Im
cn rt d
ice So ire
if ) u
e e q
d m A
u d O
m yn )
i y m
an cn ro
uhm iifc y
R d cy
)VO uno ie
eRO thO I(((((H Imm ifceod 0 :00 7
m u O u e ”, ( d n :2 4 :3
iilIiillfff-rtttssccccaaeeeeeVuunnhnnonnonnoddddgHw rsyeKodw liiiilffrrrtttttttttsssssycyccaaFTeeeeRRRuuuuunonnonnnoonnoppgOOm iiiIiiiiiIffrrrsscyccycycavSeeeeeRRRVuuuuunnohnnononqddddAAHDOOOmmmmm rySeondm iiliilirrrrtttttssssccycaaaaaeeeeeeeeeeRRRRRRnhnononondppdddgCAOOOOOO ,,,iIfrrtsycaTSeeeeuuohndQmm ““””“,iiii((((()((()rrrrrttttttsssssssyccycaaaFTTFS#eeeeee35RRRuuhononhoonnppOM ””“““”IIiiiIf[)][)])(((((()rsscycyaSeeeeeRVRVRuunnonohhnhddHHOOOMMmmmmmm iiiIiiIif)f-rrrrcycycyycccSSeeeeeeeRRuuuuonnnonoonndddqddqdAAOOmmmmmm :ill))f)))][rrrtttttssscyyyaaaavSeeeeeeeeeeRRRRuunoohonnnnonongppgbOOOO ““””“,iiii((([)]((()rrrrrttttttsssssssycyccaaaFTTFS#eeeeee34RRRuuhononhononppOOM ””““”“IIiiiIf[)][))](((((()rsscycyaSeeeeeRVRVRuunnonohhnhddHHOOOMMmmmmmm iiiIiiIif)f-rrrrcycycyycccSSeeeeeeeRRuuuuonnnonoonnddqddqddAAOOmmmmmm “,iiiilil(((((((()))))rrrrttttsscccycaaaaS#eeeeee33RRRRuhhnohondpdpddCAOOOOO ”::,,,,l][rcva3522074245808eeen ”“:,,,:,:,lifrrrttsyccavaaSS#ee11e18057085132e32nnhonb ”“:,,,::,llrrrtycycvaaSS#eeee859010845104ee31uonhoongppb ”“:,,,,::,lrrrttycycvaaSS#ee183e9127085530e30uohhonb ”“:,,,,::,lrrrrttsyccavaaSS#eee1822014580016eeee29nhongb ”“:,,,,::,llrrrttssycccavaSS#eee1835480884954eee28ohnondbA ”“:,,,::,lrrrttsyccavaaSS#eee572680989440eee27onnhonb ”“:,,,::,liirrrrttycccaavaaSS#eee413757089416ee26hondpb ”“:,,,::,liirrrrttycccavaaSS#eee612750385848ee25hondpb ”“:,,,,::,lilrrrrtyccvaaSS#eee2174180988433ee24hhnondbC ““””““”““#2,IiiIi(((f)))][rrrssccyyccaSSeeeeeee3RRVuuhnonnohhqdddAHOOMMmmm iIiiiiiif)f)rr-rrscccyyccycySeeeeeeeeRRuuuunnonoonnnodddqddqAAOOmmmmmm “,iiiiIiiI((((()f))rrrsccyccavaSS#eeee22RRRVuuuuuhhnonnddqAAHDOOOmmmmm ”:,,::,liiIifrrrrtcyyycccvaSSeeeee424852634680eeuunonnoonddbdqAmmm “”:,:,,,iiliIfrrrrrtcycyycccvaaSSS#eeeee804407388eee21uuhnonnoonqdddbAmmm “”:,:,,,iiliIfr-rrrrtscycyyccaSSS#eee0184814821ee20uuuhnonnoooqdddbpbAmmm “”:,:,,,iiliifrrrrrtscycyycccvaaSS#eeeee804307388eee19uuhnonnoonqdddbAmmm ”“:,,,::,lIrrrtyccvaaSSS#eee502617043814e18honbAD ”“:,::,,,iiilifrrrrtsccyyccavvaaSS#eeeee323484204418e17uuuhhnnonondbmmm ”“:,,,::,lIrrrtcycvaaSS#eee641135082242e16VohnbH ““””““““”,IiiIi(f[)]][rrrrtsscycyccaSSS#eeeeeee15RVuuhonnnohohqdddAHOMMmmm ““”““,iiii()((()rrrrrttttttsssssssycyccaaaFTFTS#eeeeee14RRRuuhononhononppOOM ::,,330840580224
w A O
HIV-infected children with obstructive spirometry had
positive bronchodilator responsiveness, while Githinji et al.
