1 Introduction

Acute lower respiratory infections (ALRIs) encompass a range of conditions affecting the lower respiratory tract, including pneumonia, bronchiolitis, bronchitis, and influenza. These infections are particularly significant in pediatric health due to their high prevalence and potential severity in young children. ALRIs are a leading cause of morbidity and mortality among children worldwide, especially in those under five years of age (Chaw et al., 2019a; Hasuwa et al., 2020; Oakes et al., 2023). Each year, millions of cases are reported, leading to substantial healthcare utilization and economic burden (Keita et al., 2023). In developing countries, the situation is exacerbated by limited access to healthcare and preventive measures, making ALRIs a critical public health issue (Keita et al., 2023).

The burden of ALRIs in children is immense, being one of the most common reasons for hospitalization in pediatric populations (Hasuwa et al., 2020; Oakes et al., 2023). Children with underlying health conditions, such as congenital heart disease (CHD) or bronchopulmonary dysplasia (BPD), are at an even higher risk of severe outcomes, including increased rates of hospitalization, intensive care unit (ICU) admissions, and mortality (Chaw et al., 2019a; Chaw et al., 2019b; Shi et al., 2021). The high prevalence and severe consequences of ALRIs underscore the urgent need for effective treatment strategies and preventive measures. Current treatment approaches often involve the use of antibiotics and supportive care, but there is a growing need for targeted therapies and vaccines to reduce the incidence and severity of these infections (Alasmari et al., 2018; Vinaykumar and Maruti, 2020).

This study aims to gain a comprehensive understanding of how to optimize peptide-based vaccines for oral cancer by reviewing existing literature and analyzing clinical trial data, as well as investigating the mechanisms of action and clinical outcomes of these vaccines. The research covers the selection of appropriate peptide antigens, the role of adjuvants and delivery systems, and the potential of combination therapies to overcome current limitations. The goal is to contribute to the development of more effective peptide-based vaccines for oral cancer, offering new hope to patients battling this devastating disease.

2 Research Progress in ALRIs

2.1 Recent advancements in understanding the pathophysiology of ALRIs

Recent studies have significantly advanced our understanding of the pathophysiology of acute lower respiratory infections (ALRIs) in children. Respiratory syncytial virus (RSV) has been identified as a predominant viral pathogen associated with ALRIs, particularly in children with underlying conditions such as congenital heart disease (CHD) and bronchopulmonary dysplasia (BPD). Children with CHD are at a higher risk of severe RSV-ALRI, with increased rates of hospitalization, intensive care unit (ICU) admissions, and mechanical ventilation needs (Chaw et al., 2019a) . Similarly, children with BPD exhibit higher risks of severe RSV-ALRI outcomes, including prolonged hospital stays and increased need for oxygen supplementation and mechanical ventilation (Chaw et al., 2019b). These findings underscore the importance of understanding the specific pathophysiological mechanisms in vulnerable pediatric populations to develop targeted interventions.

2.2 Innovations in diagnostic techniques

Innovations in diagnostic techniques have played a crucial role in the early detection and management of ALRIs. The use of multiplex polymerase chain reaction (PCR) has enabled the identification of multiple viral pathogens in children hospitalized with ALRIs, providing a comprehensive understanding of the viral etiology (Hasuwa et al., 2020). Patient-reported outcome measures (PROMs) have been increasingly recommended for capturing meaningful clinical outcomes in pediatric ALRI studies. However, there is a notable lack of validated PROMs for young children, highlighting the need for further development and validation of these tools to improve clinical trial outcomes and patient care (Oakes et al., 2023). Furthermore, the use of non-invasive ventilation (NIV) strategies, such as continuous positive airway pressure (CPAP) and high flow nasal cannula (HFNC), has shown promise in reducing the need for intubation and treatment failure in children with ALRIs, although more research is needed to confirm these benefits (Wang et al., 2021).

2.3 Development of new treatment protocols

The development of new treatment protocols for ALRIs has focused on both preventive and therapeutic strategies. Maternal immunization with pneumococcal conjugate vaccines (PCVs) has been proposed as a potential intervention to reduce ALRIs in infants, with ongoing randomized controlled trials (RCTs) evaluating its efficacy (Chang et al., 2022). The need for improved RSV prophylactics and treatments, particularly for children with underlying conditions such as CHD and BPD, has been emphasized (Chaw et al., 2019a; Chaw et al., 2019b). The identification of risk factors for poor outcomes and mortality in children with RSV-ALRI, such as prematurity and comorbidities, further supports the development of targeted treatment protocols to mitigate these risks (Shi et al., 2021). Moreover, addressing socio-economic and environmental determinants, such as poverty and indoor air pollution, is crucial for reducing ALRI mortality in low- and middle-income countries (Sonego et al., 2015).

