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. Author manuscript; available in PMC: 2023 Apr 28.
Published in final edited form as: Pediatr Infect Dis J. 2022 May 1;41(5):e208–e215. doi: 10.1097/INF.0000000000003494

Severe Recurrent Bacterial Pneumonia Among Children Living With HIV

David C Boettiger *,†,‡, Vu Thien An §, Pagakrong Lumbiganon , Orasri Wittawatmongkol ‖, Khanh Huu Truong **, Viet Chau Do §, Lam Van Nguyen ††, Penh Sun Ly ‡‡, Aarti Kinikar §§, Pradthana Ounchanum ¶¶, Thanyawee Puthanakit ‖‖, Nia Kurniati ***, Nagalingeswaran Kumarasamy †††, Dewi Kumara Wati ‡‡‡, Kulkanya Chokephaibulkit ‖, Thahira A Jamal Mohamed §§§, Tavitiya Sudjaritruk ¶¶¶, Nik Khairulddin Nik Yusoff ‖‖‖, Moy Siew Fong ****, Revathy A Nallusamy ††††, Azar Kariminia *, on behalf of the TREAT Asia Pediatric HIV Observational Database
PMCID: PMC10140183  NIHMSID: NIHMS1889662  PMID: 35185140

Abstract

Background:

Bacterial pneumonia imparts a major morbidity and mortality burden on children living with HIV, yet effective prevention and treatment options are underutilized. We explored clinical factors associated with severe recurrent bacterial pneumonia among children living with HIV.

Methods:

Children enrolled in the TREAT Asia Pediatric HIV Observational Database were included if they started antiretroviral therapy (ART) on or after January 1st, 2008. Factors associated with severe recurrent bacterial pneumonia were assessed using competing-risk regression.

Results:

A total of 3,944 children were included in the analysis; 136 cases of severe recurrent bacterial pneumonia were reported at a rate of 6.5 [95% confidence interval (CI): 5.5–7.7] events per 1,000 patient-years. Clinical factors associated with severe recurrent bacterial pneumonia were younger age [adjusted subdistribution hazard ratio (aHR): 4.4 for <5 years versus ≥10 years, 95% CI: 2.2–8.4, P < 0.001], lower weight-for-age z-score (aHR: 1.5 for <−3.0 versus >−2.0, 95% CI: 1.1–2.3, P = 0.024), pre-ART diagnosis of severe recurrent bacterial pneumonia (aHR: 4.0 versus no pre-ART diagnosis, 95% CI: 2.7–5.8, P < 0.001), past diagnosis of symptomatic lymphoid interstitial pneumonitis or chronic HIV-associated lung disease, including bronchiectasis (aHR: 4.8 versus no past diagnosis, 95% CI: 2.8–8.4, P < 0.001), low CD4% (aHR: 3.5 for <10% versus ≥25%, 95% CI: 1.9–6.4, P < 0.001) and detectable HIV viral load (aHR: 2.6 versus undetectable, 95% CI: 1.2–5.9, P = 0.018).

Conclusions:

Children <10-years-old and those with low weight-for-age, a history of respiratory illness, low CD4% or poorly controlled HIV are likely to gain the greatest benefit from targeted prevention and treatment programs to reduce the burden of bacterial pneumonia in children living with HIV.

Keywords: HIV, pneumonia, bacteria, children, Asia

Bacterial pneumonia imparts a major morbidity and mortality burden on children living with HIV. Among children receiving antiretroviral therapy (ART) in Asia, severe recurrent bacterial pneumonia was one of the most commonly occurring opportunistic infections between 1993 and 2009 (10.0 cases per 1,000 person-years),1 and non-Pneumocystis pneumonia accounted for approximately 17% of mortality between 2008 and 2017.2

Although the etiology of bacterial pneumonia is usually unidentified in routine clinical practice, the most common causative organisms in children living with HIV in low- and middle-income countries are Streptococcus pneumoniae, Staphylococcus aureus and Hemophilus influenzae.3 There are vaccine options for both S. pneumoniae and H. influenzae which show good efficacy among children living with HIV,4–7 and co-trimoxazole prophylaxis prevents severe bacterial infection among children on ART.8 Early ART initiation, good ART adherence, measles vaccination, influenza vaccination, exclusive breast-feeding, nutritional supplements and preventing indoor air pollution also help to prevent bacterial pneumonia.9 However, preventative measures against childhood pneumonia are underutilized in resource-limited settings.10–14 Furthermore, antibiotic treatment is often not available for children with pneumonia in resource-limited settings14 and high rates of pneumonia treatment failure have been reported with the use of standard protocols in children living with HIV, probably due to a wider spectrum of pathogens, increased antimicrobial resistance and increased severity of the disease.15,16

To understand which sub-populations of children living with HIV could benefit most from targeted use of prevention and treatment strategies against bacterial pneumonia, we aimed to explore clinical factors associated with severe recurrent bacterial pneumonia among children living with HIV in low- and middle-income countries in Asia.