] reported 15% of HIV-infected adolescents had
bronchodilator responsiveness compared to 8% HIV-uninfected
adolescents (p = 0.058). Mwalukomo et al. [
31.9% of the HIV-infected participants had bronchodilator
responsiveness. Shearer et al. [
] reported similar rates of
obstructive pattern spirometry between HIV-infected youth
and HIV-exposed uninfected youth (22% vs 21%), but a
lower rate of bronchodilator responsiveness in the
HIV-infected youth (17% vs 9%, p = 0.05).
Two studies reported diffusion tests (Table 2) that
were found to be lower or impaired in the HIV-infected
group compared to the uninfected. Airway obstruction
and reduced diffusion capacity were consistent findings
across age-groups from childhood [
adolescence (Table 2).
Seven studies reported exercise tests for
cardiopulmonary function status (6MWT or treadmill test) (Table 2),
which showed that HIV-infected participants had
functional aerobic impairment except for 1 study where no
difference in distance walked or oxygen desaturation was
reported after exertion (Table 2).
Determinants of lung function were reported in 4
5, 6, 12, 13
]. History of previous lower
respiratory tract infection or pulmonary TB was associated with
reduced FEV1 and DLCO . Cough > 1 month was
2.9 times more likely to be associated with abnormal
spirometry (95%CI 1.21–7.10) [
]. Mosaic attenuation
and extent of bronchiectasis were significantly associated
with reduced FEV1, (r = − 0.52 and r = − 0.50, p < 001,
One study reported MBW and FOT besides
spirometry (Table 2), where HIV-infected adolescents had
increased resistance, lower compliance, reduced functional
residual capacity and increased lung clearance index
compared to HIV-uninfected adolescents.
Two studies involved HIV-exposed uninfected children
], and 1 study had HIV-exposed uninfected youth as
a comparator group . Forced expiratory flow was
about 20% less in the HIV-exposed group but this
difference was not significant [
A summary of all studies included in this review is
presented in Table 2. Overall, results showed that
HIV-infected participants had reduced flow and volume
and functional aerobic impairment on exercise, reduced
ce itsc ts ud
s s en T
lo rtce lsce ,RA
d a o 3
a ad 19
d c d =
an t e n
n tc ,
n a e rs
e ip f a
r ic in e
lid rta I-V y1
h P H 1
p 1 h
-TeR .00 23%
A < ;
tc p n
sv in fe m g
% 9% i-n co itn
2 s IV d s
(2 v H te te
sp RD in fce ise
u B r n c
o e i- r
r e e
g iv ow IVH x
t l e
o o ity in on e in ,p FV
iiliiirrrrrttttssycaaveeeunnoppbmm iIf-ttsxcyaeeeeVuunnohhodddppH ,.fttcye0502euhod=p ,,,iliilffsccccvaaaeeuunonoopdpmm ;iiiIfrrttssccaaLeeeeeuhnnnngddCH .,iftc500eennd<p iiiiifrrrrrtttsyccaaaeeunononopdpmm sp iillifrttssxaavaeeeuhhhnoondgddpm ,.Iifr-tttsceee004Vuhonnod=Hmp ;.iirrrtttssycve13eBRuoopbD%m rcFeeVuddC irrtttssxcaa88eeeeeuoondd<% liiilifrrrrrttssyaaaeoononoopbmmm ..ï()rsavv652243euogp%% iïii-rtscavaTT6eeRunnonngpdAMW ,iirrrrtttssyccve20eeeuuoopddb%m
tsb 7% i-Vn low an u o uo I-V rn 10% 18% 10% rop -Tn ss 8%
-O −1 IH -F th to -N rg -H ob − − − -P RA -Le -1
g m it
h o w e
ta v rtye lttu ts rty
ry ry ,
te RD te RD M2 rb
m B m B N le T lb lfo s m s t m T