3 Treatment Strategies for ALRIs in Children

3.1 Antiviral therapies

Antiviral therapies are crucial in managing acute lower respiratory infections (ALRIs) caused by viral pathogens such as respiratory syncytial virus (RSV). One promising antiviral treatment is ALX-0171, a trivalent Nanobody with antiviral properties against RSV. A double-blind, randomized, placebo-controlled trial assessed the safety and antiviral activity of nebulized ALX-0171 in hospitalized children with RSV lower respiratory tract infection. The study found that ALX-0171 significantly reduced the RSV viral load compared to placebo, although it did not improve clinical outcomes such as time to clinical response or change in global severity score (Chaw et al., 2019b). This suggests that while antiviral therapies can effectively reduce viral load, their impact on clinical outcomes may require further investigation and earlier intervention.

3.2 Antibiotic regimens

Antibiotics are often prescribed for ALRIs to prevent bacterial complications, although their effectiveness in children with uncomplicated lower respiratory tract infections (LRTIs) is debated. A systematic review and meta-analysis found insufficient evidence to support the use of antibiotics for preventing bacterial complications in children with undifferentiated acute respiratory infections (ARIs) (Galvão, 2016). Another randomized, placebo-controlled trial (ARTIC PC) evaluated the effectiveness of amoxicillin in children with uncomplicated LRTI and found no significant difference in the duration of symptoms between the antibiotic and placebo groups, suggesting that antibiotics may not be clinically effective for most children with chest infections unless pneumonia is suspected (Little et al., 2021). These findings highlight the need for judicious use of antibiotics to prevent resistance and unnecessary side effects.

3.3 Supportive care

Supportive care remains a cornerstone in the management of ALRIs in children. Non-invasive ventilation (NIV) strategies, such as continuous positive airway pressure (CPAP) and high-flow nasal cannula (HFNC), have been shown to improve outcomes in pediatric patients with ALRIs. A systematic review and Bayesian network meta-analysis found that CPAP reduced the risk of intubation and treatment failure compared to standard oxygen therapy, while both CPAP and HFNC were associated with a lower risk of treatment failure (Figure 1). Additionally, supportive care measures such as supplemental oxygen, hydration, and nutritional support are essential in managing the symptoms and preventing complications in children with ALRIs.

Figure 1 Network meta-analyses results (A) and cumulative probability under different rankings (B) for treatment failure and intubation (Adapted from Wang et al., 2021) Image caption: CPAP, continuous positive airway pressure; HFNC, high-flow nasal cannula; SOT, standard oxygen therapy (Adapted from Wang et al., 2021)

In Figure 1, panels A and B comprehensively analyze the effectiveness of non-invasive ventilation (NIV) strategies in treating acute lower respiratory infections (ALRIs) in children. Panel A shows that CPAP and HFNC are more effective than standard oxygen therapy in reducing treatment failure, with CPAP being particularly notable. Panel B demonstrates the advantage of CPAP in reducing intubation rates, again significantly outperforming standard oxygen therapy. Overall, CPAP and HFNC, as NIV strategies, not only excel in reducing the risk of treatment failure but also significantly decrease the need for intubation, highlighting their critical role in the treatment of pediatric ALRIs.

3.4 Emerging treatments and novel therapies

Emerging treatments and novel therapies are being explored to improve outcomes in children with ALRIs. The use of C-reactive protein (CRP) testing to guide antibiotic use in febrile children at risk of pneumonia has shown promise. A randomized, controlled trial in Tanzania found that a CRP-informed strategy combined with an electronic decision algorithm significantly reduced antibiotic prescription rates and improved clinical outcomes compared to the current WHO standard (Keitel et al., 2019). This approach highlights the potential of integrating biomarkers and decision-support tools to optimize treatment strategies and reduce antibiotic overuse. Additionally, ongoing research into RSV-specific treatments and vaccines aims to provide more targeted and effective therapies for children with ALRIs (Chaw et al., 2019b).

