The burden of child pneumonia mortality predominantly occurs in low-income and middle-income countries (LMICs) (1). Hypoxemia—a low blood oxyhemoglobin saturation—conveys increased pneumonia mortality risk, yet most children in LMICs lack pulse oximeter access (2, 3). Pulse oximeters identify hypoxemia by non-invasively measuring the peripheral arterial oxyhemoglobin saturation (SpO₂) (4). To simplify diagnosis in LMICs the World Health Organization (WHO) Integrated Management of Childhood Illness (IMCI) guidelines consider pneumonia a clinical syndrome (5). Although IMCI recommends oximeter use when available, it also provides guidance for settings without pulse oximetry (5).

There are challenges in the application of the IMCI algorithm for pneumonia management, which have remained largely unchanged since their inception in the mid-1990s. Since then, the guidelines have undergone one technical update that recommends children with chest indrawing but without clinical danger signs no longer require hospital referral (6, 7). Evidence suggests that gaps remain with the IMCI case management strategy, especially regarding use of the algorithm without pulse oximetry. Specifically, research reported IMCI missed ∼70% of outpatient child pneumonia cases with a SpO₂< 90% in Malawi and ∼90% in Bangladesh (8, 9). However, a stronger emphasis on the integration of pulse oximetry into IMCI guidance—while an important next step—is unlikely to immediately solve this issue as healthcare providers in most high pneumonia burden LMICs lack access to pulse oximeter devices in outpatient settings where children usually present to care first. High quality, affordable devices designed for the needs of infants and children in LMICs are not yet available. As a result, healthcare providers instead rely on clinical signs included in the IMCI guidelines to aid in the management of pneumonia cases. As most children first access health systems at outpatient clinics, improving outpatient hypoxemia identification may be key to reducing LMIC pneumonia mortality (4).

Prior research attempted to determine whether clinical signs accurately identify a SpO₂< 90% in hospitalized children as current guidelines limit severe case definitions to SpO₂ measurements <90% (10, 11). While these hospital-based studies report high specificity of clinical signs for a SpO₂ < 90%, sensitivity was low (10, 11). Similar studies in outpatient contexts are lacking, and may reveal new evidence than research from hospitals relying on study populations of more severely ill children not representative of outpatient settings. In settings where pulse oximeters are available, recent data also showed elevated mortality among children with a SpO₂ 90%–92% or 93%, as compared to higher SpO₂ levels (8, 12–14). These findings further challenge the current guidelines, which recommend SpO₂< 90% threshold for hospitalization and oxygen treatment in LMICs.

Given the need for healthcare providers in low-resource settings to rely mainly on IMCI-derived clinical signs for outpatient child pneumonia management, we sought to utilize two unique, contemporary outpatient pediatric pneumonia datasets from Bangladesh and Malawi to accomplish three objectives (15, 16). We first sought to evaluate the performance of IMCI clinical signs for identifying hypoxemia at a higher SpO₂ threshold (<93%) than recommended. Second, we examined whether other combinations of clinical features not included in IMCI guidelines better identify children with a SpO₂< 93%, followed by development and internal validation of pragmatic hypoxemia clinical scores that could be implemented where pulse oximeters remain unavailable. Third, we repeated these analyses using the currently recommended SpO₂< 90% threshold.

Using pooled data from 12,712 IMCI-defined child pneumonia cases evaluated at 21 clinics in Malawi and Bangladesh we examined WHO IMCI guideline hypoxemia identification performance and developed and internally validated clinical hypoxemia scores for use in LMICs where pulse oximeters suitable for pediatric outpatient care are scarce. Our findings suggest more hypoxemic children could be identified during outpatient care lacking pulse oximeters if additional signs of respiratory distress are incorporated into IMCI. Notably, >80% of hypoxemic cases with a SpO₂< 93% and >70% with a SpO₂< 90% were misclassified by IMCI as ineligible for hospital referral when pulse oximeters are unavailable. The independent LASSO model added age, severe respiratory distress, chest indrawing, cyanosis, fever, and wheezing parameters into the base IMCI guideline model and better identified children with a SpO₂< 93% than the IMCI and WHO-composite models. The composite LASSO model's simplified composite variables may facilitate implementation. Both LASSO models also achieved excellent discrimination of SpO₂< 90% cases.