irop ith irop ith ,TO ing O MW iaTd and loop irop ,RD lka irop MW
S w S w F S C 6 S B w S 6
-Th 15 −1
icno rteod iicvengA syaenpd ilycaodd irtsyoh e ifrengd irtsengd irchond syendpd zeeehw
rch rep aeo rsee ahd ah ahd zeeh ah ing ah ia ah ah ahd
4 6 p % 5 % w 22 b 0% xo 15% uhg 15% 5%
% % n % % b
5 1 y
8 f lu 2 yp o
− o − c − h − c − − –
2 Jo .la cD te C te 71 fo
leaTb ,rtuohA itsaeeD 17025 IlifennC rraSeeh llrJyegA ijiitnhG ][1202 lsannA
is .la iln .la TSA
; m g
te ed n
c t ia
fe ce d
n f e
n i m
u n ,
ed I-V re
s ld T
o H s i R TR rsa
xp to ya ch A A e
e n d d y
I-V ro 50 tced eon tce 11
ts ts eg fe on fe e
n n a i-n ,n i-n ag
ifan ifan ian IVH rae IVH ian
9 6 ed 5 y 5 ed
2 4 8 1 8
1 5 m 3 1 3 m
- laon abbw - n
ss i ss io
ro ce im ro c
C s Z C s
n se n
r o o
o p ll
b x a
s e ;
t n rs
n u a
fan I-V ye
n , t e
c , g
ce ed fe rs a
lseod ftce rsa iunn teho s aen
a in ye d m tn m
d u 8 se d fa d
tce I-V e1 op tce in tce
if-en edH ang I-xeV if-en tced if-en
IVH tch iad H IV fe IV
re IV m g ,
lid H 0 a n FEV lka
h 0 1 ian itco ls
c 16 e ro , w
rn ts ted d ag ed ifen ton tced teu
tsob ifann tsh if-cen tsanh aenm ,renm IlVH ltych ifenn i-xnm
5 H in H T ifann fo% nom I2VH onm ;tsan lichd irtaan ae5h eud iST
5 7 R
1 m m 28 to un 1 A
- n rt
ss io o
ro tce SA o
C s U C
41 (34 42 13 47 ifn 45 ep 13 so W
SA SAU itve ilan lItya I-VH icca
,t c ud ,rt EU it
roh sep itg o ,H cae
rPo lon coh % ta
EV in y
se PA on
r T it
o D u
a cT lso
h , h
cn ity ig
ftceen isendg rty - ,lan ifrcaA - ,lan ,rtSAU
iI-V tyud cuno rsso itco tuh rsso itceo SA oho
H S & C s S C s U C
– – –
.ltaee 2002 aeRhb .liltaenA 2001 RCCM .lrtsyaee ]0002 syePhhdM .lrttzkaee 0002 RCCM .lrtsaeeno ]9991 liyoog irttaeon
compliance, increased respiratory system resistance and
reduced diffusion capacity compared to HIV-uninfected
participants. Participants who had longer ART duration
had less severe respiratory symptoms, less severe lower
airway obstruction and no aerobic impairment.
This review provides evidence of impairments in lung
function in perinatally HIV-infected children and
youth—predominantly irreversible lower airway
obstruction, reduction in exercise tolerance and reduced
diffusion capacity [
1, 6, 15, 16
]. Fixed airflow obstruction was
the most commonly reported finding, irrespective of
ART status (Table 2).
Irreversible airway obstruction is likely to be a
response to airway epithelium injury by opportunistic
infections (OIs) or from HIV, repair of which can lead to
proliferation of granulation tissue, fibrosis of airways and
subsequent obliteration of the lumen [
obliterans, which may result in irreversible lower airway
obstruction, has been reported as a predominant
pathology, evidenced by radiological manifestation of mosaic
attenuation on chest tomography in HIV-infected
adolescents with delayed access to ART [
inflammatory markers have also been found to be
increased in uncontrolled HIV or following repeated
infections . Lung infections like PCP [
] have been
associated with increased metalloproteinases and
chronic airflow obstruction in adults but none of the
studies in this review reported prior PCP in participants.