METHODS

Study Population

The TREAT Asia Pediatric HIV Observational Database (TApHOD) was established in 2008 and is a member cohort of the International Epidemiology Databases to Evaluate AIDS.17 The database includes routinely collected, patient-level data from more than 7,000 infants, children and adolescents with HIV who have been followed at one of 17 network sites in Cambodia (n = 1), India (n = 2), Indonesia (n = 2), Malaysia (n = 4), Thailand (n = 5) and Vietnam (n = 3). Network sites are pediatric referral clinics within larger healthcare facilities or freestanding pediatric hospitals; all but one (a research clinic) are public HIV treatment centers. TApHOD enrolees starting ART on or after January 1st, 2008 were eligible for this analysis. The dataset included data up to March 2020.

All network sites, the coordinating center (TREATAsia/amfAR, Thailand) and the data management and biostatistics center (Kirby Institute, UNSW Australia) have local institutional review board approval to participate in the cohort study. Consent by parents or legal guardians and assent of the children and adolescents under care are not routinely obtained unless required by the local institutional review board.

Definitions

Severe recurrent bacterial pneumonia was defined by physician diagnosis/confirmation of: cough with fast breathing, chest in-drawing, nasal flaring, wheezing and grunting; crackles or consolidation on auscultation; patient being responsive to a course of antibiotics and the current episode following 1 or more episodes in the previous 6 months. This is consistent with the World Health Organization (WHO) definition of a presumptive diagnosis.18 Isolation of bacteria from a specimen of induced sputum, bronchoalveolar lavage or lung aspirate could upgrade the diagnosis to definitive. However, confirmation of bacterial infection is rare in most clinical settings and presumptive and definitive diagnoses are not distinguished in TApHOD.

Baseline was defined as the date of ART initiation. The window period for baseline height, weight, hemoglobin concentration, CD4% and HIV viral load was between 6 months before and 14 days after baseline. When more than 1 measurement was available in the window period, the measurement taken closest to baseline was used. Height and weight measurements were converted into age- and sex-standardized z scores. Height-for-age z scores were calculated using the 2007 WHO child growth standards and macros.19, 20 Weight-for-age z scores were calculated using the WHO child growth standards and macros for 1977.21 The 1977 standards were used because the 2007 WHO weight-for-age standards are limited to children ≤10 years of age, and a previous analysis of the Asia Pacific cohort found that the 1977 and 2007 standards provided similar results.22 Pulmonary tuberculosis, pneumocystis pneumonia, symptomatic lymphoid interstitial pneumonitis, chronic HIV-associated lung disease including bronchiectasis and recurrent severe bacterial infection (excluding pneumonia) diagnoses definitions were consistent with WHO guidelines.18 Anemia was defined according to the age- and sex-specific limits outlined in the Division of AIDS table for grading the severity of adult and pediatric adverse events.23 HIV viral load was defined as undetectable if <400 copies/ml. Children were considered to be using co-trimoxazole if they were using any form of prophylactic co-trimoxazole. Country income status was based on the World Bank classification.24 Patients were defined as lost to follow-up if they had not been seen at their treating clinic for >12 months without documentation of transfer or death.

Statistical Analysis

Factors associated with severe recurrent bacterial pneumonia on ART were assessed using Kaplan–Meier curves and competing-risk regression. Deaths not associated with severe recurrent bacterial pneumonia, loss to follow-up and clinic transfer were considered competing risks. Follow-up was censored at the last recorded clinic visit.

Sex, pre-ART severe recurrent bacterial pneumonia, year of ART initiation and country income status were modeled as fixed covariates. Age, height-for-age, weight-for-age, anemia, past pulmonary tuberculosis, past pneumocystis pneumonia, past symptomatic lymphoid interstitial pneumonitis or chronic HIV-associated lung disease, including bronchiectasis, past recurrent severe bacterial infection (excluding pneumonia), CD4%, HIV viral load, ART regimen and trimethoprim-sulfamethoxazole use were evaluated as time-updated covariates.