4 Evaluation of Treatment Outcomes

4.1 Clinical recovery and symptom resolution

Clinical recovery and symptom resolution are critical indicators of treatment efficacy in children with acute lower respiratory infections (ALRIs). Studies have shown varying recovery times and symptom resolution rates depending on the type of infection and treatment administered. For instance, a study on children with pneumonia and bronchiolitis found that the length of hospital stay (LOS) was significantly different between the two conditions, with pneumonia cases having a longer LOS (5.8 ± 2.1 days) compared to bronchiolitis (3.2 ± 0.7 days) (Sultana et al., 2022). Additionally, the study highlighted that 89% of pneumonia cases and 100% of bronchiolitis cases showed clinical recovery, with bronchiolitis patients recovering faster from symptoms such as breathing difficulty and feeding issues (Sultana et al., 2022).

In another study, the use of amoxicillin for uncomplicated lower respiratory tract infections (LRTIs) in children did not significantly reduce the duration of symptoms rated as moderately bad or worse compared to a placebo (Little et al., 2021). This suggests that antibiotics may not be necessary for uncomplicated cases, and clinicians should consider alternative management strategies.

4.2 Hospitalization rates and duration

Hospitalization rates and the duration of hospital stays are important metrics for evaluating the burden of ALRIs on healthcare systems. Children with underlying conditions such as bronchopulmonary dysplasia (BPD) and congenital heart disease (CHD) are at a higher risk of severe ALRIs, leading to increased hospitalization rates and longer hospital stays. For example, children with BPD had a median LOS of 7.2 days compared to 2.5 days for those without BPD (Chaw et al., 2019b). Similarly, children with CHD had higher hospitalization rates and longer stays compared to those without CHD (Chaw et al., 2019a).

A systematic review and meta-analysis identified several risk factors associated with prolonged hospital stays, including prematurity, young age, and the presence of comorbidities (Shi et al., 2021). These findings underscore the need for targeted interventions to reduce hospitalization rates and durations in high-risk populations.

4.3 Complications and adverse effects

Complications and adverse effects are significant concerns in the treatment of ALRIs. The risk of complications such as the need for mechanical ventilation and intensive care unit (ICU) admission is higher in children with underlying conditions. For instance, children with BPD had higher odds of requiring mechanical ventilation (OR, 8.2) and ICU admission (OR, 2.9) compared to those without BPD (Chaw et al., 2019b). Similarly, children with CHD had higher risks of ICU admission and the need for supplemental oxygen therapy (Chaw et al., 2019a).

The use of non-invasive ventilation (NIV) strategies such as continuous positive airway pressure (CPAP) and high flow nasal cannula (HFNC) has shown promise in reducing the need for intubation and treatment failure in children with ALRIs (Wang et al., 2021). However, there is still a lack of evidence showing significant benefits concerning mortality between different NIV interventions, indicating the need for further research.

In terms of adverse effects, a study comparing delayed antibiotic prescription (DAP) to immediate antibiotic prescription (IAP) and no antibiotic prescription (NAP) found that DAP reduced antibiotic use and gastrointestinal adverse effects without significantly affecting symptom duration or severity (Mas-Dalmau et al., 2021). This suggests that DAP could be a safer alternative to IAP in managing uncomplicated respiratory infections in children.

4.4 Mortality rates

Mortality rates are a crucial outcome measure in evaluating the effectiveness of treatments for ALRIs. The mortality rate among children with severe ALRIs and SARS-CoV-2 infection was higher compared to those without the infection, with 8.1% of SARS-CoV-2 positive cases resulting in death compared to 2.0% of non-SARS-CoV-2 cases11. In contrast, a study on children with BPD and RSV-ALRI reported a higher in-hospital case fatality rate (hCFR) for BPD children compared to non-BPD children, with an odds ratio of 12.8 (Chaw et al., 2019b). These findings underscore the importance of identifying and managing high-risk groups to reduce mortality rates in children with ALRIs.

5 Comparative Analysis of Treatment Approaches

5.1 Comparison of treatment efficacy

The efficacy of various treatment approaches for acute lower respiratory infections (ALRI) in children has been extensively studied. Non-invasive ventilation (NIV) strategies, such as continuous positive airway pressure (CPAP) and high flow nasal cannula (HFNC), have shown promising results. A systematic review and Bayesian network meta-analysis revealed that CPAP significantly reduced the risk of intubation compared to standard oxygen therapy (OR: 0.40, 95% CrI: 0.16–0.90) and both CPAP and HFNC were associated with a lower risk of treatment failure (OR: 0.42, 95% CrI: 0.19–0.81 for CPAP and OR: 0.51, 95% CrI: 0.29–0.81 for HFNC) (Wang et al., 2021). However, no significant differences were observed among the interventions for in-hospital mortality.