ART has been reported in HIV-infected adults to be
independently associated with irreversible airway
obstruction but the mechanism remains unproven [
A direct effect of ART on inflammation in the lung and
airways by reduction of peroxisome proliferator-activated
receptor has been reported in adults . Bronchodilator
reversibility was reported to be present in 15–35% of
participants. Despite the available evidence that irreversible
airway obstruction is common in HIV-infected children,
use of inhaled asthma medications has been reported to
be widely used in HIV-infected children and adolescents
]. Although bronchodilator reversibility was more
common in HIV-exposed uninfected youths than in the
HIV-infected youths, Shearer et al. [
] reported that
self-reported asthma diagnosis was higher in HIV-infected
youths than uninfected. This may be due to constellation
of symptoms of asthma-like respiratory illness; for
example, wheeze and cough in HIV-infected population and
physician use of inhalers in the patients who present with
Differences in disease severity across study populations
were more likely a result of varying duration of HIV
infection and ART use. Those who had ART therapy for a
duration of more than 7 years reported lower prevalence
of respiratory symptoms [
] than those who initiated
ART in later childhood [
]. Chronic lung diseases like
bronchiectasis and bronchiolitis obliterans are likely to
have occurred by the time of ART initiation, with most
of these studies reporting higher prevalence of chronic
cough and wheeze [
1, 5, 6
Functional aerobic impairment was more common in
HIV-infected participants than uninfected [
1, 16, 17, 29,
]. Those on ART were reported to have done better on
exertion than those not on ART [
]. The exercise
intolerance may have been due to impaired ventilation-perfusion
mechanics with possible heart dysfunction, though no
study in this review reported cardiac function. The
cardio-pulmonary function status results across studies
were inconsistent due to patient selection differences, with
Githinji et al. [
] reporting no significant difference in
exercise status between the HIV-infected adolescents and
the uninfected, and Chisati et al. [
] reporting low
aerobic endurance in the HIV-infected group. These
differences may be explained by differences in the cohorts and
ART use; all children in the former cohort were stable on
ART for a median duration of 8 years, whereas none of
the youth in the latter study were on ART.
While adult studies [
] have reported diffusion
impairment as predominant lung function abnormality,
diffusion impairment in HIV-infected children and
adolescents has not been commonly investigated.
However, HIV-infected adolescents on ART were reported to
have lower diffusion capacity compared to
HIV-uninfected adolescents . This suggests that HIV
or opportunistic infections may impair oxygen diffusion
either by thickening of alveolar-capillary membrane due
to interstitial inflammation or post-inflammation fibrosis,
or due to reduced surface area for gas exchange, as seen
in HIV-related bronchiectasis or bronchiolitis obliterans.
Alveolar-capillary membrane integrity may be damaged by
HIV and/or opportunistic infections well before the
presence of clinical symptoms, as reported by Alderson et al.
]. Emphysema, unlike in adults, was not documented
as a common presentation in HIV-infected adolescents in
]. Inflammation of the alveolar-capillary
membrane by opportunistic infections like PCP and other
acquired immunodeficiency syndrome (AIDS)-related
complications has also been documented [
diffusion capacity has been reported in adult patients who
had previous TB in a South African cohort [
study reported that pulmonary TB was associated with
reduced DLCO in HIV-infected adolescents [
The evidence on the impact of HIV in utero is
evolving, with only a few studies to date investigating
HIV-exposed uninfected infants. These found no
difference in spirometry pattern or forced expiratory
flow on thoraco-abdominal compression between
HIV-unexposed infants and HIV-exposed uninfected
]. Gray , however, reported increased
tidal volumes in HIV-exposed uninfected infants
compared to unexposed infants soon after birth.
Although accelerated lung function decline has been
shown in HIV-infected adults [
], published data on
longitudinal lung function changes in HIV-infected
children and adolescents are lacking. HIV has been reported
to cause decline in lung function after controlling for
other respiratory infections . Bacterial pneumonia in
HIV has been associated with permanent declines in
FEV1, FVC, FEV1/FVC and DLCO [
]. Pneumonia and
pulmonary TB were reported to be more common in
HIV-infected adolescents than uninfected in two of the
]. A result of prenatal and postnatal origin
of adult chronic obstructive airway disease as reported
in several studies [
7, 37, 38
] remains to be proven by
longitudinal studies where these HIV-infected children
and adolescents are followed to adulthood.
Limitations of this review include heterogeneity among
studies and lack of reporting by some studies on the
duration of ART. The studies were also carried out in
different eras of PMTCT and ART roll-out, where ART
was initiated at varying CD4 counts or clinical stages
]. Description of obstructive and restrictive
spirometry patterns was not uniform across studies with most
studies reporting reduced FVC as a spirometry pattern
and 1 study also including FEF25–75 in the definition of
obstructive spirometry. Determinants of lung function
were also not widely reported. Almost all studies were
cross sectional with very limited data on longitudinal
changes in lung function over time.