Covariates were included in the initial multivariate model if 1 or more categories had a univariate P value of <0.25 and retained in the final model if 1 or more categories exhibited an adjusted P value of <0.05. Patients with missing data were included in all analyses, but we do not report sub-distribution hazard ratios (HRs) for missing categories.

Sensitivity Analysis

We repeated the above-described regression analysis in the subset of our cohort who started ART during or after 2012 to assess whether the associations found in our main model would be consistent in a more recent cohort.

Software

We performed all data management using SAS 9.4 (SAS Institute, Inc, Cary, NC) and all statistical analyses with Stata 16 (Stata Corp., College Station, TX).

RESULTS

Of 7,385 children in the March 2020 TApHOD, 6,615 (89.6%) had a history of initiating ART and 3,944 (53.4%) started ART on or after January 1st, 2008 and were included in the analysis. Their baseline characteristics are described in Table 1.

TABLE 1.

Characteristics of Children at Antiretroviral Therapy Initiation

Characteristic N = 3,944
Age (years) <5 1,926 48.8%
5 to <10 1,165 29.5%
10 to <15 672 17.0%
≥15 181 4.6%
Median (IQR) 5.1 (2.1, 9.3)
Sex Male 2,090 53.0%
Female 1,854 47.0%
Height-for-age z-score >−2.0 1,260 31.9%
−2.0 to −3.0 753 19.1%
<−3.0 848 21.5%
Unknown 1,083 27.5%
Median (IQR) −2.2 (−3.2 to −1.3)
Weight-for-age z-score >−2.0 1,420 36.0%
−2.0 to −3.0 694 17.6%
<−3.0 1,221 31.0%
Unknown 609 15.4%
Median (IQR) −2.4 (−3.7 to −1.1)
Hemoglobin Normal 1,434 36.4%
Mild/moderate 965 24.5%
anemia Severe anemia 345 8.7%
Unknown 1,210 30.7%
Past severe recurrent bacterial pneumonia No 3,674 93.2%
Yes 270 6.8%
Past pulmonary tuberculosis No 3,497 88.7%
Yes 447 11.3%
Past pneumocystis pneumonia No 3,863 97.9%
Yes 81 2.1%
Past symptomatic lymphoid No 3,922 99.4%
interstitial pneumonitis
Yes 22 0.6%
Past chronic HIV-associated No 3,908 99.1%
lung disease*
Yes 36 0.9%
Past recurrent severe No 3,931 99.7%
bacterial infection (excluding pneumonia)
Yes 13 0.3%
CD4% ≥25% 489 12.4%
1024% 1,348 34.2%
<10% 1,142 29.0%
Unknown 965 24.5%
Median (IQR) 13.0 (5.0, 20.9)
HIV viral load, copies/ml Unknown 2,934 74.4%
Median (IQR) 138,418 (27,012, 648,114)
ART regimen NNRTI-based 3,375 85.6%
PI-based 459 11.6%
Other ART 110 2.8%
Trimethoprim-sulfamethox- No 1,512 38.3%
azole use
Yes 2,432 61.7%
Year of ART initiation 2008–2011 1,898 48.1%
2012–2015 1,289 32.7%
2016–2020 757 19.2%
Country income status Lower-middle 2,742 69.5%
Upper-middle 1,202 30.5%
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ART, antiretroviral therapy; IQR, interquartile range; NNRTI, non-nucleoside reverse transcriptase inhibitor; PI, protease inhibitor; WHO, World Health Organization.

All values are n (%N) unless otherwise specified.

*

including bronchiectasis.

One hundred and thirty-six cases of severe recurrent bacterial pneumonia occurred over 20,950.One patient-years at a rate of 6.5 [95% confidence interval (CI): 5.5–7.7] events per 1,000 patient-years. Six of the 136 events (4.4%) were documented as a cause of death and all 6 of these deaths occurred in the first year of ART use. A total of 216 all-cause deaths occurred at a rate of 10.3 (95% CI: 9.0–11.8) events per 1,000 patient-years. There were 231 children lost to follow-up at a rate of 11.0 (95% CI: 9.7–12.5) events per 1,000 patient-years. Among children who remained alive after a diagnosis of severe recurrent bacterial pneumonia and who had ≥1 day of follow-up after diagnosis (n = 127), 13 deaths occurred over the course of 761.4 patient-years at a rate of 17.1 (95% CI: 9.9–29.4) events per 1,000 patient-years.