Unlike other studies evaluating hypoxemia predictors we focused on ambulatory rather than hospital settings. This distinction is important as our findings should therefore be generalizable to outpatient settings without oximeters and with lower hypoxemia prevalence than hospitals (33, 34). Notably, individual variable sensitivity and specificity for hypoxemia are largely similar to hospital-based studies (11). However, our WHO-composite model and two LASSO models have good to excellent discriminatory values distinguishing between hypoxemic and non-hypoxemic pneumonia cases, contrasting to other work with smaller samples that limited analyses (11). An exception is a large, multi-center, hospital-based Nigerian study that found a combination of respiratory distress, inability to feed, cyanosis, lethargy and severe tachypnea had lower discrimination (C-statistic = 0.655) for SpO₂< 90% amongst respiratory and non-respiratory cases than in our data (10). The lower C-statistic may reflect the authors inclusion of older children <15 years.

It is also important our results are interpreted within the broader child pneumonia context of known mortality risk factors. In the IMCI and WHO-composite models WAZ ≤ −3 was not associated with a SpO₂< 90%, yet is a known mortality risk factor (14, 35). Conversely wheezing was retained in both LASSO models but, when identified alone without accompanying respiratory distress, it is not associated with radiographic pneumonia or in-hospital mortality (Supplementary Material) (14, 36). Isolated wheeze usually reflects milder, self-limited viral illness (e.g., bronchiolitis) and is susceptible to non-differential misclassification when confused with transmitted upper respiratory sounds.

While our pooling of data from studies in South Asia and Africa aimed to improve generalizability, there are several differences between the settings and studies that may be limitations. Malawi data had a higher frequency of hypoxemia, danger signs, and respiratory distress than Bangladesh data. Alternatively, WAZ ≤ −3 was more frequent in Bangladesh than Malawi. These differences, in part, may reflect higher HIV and malaria prevalence or modestly higher altitude in Malawi. These diseases increase susceptibility for hypoxemia or, for malaria, increase the frequency of signs overlapping with IMCI pneumonia (37). Although the designs differed, all personnel were similarly trained per IMCI and followed similar data collection procedures. Two different pulse oximeter devices were used in each study. In Malawi, healthcare workers used Acare pulse oximeters with the adult clip probes while in Bangladesh study staff used Masimo Rad5 pulse oximeters with wrap sensors. Although the devices differed, healthcare workers followed similar measurement procedures that relied on SpO₂ measurement of the child's big toe, which mitigated probe fit issues with the Acare device. Additionally, while pulse oximeter manufacturer algorithms for SpO₂ calculation may differ, we do not expect systematic, clinically relevant differences in population-level SpO₂ summary statistics between these devices as both were used similarly on patients by frequently supervised healthcare workers, met ISO 80601-2-61:2017 requirements for the basic safety and essential accuracy performance of pulse oximeters during laboratory testing, are CE marked, and commercially available. Lastly, the under 5 mortality rate in Malawi is higher than Bangladesh, (17, 18) which aligns with our results suggesting Malawi cases were more severe. Nevertheless, we attempted to account for unmeasured confounders from epidemiological, health system, and methodological differences by fitting models with a country variable.

We recognize that the future use of a clinical hypoxemia score would require further external validation and evaluation of implementation acceptability, feasibility, fidelity, and other early implementation indicators. Broader use of such clinical scores largely depend on health system capacity—for example, developing and maintaining well-trained clinical staff who can recognize the clinical features that comprise the score and who accept new guidelines, local expertise for overseeing and advising any adapted implementation, and, most importantly, resources such as oxygen and antibiotics to act on these symptoms and improve care with resultant improved outcomes. To optimize implementation further studies are needed to examine and adapt to changes to clinical procedure flows as well as assessment and adaptation of health system dynamics that include the capacity to handle additional referrals. These steps should be conducted within the context of strengthening the outpatient system for subsequent pulse oximeter implementation when appropriate, high quality devices for infants and children become accessible (38).

In sum, these findings may improve hypoxemic pneumonia identification in clinics either without pulse oximetry at all or lacking pulse oximeters suitable for pediatric use. Given a SpO₂ < 93% is highly associated with mortality, (3, 12, 14) earlier hypoxemic case identification with successful referral may reduce fatality. While these models could advance care for hypoxemic children they are an inadequate substitution for pulse oximeters. Pulse oximetry scale up in ambulatory settings must be prioritized, as should pulse oximeter device development targeted for young children in LMICs. Where pulse oximetry is unavailable for children, our models suggest children with chest indrawing and/or with other signs of respiratory distress could be referred. To successfully implement these models ambulatory health workers of varying pediatric experience will need further training to recognize signs of respiratory distress in children. Understanding how these changes may affect referral quality, uptake, and hospitalizations is critical. Next steps include external validation and research evaluating implementation feasibility of the hypoxemia scores.