There is increasing evidence that HIV-infected children
and adolescents have high prevalence of lung function
impairment, predominantly irreversible lower airway
obstruction and reduced aerobic function. Lung function
impairment was milder in cohorts of
adolescents/children who had had earlier access to ART. Lung function
impairment starts early in life in the absence of ART, as
evidenced by the papers published in the pre-ART era.
Achievement of viral suppression through ART may
preserve lung function, though at a lower level compared to
HIV-uninfected individuals [
1, 12, 20, 34
There is a need for longitudinal studies on lung function
in HIV-infected children and adolescents in the post-ART
era into adulthood, as there is increasing evidence that
chronic obstructive pulmonary disease has its origins in
early life [
]. There is also need for more studies
comparing lung function among HIV-infected, HIV-exposed
uninfected and HIV-uninfected children and adolescents, to
provide evidence on how exposure to maternal virus in
utero may affect lung function and how early intervention
with ART in HIV-infected pregnant mothers may help to
preserve lung function in infants and children.
6MWT: Six-minute-walk test; ART: Antiretroviral therapy; BDR: Bronchodilator
responsiveness; CLD: Chronic lung disease; DLCO: Single breath diffusion test
for carbon monoxide; FOT: Forced oscillation technique; MBW: Nitrogen
multiple-breath washout test; PCP: Pneumocystis jirovecii pneumonia;
PMTCT: Prevention of mother-to-child transmission
Dilshaad Brey, University of Cape Town, South Africa, for expert assistance on
searching electronic databases.
African Partnership for Chronic Diseases and South Africa Medical Research
Availability of data and materials
Data sharing not applicable to this article as no datasets were generated
during the current study.
LG: abstracted data and wrote the manuscript. HZ: initial idea conception
and wrote manuscript. DG: wrote manuscript. All authors read and approved
the final manuscript.
Ethics approval and consent to participate
Obtained from University of Cape Town, Human Research Ethics Committee
Consent for publication
Authors declare that they have no competing interests.
Springer Nature remains neutral with regard to jurisdictional claims in
published maps and institutional affiliations.
1. McHugh G , Rylance J , Mujuru H , Nathoo K , Chonzi P , Dauya E , Bandason T , Simms V , Kranzer K , Ferrand RA . Chronic morbidity among older children and adolescents at diagnosis of HIV infection . Jaids-J Acquir Immune Defic Syndr . 2016 ; 73 : 275 - 81 .
2. Ue: UNAIDS 2016 estimates . http://aidsinfo.unaids.org/.
3. UNAIDS. Fact sheet July 2017 . 2017 . Available at http://www.unaids.org/en/ resources/fact-sheet.
4. Pitcher R , Beningfield S , Zar H . Chest radiographic features of lymphocytic interstitial pneumonitis in HIV-infected children . Clin Radiol . 2010 ; 65 : 150 - 4 .
5. Desai SR , Nair A , Rylance J , Mujuru H , Nathoo K , McHugh G , Majonga E , Metcalfe J , Kranzer K , Ferrand RA . Human Immunodeficiency VirusAssociated Chronic Lung Disease in Children and Adolescents in Zimbabwe: Chest Radiographic and High-Resolution Computed Tomographic Findings . Clin Infect Dis . 2018 ; 66 : 274 - 81 .
6. Ferrand RA , Desai SR , Hopkins C , Elston CM , Copley SJ , Nathoo K , Ndhlovu CE , Munyati S , Barker RD , Miller RF . Chronic lung disease in adolescents with delayed diagnosis of vertically acquired HIV infection . Clin Infect Dis . 2012 ; 55 : 145 - 52 .
7. Gray D , Willemse L , Visagie A , Czovek D , Nduru P , Vanker A , Stein DJ , Koen N , Sly PD , Hantos Z , et al. Determinants of early-life lung function in African infants . Thorax . 2017 ; 72 : 445 - 50 .
8. Platzker AC , Colin AA , Chen XC , Hiatt P , Hunter J , Koumbourlis AC , Schluchter MD , Ting A , Wohl ME . Thoracoabdominal compression and respiratory system compliance in HIV-infected infants . Am J Respir Crit Care Med . 2000 ; 161 : 1567 - 71 .
9. Colin AA , Sunil Rao J , Chen XC , Hunter JM , Hanrahan J , Hiatt P , Kattan M , Koumbourlis A , Mellins RB , Peavy HH , et al. Forced expiratory flow in uninfected infants and children born to HIV-infected mothers . Am J Respir Crit Care Med . 2001 ; 163 : 865 - 73 .