Figure 1 and Table 2 show that clinical factors associated with severe recurrent bacterial pneumonia were younger age [adjusted HR (aHR): 4.4 for <5 years vs. ≥10 years, 95% CI: 2.2–8.4, P < 0.001 and aHR: 2.4 for 5 to <10 years vs. ≥10 years, 95% CI: 1.2–4.8, P = 0.01], lower weight-for-age z-score (aHR: 1.5 for <−3.0 vs. >−2.0, 95% CI: 1.1–2.3, P = 0.024), pre-ART diagnosis of severe recurrent bacterial pneumonia (aHR: 4.0 vs. no pre-ART diagnosis, 95% CI: 2.7–5.8, P < 0.001), past diagnosis of symptomatic lymphoid interstitial pneumonitis or chronic HIV-associated lung disease including bronchiectasis (aHR: 4.8 vs. no past diagnosis, 95% CI: 2.8–8.4, P < 0.001), low CD4% (aHR: 3.5 for <10% vs. ≥25%, 95% CI: 1.9–6.4, P < 0.001 and aHR: 2.0 for 10–24% vs. ≥25%, 95% CI: 1.1–3.6, P = 0.018) and detectable HIV viral load (aHR: 2.6 vs. undetectable, 95% CI: 1.2–5.9, P = 0.018). Later year of ART initiation (aHR: 0.1 for 2016–2020 vs. 2008–2011, 95% CI: 0.0–0.3, P < 0.001 and aHR: 0.4 for 2012–2015 vs. 2008–2011, 95% CI: 0.2–0.6, P < 0.001) and receiving care in an upper-middle-income country (aHR: 0.6 vs. lower-middle-income, 95% CI: 0.3–0.9, P = 0.023) were associated with a lower hazard of severe recurrent bacterial pneumonia. Results from our sensitivity analysis, which only included children who started ART during or after 2012, were broadly consistent with our main model (Table 1, Supplemental Digital Content 1, http://links.lww.com/INF/E679).

FIGURE 1.

FIGURE 1.

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Kaplan-Meier curves showing clinical factors associated with severe recurrent bacterial pneumonia. *Symptomatic lymphoid interstitial pneumonitis or chronic HIV-associated lung disease including bronchiectasis; ART, antiretroviral therapy.

TABLE 2.

Competing Risk Regression Models Showing Factors Associated with Severe Recurrent Bacterial Pneumonia

Characteristic Severe recurrent bacterial pneumonia Patient-years Rate per 1,000 patient years (95% CI) Univariate HR (95% CI) P Multivariate HR (95% CI) P
Age (years)
 <5 89 4,552.4 19.5 (15.9, 24.1) 6.2 (3.4, 11.4) <0.001 4.4 (2.3, 8.4) <0.001
 5 to <10 37 7,598.8 4.9 (3.5, 6.7) 3.3 (1.7, 6.4) 0.001 2.4 (1.2, 4.8) 0.010
 ≥10 10 8,798.9 1.1 (0.6, 2.1) 1.00 1.00
Sex
 Male 75 10,971.5 6.8 (5.5, 8.6) 1.00
 Female 61 9,978.7 6.1 (4.8, 7.9) 0.9 (0.7, 1.3) 0.596
Height-for-age z-score
 >−2.0 34 10,525.1 3.2 (2.3, 4.5) 1.00
 −2.0 to −3.0 22 4,483.8 4.9 (3.2, 7.5) 1.1 (0.7, 1.9) 0.646
 <−3.0 38 3,982.4 9.5 (6.9, 13.1) 1.8 (1.1, 2.9) 0.012
 Unknown 42 1,958.9 21.4 (15.8, 29.0) –
Weight-for-age z-score
 >−2.0 44 11,380.0 3.9 (2.9, 5.2) 1.00 1.00
 −2.0 to −3.0 26 4,233.1 6.1 (4.2, 9.0) 1.3 (0.8, 2.2) 0.252 1.2 (0.8, 2.0) 0.386
 <−3.0 59 4,377.7 13.5 (10.4, 17.4) 1.9 (1.3, 2.8) 0.001 1.5 (1.1, 2.3) 0.024
 Unknown 7 959.3 7.3 (3.5, 15.3) -
Hemoglobin
 Normal 51 14,906.5 3.4 (2.6, 4.5) 1.00
 Anemia 43 2,950.8 14.6 (10.8, 19.6) 1.5 (1.0, 2.2) 0.047
 Unknown 42 3,092.8 13.6 (10.0, 18.4) –
Pre-ART severe recurrent bacterial pneumonia
 No 99 19,782.3 5.0 (4.1, 6.1) 1.00 1.00
 Yes 37 1,167.8 31.7 (23.0, 43.7) 5.4 (3.7, 7.9) <0.001 4.0 (2.7, 5.8) <0.001
Past pulmonary tuberculosis
 No 122 17,803.6 6.9 (5.7, 8.2) 1.00
 Yes 14 3,146.5 4.4 (2.6, 7.5) 0.8 (0.4, 1.3) 0.336
Past Pneumocystis pneumonia
 No 133 20,409.1 6.5 (5.5, 7.7) 1.00
 Yes 3 541.0 5.5 (1.8, 17.2) 0.9 (0.3, 2.8) 0.819
Past pneumonitis or lung disease*
 No 125 20,388.7 6.1 (5.1, 7.3) 1.00 1.00
 Yes 11 561.5 19.6 (10.8, 35.4) 4.4 (2.4, 8.2) <0.001 4.8 (2.8, 8.4) <0.001
Past recurrent severe bacterial infection (excluding pneumonia)
 No 135 20,835.6 6.5 (5.5, 7.7) 1.00
 Yes 1 114.6 8.7 (1.2, 62.0) 1.6 (0.2, 11.8) 0.653
CD4%
 ≥25% 17 12,120.7 1.4 (0.9, 2.3) 1.00 1.00
 10–24% 39 6,075.3 6.4 (4.7, 8.8) 2.0 (1.1, 3.6) 0.020 2.0 (1.1, 3.6) 0.018
 <10% 40 1,361.6 29.4 (21.5, 40.0) 3.7 (2.0, 6.8) <0.001 3.5 (1.9, 6.4) <0.001
 Unknown 40 1,392.5 28.7 (21.1, 39.2) – –
HIV viral load
 Undetectable 9 11,174.3 0.8 (0.4, 1.5) 1.00 1.00
 Detectable 41 3,654.7 11.2 (8.3, 15.2) 4.8 (2.2, 10.4) <0.001 2.6 (1.2, 5.9) 0.018
 Unknown 86 6,121.1 14.0 (11.4, 17.4) – –
ART regimen
 NNRTI-based 122 16,415.3 7.4 (6.2, 8.9) 1.00
 PI-based 11 3,755.5 2.9 (1.6, 5.3) 0.6 (0.3, 1.0) 0.066
 Other ART 1 542.1 1.8 (0.3, 13.1) 0.2 (0.0, 1.6) 0.142
 Treatment break 2 237.3 8.4 (2.1, 33.7) 2.0 (0.5, 8.3) 0.330
Trimethoprim-sulfamethoxazole use
 No 37 16,244.8 2.3 (1.7, 3.1) 1.00
 Yes 99 4,705.4 21.0 (17.3, 25.6) 2.9 (2.0, 4.2) <0.001
Year of ART initiation
 2008–2011 107 13,432.8 8.0 (6.6, 9.6) 1.00 1.00
 2012–2015 26 5,954.5 4.4 (3.0, 6.4) 0.4 (0.2, 0.6) <0.001 0.4 (0.2, 0.6) <0.001
 2016–2020 3 1,562.8 1.9 (0.6, 6.0) 0.1 (0.0, 0.3) <0.001 0.1 (0.0, 0.3) <0.001
Country income status
 Lower-middle 111 14,271.6 7.8 (6.5, 9.4) 1.00 1.00
 Upper-middle 25 6,678.6 3.7 (2.5, 5.5) 0.5 (0.3, 0.8) 0.002 0.6 (0.3, 0.9) 0.023
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ART, antiretroviral therapy; CI, confidence interval; HR, sub-distribution hazard ratio; NNRTI, non-nucleoside reverse transcriptase inhibitor; PI, protease inhibitor.

Patients with missing data were included in all analyses, but we do not report sub-distribution hazard ratios for missing categories.

*

Symptomatic lymphoid interstitial pneumonitis or chronic HIV-associated lung disease including bronchiectasis.