10. Alderson PO , Chen DC , Fleishman MJ , Hoh CK , Kim CK , Lee VW , Mellins RB , Miller JH , Moore WH , Peavy HH . Radioaerosol Scintigraphy in infants and children born to mothers with HIV disease . Radiology . 1999 ; 210 : 815 - 22 .
11. De Martino M , Veneruso G , Gabiano C , Frongia G , Tulisso S , Lombardi E , Tovo PA , Galli L , Vierucci A . Airway resistance and spirometry in children with perinatally acquired human immunodeficiency virus-type 1 infection . Pediatr Pulmonol . 1997 ; 24 : 406 - 14 .
12. Githinji LN , Gray DM , Hlengwa S , Myer L , Zar HJ . Lung function in south African adolescents infected perinatally with HIV and treated long-term with antiretroviral therapy . Ann Am Thorac Soc . 2017 ; 14 : 722 - 9 .
13. Mwalukomo T , Rylance SJ , Webb EL , Anderson S , O'Hare B , van Oosterhout JJ , Ferrand RA , Corbett EL , Rylance J. Clinical characteristics and lung function in older children vertically infected with human immunodeficiency virus in Malawi . J Pediatric Infect Dis Soc . 2016 ; 5 : 161 - 9 .
14. Masekela R , Anderson R , Moodley T , Kitchin OP , Risenga SM , Becker PJ , Green RJ . HIV-related bronchiectasis in children: an emerging spectre in high tuberculosis burden areas . Int J Tuberc Lung Dis . 2012 ; 16 : 114 - 9 .
15. Rylance S , Rylance J , McHugh G , Mujuru H , Munyati S , Bandason T , Metcalfe J , Kranzer K , Ferrand R. G276 (P) chronic respiratory morbidity among HIVinfected children in Zimbabwe; a comparison of ART naïve and treated cohorts . Arch Dis Child . 2016 ; 101 : A156 - 7 .
16. Rylance J , Mchugh G , Metcalfe J , Mujuru H , Nathoo K , Wilmore S , RowlandJones S , Majonga E , Kranzer K , Ferrand RA . Chronic lung disease in HIV-infected children established on antiretroviral therapy . AIDS . 2016 ; 30 : 2795 - 803 .
17. Chisati EM , Vasseljen O . Aerobic endurance in HIV-positive young adults and HIV-negative controls in Malawi . Malawi Med J. 2015 ; 27 : 5 .
18. Miller MR , Hankinson J , Brusasco V , Burgos F , Casaburi R , Coates A , Crapo R , Enright P , Van der Grinten C , Gustafsson P. Standardisation of spirometry . Eur Respir J . 2005 ; 26 : 319 - 38 .
19. Quanjer PH , Stanojevic S , Cole TJ , Baur X , Hall GL , Culver BH , Enright PL , Hankinson JL , Ip MS , Zheng J. Multi-ethnic reference values for spirometry for the 3-95-yr age range: the global lung function 2012 equations . Eur Respir J . 2012 ; 40 : 1324 - 43 .
20. Shearer WT , Jacobson DL , Yu W , Siberry GK , Purswani M , Siminski S , Butler L , Leister E , Scott G , Van Dyke RB. Long-term pulmonary complications in perinatally HIV-infected youth . J Allergy Clin Immunol . 2017 ; 140 : 1101 - 11 . e1107 .
21. Colin AA , Sunil Rao J , Chen XC , Hunter JM , Hanrahan J , Hiatt P , Kattan M , Koumbourlis A , Mellins RB , Peavy HH . Forced expiratory flow in uninfected infants and children born to HIV-infected mothers . Am J Respir Crit Care Med . 2001 ; 163 : 865 - 73 .
22. Kurland G , Michelson P . Bronchiolitis obliterans in children . Pediatr Pulmonol . 2005 ; 39 : 193 - 208 .
23. Gingo MR , Wenzel SE , Steele C , Kessinger CJ , Lucht L , Lawther T , Busch M , Hillenbrand ME , Weinman R , Slivka WA . Asthma diagnosis and airway bronchodilator response in HIV-infected patients . J Allergy Clin Immunol . 2012 ; 129 : 708 - 714 . e708 .