Table 3 shows that, at the time of severe recurrent bacterial pneumonia diagnosis, the median age was 4.1 [interquartile range (IQR) 1.9–6.3] years, median weight-for-age z-score was −2.8 (IQR −3.7, −1.7) and median CD4% was 11.3% (IQR 2.9–23.0%). Past severe recurrent bacterial pneumonia was documented among 37 (27.2%) children and past symptomatic lymphoid interstitial pneumonitis or chronic HIV-associated lung disease, including bronchiectasis was documented among 11 (8.1%) children. Of 51 children with an HIV viral load measurement available at the time of severe recurrent bacterial pneumonia diagnosis, 42 (82.4%) had a detectable level.

TABLE 3.

Characteristics of Children with Severe Recurrent Bacterial Pneumonia at Time of Diagnosis

Characteristic N = 136
Age (years) <5 84 61.8%
5 to <10 41 30.1%
10 to <15 10 7.4%
≥15 1 0.7%
Median (IQR) 4.1 (1.9, 6.3)
Sex Male 75 55.1%
Female 61 44.9%
Height-for-age z-score >−2.0 32 23.5%
−2.0 to −3.0 22 16.2%
<−3.0 45 33.1%
Unknown 37 27.2%
Median (IQR) −2.7 (−3.7, −1.7)
Weight-for-age z-score >−2.0 40 29.4%
−2.0 to −3.0 30 22.1%
<−3.0 61 44.9%
Unknown 5 3.7%
Median (IQR) −2.8 (−4.6, −1.7)
Hemoglobin Normal 52 38.2%
Mild/moderate anemia 35 25.7%
Severe anemia 11 8.1%
Unknown 38 27.9%
Past severe recurrent bacterial pneumonia No 99 72.8%
Yes 37 27.2%
Past pulmonary tuberculosis No 121 89.0%
Yes 15 11.0%
Past Pneumocystis pneumonia No 132 97.1%
Yes 4 2.9%
Past symptomatic lymphoid interstitial pneumonitis No 130 95.6%
Yes 6 4.4%
Past chronic HIV-associated lung disease* No 131 96.3%
Yes 5 3.7%
Past recurrent severe bacterial infection (excluding pneumonia) No 134 98.5%
Yes 2 1.5%
CD4% ≥25% 19 14.0%
10–24% 37 27.2%
<10% 43 31.6%
Unknown 37 27.2%
Median (IQR) 11.3 (2.9, 23.0)
HIV viral load, copies/ml Undetectable 9 6.6%
Detectable 42 30.9%
Unknown 85 62.5%
Median (IQR) 25,163 (400, 138,795)
ART regimen NNRTI-based 122 89.7%
PI-based 11 8.1%
Other ART 1 0.7%
Treatment break 2 1.5%
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ART, antiretroviral therapy; IQR, interquartile range; NNRTI, non-nucleoside reverse transcriptase inhibitor; PI, protease inhibitor.

All values are n (%N) unless otherwise specified.

*

including bronchiectasis.

DISCUSSION

Severe recurrent bacterial pneumonia occurred at a rate of 6.5 events per 1,000 patient-years among children using ART. In 4.4% of cases, the diagnosis was a contributing cause of death. Among children that survived beyond their diagnosis, the rate of death was approximately 1.7 times that of children without a history of severe recurrent bacterial pneumonia on ART. Clinical factors associated with severe recurrent bacterial pneumonia were younger age, lower weight-for-age z-score, pre-ART diagnosis of severe recurrent bacterial pneumonia, past diagnosis of symptomatic lymphoid interstitial pneumonitis or chronic HIV-associated lung disease, including bronchiectasis, low CD4%, and having detectable HIV viral load.

The clinical factors we found to be associated with severe recurrent bacterial pneumonia are broadly aligned with earlier work25–29 and highlight sub-populations of children living with HIV who may experience substantial benefit from targeted intervention to improve prevention and treatment of bacterial pneumonia. In particular, children under 5-years-old and those with a history of severe recurrent bacterial pneumonia, lymphoid interstitial pneumonitis or chronic HIV-associated lung disease appear to be subgroups that could benefit. Such interventions could include wider coverage of S. pneumoniae, H. influenzae, measles and influenza vaccination; further expansion of early ART initiation; broader use of trimethoprim-sulfamethoxazole prophylaxis; increased breast-feeding and availability of nutritional supplements and minimization of indoor air pollution.

The early initiation of ART among perinatally infected children has been shown to dramatically reduce the incidence of AIDS-defining illnesses.30,31 However, in 2019, only 52.7% of children living with HIV <14 years old were receiving ART.13 The WHO currently recommends trimethoprim-sulfamethoxazole initiation in all children living with HIV, irrespective of disease stage or use ART, to prevent infections and reduce overall mortality risk.32 Yet, an analysis of clinics in Africa and Asia found that trimethoprim-sulfamethoxazole was being used by only 48.5% of children starting ART in 2015–2016.10 Nutritional deficiencies and malnutrition are common in children living with HIV and are associated with increased morbidity and mortality.33,34 Modeling has shown that the expanded use of zinc supplements and promotion of breast-feeding have the potential to cost-effectively reduce pneumonia incidence in low- and middle-income settings.35 Exposure to indoor air pollution increases the risk of childhood pneumonia.36 Minimizing this risk by promoting good ventilation in homes and avoiding tobacco smoke exposure should be part of the general measures to reduce childhood pneumonia in children living with HIV.

Vaccination against S. pneumoniae is immunogenic in HIV-infected children and reduces vaccine-type invasive disease by 83%–91%.5,6 Similarly, the H. influenzae type b vaccine confers substantial protection against pneumonia and invasive disease in children living with HIV.7 In 2016, median national S. pneumoniae vaccine coverage among children in lower- and middle-income countries was 84% (range 7%–99%) and, for H. influenzae type b vaccine, 91% (range 11%–99%).14 Measles and influenza vaccines also exert immunogenic responses in children living with HIV.37–41 Both vaccines prevent the development of secondary bacterial infections, including pneumonia. In 2016, median national measles vaccination coverage among children 12–23 months of age in low- and middle-income countries was 90% (range 20%–99%).14 Annual coverage rates for influenza vaccination are not well documented for children, however, among children who turned 2-years-old in the US between 2016 and 2017, 58.1% had received ≥2 doses of vaccine.42 Despite the abovementioned coverage rates being reasonably good, many of the countries lagging behind are those with a heavy HIV burden.

It is recommended that all HIV-infected children with severe bacterial pneumonia be admitted to the hospital due to a high risk of rapid progression and treatment failure.43 Initial antibiotic therapy should include broad-spectrum antibiotic cover based on previous use of therapeutic or prophylactic antibiotics and local prevalence of antimicrobial resistance. HIV-infected children with mild pneumonia should be treated with amoxicillin 25–30 mg/kg/dose either twice or 3 times daily for 5 days.43 Nevertheless, among low- and middle-income countries, the median national percentage of children <5-years-old with pneumonia taken for treatment at a health facility or provider is approximately 64% (range 0%–98%).14 Among children <5-years-old with pneumonia, the median national percentage who receive antibiotic treatment is approximately 49% (range 8%–88%).14

Prior studies of children on ART have focused on a singular diagnosis of bacterial pneumonia rather than severe recurrent bacterial pneumonia. Therefore, reported incidence rates are substantially higher than what we found. For example, Alcaron et al44 described an incidence of 78.2 events per 1,000 patient-years between 2002 and 2007 among children ≤21 years of age in Latin America; Mubiana-Mbewe et al45 reported an incidence of 133 events per 1,000 patient-years between 2004 and 2006 among children <15 years old in Zambia and Melkamu et al46 described an incidence of 26.9 events per 1,000 patient-years between 2005 and 2019 among children <15 years old in Ethiopia. Consistent with our findings, however, studies evaluating changes in bacterial pneumonia incidence by calendar year have found a steady decline over time.28, 47, 48 This is probably due to early initiation of ART becoming more common,10 increasing use of vaccines that prevent bacterial pneumonia14 and improvements in pediatric ART formulation leading to better adherence and HIV control.49

Although we lacked data on definitive diagnoses of bacterial pneumonia, our presumptive diagnosis definition was thorough, consistent with WHO guidelines,18 and indicative of how bacterial pneumonia is typically diagnosed in clinical practice. Unfortunately, our study database lacked information on participant vaccination history. This would have allowed us to assess the role of vaccination in the declining incidence of severe recurrent bacterial pneumonia over time and may have modified the strength of the associations identified.