24. Morris A , Alexander T , Radhi S , Lucht L , Sciurba FC , Kolls JK , Srivastava R , Steele C , Norris KA . Airway obstruction is increased in pneumocystiscolonized human immunodeficiency virus-infected outpatients . J Clin Microbiol . 2009 ; 47 : 3773 - 6 .
25. Gingo MR , George MP , Kessinger CJ , Lucht L , Rissler B , Weinman R , Slivka WA , McMahon DK , Wenzel SE , Sciurba FC . Pulmonary function abnormalities in HIV-infected patients during the current antiretroviral therapy era . Am J Respir Crit Care Med . 2010 ; 182 : 790 - 6 .
26. George MP , Kannass M , Huang L , Sciurba FC , Morris A . Respiratory symptoms and airway obstruction in HIV-infected subjects in the HAART era . PLoS One . 2009 ; 4 : e6328 .
27. Mallon PWG , Unemori P , Sedwell R , Morey A , Rafferty M , William K , Chisholm D , Samaras K , Emery S , Kelleher A , et al. In vivo, nucleoside reverse-transcriptase inhibitors Alter expression of both mitochondrial and lipid metabolism genes in the absence of depletion of mitochondrial DNA . J Infect Dis . 2005 ; 191 : 1686 - 96 .
28. Siberry GK , Leister E , Jacobson DL , Foster SB , Seage GR , Lipshultz SE , Paul ME , Purswani M , Colin AA , Scott G. Increased risk of asthma and atopic dermatitis in perinatally HIV-infected children and adolescents . Clin Immunol . 2012 ; 142 : 201 - 8 .
29. Cade WT , Peralta L , Keyser RE . Aerobic capacity in late adolescents infected with HIV and controls . Pediatr Rehabil . 2002 ; 5 : 161 - 9 .
30. Keyser RE , Peralta L , Cade WT , Miller S , Anixt J . Functional aerobic impairment in adolescents seropositive for HIV: a quasiexperimental analysis . Arch Phys Med Rehabil . 2000 ; 81 : 1479 - 84 .
31. Diaz PT , King MA , Pacht ER , Wewers MD , GADEK JE , Neal D , Nagaraja HN , Drake J , Clanton TL . The pathophysiology of pulmonary diffusion impairment in human immunodeficiency virus infection . Am J Respir Crit Care Med . 1999 ; 160 : 272 - 7 .
32. Crothers K , McGinnis K , Kleerup E , Wongtrakool C , Hoo GS , Kim J , Sharafkhaneh A , Huang L , Luo Z , Thompson B . HIV infection is associated with reduced pulmonary diffusing capacity . J Acquir Immune Defic Syndr ( 1999 ). 2013 ; 64 : 271 - 8 .
33. Bateman E , Rom W , Dheda K , van Zyl-Smit R , Weiden M , Dawson R , Calligaro G . Respiratory symptoms and pulmonary function abnormalities in Hiv-infected patients on antiretroviral therapy in a high tuberculosis burden country . Am J Respir Crit Care Med . 2011 ; 183 : A6262 .
34. Kristoffersen US , Lebech AM , Mortensen J , Gerstoft J , Gutte H , Kjaer A . Changes in lung function of HIV-infected patients: a 4.5-year follow-up study . Clin Physiol Funct Imaging . 2012 ; 32 : 288 - 95 .
35. Drummond MB , Merlo CA , Astemborski J , Marshall MM , Kisalu A , McDyer JF , Mehta SH , Brown RH , Wise RA , Kirk GD . The effect of HIV infection on longitudinal lung function decline among injection drug users: a prospective cohort . Aids . 2013 ; 27 : 1303 - 11 .
36. Morris AM , Huang L , Bacchetti P , Turner J , Hopewell PC , Wallace JM , Kvale PA , Rosen MJ , Glassroth J , Reichman LB . Permanent declines in pulmonary function following pneumonia in human immunodeficiency virus-infected persons . Am J Respir Crit Care Med . 2000 ; 162 : 612 - 6 .
37. Postma DS , Bush A , van den Berge M. Risk factors and early origins of chronic obstructive pulmonary disease . Lancet . 2015 ; 385 : 899 - 909 .
38. Sly PD , Bush A. From the cradle to the grave: the early-life origins of chronic obstructive pulmonary disease . Am Thoracic Soc . 2016 ;
39. Organization WH : Consolidated guidelines on HIV prevention, diagnosis, treatment and care for key populations . 2016 .