Bacterial pneumonia is common in children living with HIV in low- and middle-income countries and can progress to severe recurrent bacterial pneumonia. We found that severe recurrent bacterial pneumonia is associated with a high rate of mortality, both at the time of diagnosis and postdiagnosis. Children <10-years-old and those with low weight-for-age, a history of respiratory illness, a low CD4% or poorly controlled HIV are likely to gain the greatest benefit from targeted prevention and treatment programs to reduce the burden of bacterial pneumonia in children living with HIV.

Supplementary Material

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ACKNOWLEDGMENTS

PS Ly, V Khol, National Centre for HIV/AIDS, Dermatology and STDs, Phnom Penh, Cambodia; J Tucker, New Hope for Cambodian Children, Phnom Penh, Cambodia; N Kumarasamy, E Chandrasekaran, Chennai Antiviral Research and Treatment Clinical Research Site (CART CRS), VHS-Infectious Diseases Medical Centre, VHS, Chennai, India; A Kinikar, V Mave, S Nimkar, I Marbaniang, BJ Medical College and Sassoon General Hospitals, Maharashtra, India; DK Wati, D Vedaswari, IB Ramajaya, Sanglah Hospital, Udayana University, Bali, Indonesia; N Kurniati, D Muktiarti, Cipto Mangunkusumo – Faculty of Medicine Universitas Indonesia, Jakarta, Indonesia; SM Fong, M Lim, F Daut, Hospital Likas, Kota Kinabalu, Malaysia; NK Nik Yusoff, P Mohamad, Hospital Raja Perempuan Zainab II, Kelantan, Malaysia; TJ Mohamed, MR Drawis, Department of Pediatrics, Women and Children Hospital Kuala Lumpur, Kuala Lumpur, Malaysia; R Nallusamy, KC Chan, Penang Hospital, Penang, Malaysia; T Sudjaritruk, V Sirisanthana, L Aurpibul, Department of Pediatrics, Faculty of Medicine, and Research Institute for Health Sciences, Chiang Mai University, Chiang Mai, Thailand; P Ounchanum, R Hansudewechakul, S Denjanta, A Kongphonoi, Chiangrai Prachanukroh Hospital, Chiang Rai, Thailand; P Lumbiganon, P Kosalaraksa, P Tharnprisan, T Udomphanit, Division of Infectious Diseases, Department of Pediatrics, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand; G Jourdain, PHPT-IRD UMI 174 (Institut de recherche pour le développement and Chiang Mai University), Chiang Mai, Thailand; T Puthanakit, S Anugulruengkit, W Jantarabenjakul, R Nadsasarn, Department of Pediatrics and Center of Excellence for Pediatric Infectious Diseases and Vaccines, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand; K Chokephaibulkit, K Lapphra, W Phongsamart, S Sricharoenchai, Department of Pediatrics, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand; KH Truong, QT Du, CH Nguyen, Children’s Hospital 1, Ho Chi Minh City, Vietnam; VC Do, TM Ha, VT An Children’s Hospital 2, Ho Chi Minh City, Vietnam; LV Nguyen, DM Tran, HTT Tran, TTT Giang, National Hospital of Pediatrics, Hanoi, Vietnam; ON Le, Worldwide Orphans Foundation, Ho Chi Minh City, Vietnam; AH Sohn, JL Ross, T Suwanlerk, TREAT Asia/amfAR - The Foundation for AIDS Research, Bangkok, Thailand; MG Law, A Kariminia, The Kirby Institute, UNSW Sydney, NSW, Australia.

The TREAT Asia Pediatric HIV Observational Database is an initiative of TREAT Asia, a program of amfAR, The Foundation for AIDS Research, with support from the US National Institutes of Health’s National Institute of Allergy and Infectious Diseases, the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Cancer Institute, National Institute of Mental Health, National Institute on Drug Abuse, the National Heart, Lung, and Blood Institute, the National Institute on Alcohol Abuse and Alcoholism, the National Institute of Diabetes and Digestive and Kidney Diseases and the Fogarty International Center, as part of the International Epidemiology Databases to Evaluate AIDS (IeDEA; U01AI069907). The Kirby Institute is funded by the Australian Government Department of Health and Ageing, and is affiliated with the Faculty of Medicine, UNSW Australia. The content of this publication is solely the responsibility of the authors and does not necessarily represent the official views of any of the governments or institutions mentioned above.

Footnotes

The authors have no conflicts of interest to disclose.

Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s website (www.pidj.com).

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