In contrast, the use of antibiotics for uncomplicated lower respiratory tract infections (LRTIs) in children has been questioned. A double-blind, randomized, placebo-controlled trial found that amoxicillin did not significantly reduce the duration of symptoms rated moderately bad or worse compared to placebo (HR 1.13, 95% CI 0.90-1.42) (Little et al., 2021). This suggests that antibiotics may not be clinically effective for uncomplicated chest infections in children.

5.2 Factors influencing treatment outcomes

Several factors have been identified that influence the outcomes of ALRI treatments in children. A systematic review and meta-analysis identified key risk factors for poor outcomes and mortality in children with respiratory syncytial virus-associated ALRI (RSV-ALRI). These factors include any comorbidity (OR 2.69, 95% CI 1.89-3.83), congenital heart disease (OR 3.40, 95% CI 2.14-5.40), prematurity with gestational age (GA) <37 weeks (OR 1.75, 95% CI 1.31-2.36), and age <6 months (OR 2.02, 95% CI 1.73-2.35) (Shi et al., 2021). These findings highlight the importance of considering underlying health conditions and age when evaluating treatment strategies.

Additionally, children with bronchopulmonary dysplasia (BPD) are at a higher risk of severe RSV disease, with increased rates of hospitalization, ICU admission, and mechanical ventilation compared to those without BPD (Chaw et al., 2019b). This underscores the need for tailored treatment approaches for high-risk groups.

5.3 Cost-effectiveness of treatments

The cost-effectiveness of different treatment strategies for ALRI in children has also been evaluated. A study on the implementation of a decision rule-based treatment strategy in children with suspected lower respiratory tract infections in the emergency department (ED) found that this approach was cost-saving. The mean costs per patient were reduced from €2300 during usual care to €1870 during the intervention phase, primarily due to reduced hospitalization and parental absenteeism (Maat et al., 2020). This suggests that decision rule-based strategies can be economically beneficial while maintaining clinical effectiveness.

Moreover, a randomized trial comparing delayed antibiotic prescription (DAP) to immediate antibiotic prescription (IAP) and no antibiotic prescription (NAP) found that DAP significantly reduced antibiotic use and gastrointestinal adverse effects without compromising symptom duration or severity (Mas-Dalmau et al., 2021). This indicates that DAP can be a cost-effective strategy by minimizing unnecessary antibiotic use and associated side effects.

6 Representative Clinical Cases of ALRIs

6.1 Case 1: severe bronchiolitis in an infant

Presentation and Symptoms: An infant presented with symptoms of severe bronchiolitis, including nasal congestion, rhinorrhea, mild fever, and wheezing. The symptoms worsened over several days, leading to hypoxemia and respiratory distress, necessitating hospitalization (Alasmari et al., 2018; Lowe, 2022).

Diagnostic Findings: The diagnosis was primarily clinical, based on the history and physical examination findings. Routine chest x-rays and blood tests were not recommended. The infant exhibited tachypnea, crackles, and wheezing upon auscultation (Alasmari et al., 2018; Lowe, 2022).

Treatment and Outcomes: Management was supportive, including nasal suctioning, oxygen supplementation for hypoxemia, and hydration. The use of bronchodilators and systemic corticosteroids was not recommended for infants aged 1 to 23 months. The infant showed significant improvement with supportive care and was discharged after a few days of hospitalization (Alasmari et al., 2018; Lowe, 2022).

6.2 Case 2: pneumonia in a toddler

Presentation and Symptoms: A toddler presented with symptoms of pneumonia, including fever, cough, breathing difficulty, and chest indrawing. The child also exhibited fast breathing and bronchial breath sounds or crackles on examination (Lowe, 2022; Sultana et al., 2022).

Diagnostic Findings: The diagnosis was based on clinical features and confirmed by chest x-ray showing consolidation or patchy opacity. Blood cultures were not required for patients well enough to be treated as outpatients (Lowe, 2022; Sultana et al., 2022).

Treatment and Outcomes: The toddler was treated with antibiotics, specifically amoxicillin, as the pneumonia was suspected to be of bacterial origin. Supportive care included hydration and oxygen supplementation as needed. The child showed significant improvement within a few days and was discharged with a follow-up plan. The length of hospital stay was approximately 5.8 days, and the child fully recovered (Lowe, 2022; Sultana et al., 2022).

6.3 Case 3: recurrent lower respiratory tract infections in a preschooler

Presentation and Symptoms: A preschooler presented with recurrent episodes of lower respiratory tract infections (LRTIs), characterized by persistent cough, wheezing, and episodes of breathlessness. The child had a history of multiple hospitalizations for similar symptoms (McCallum et al., 2018; Vinaykumar and Maruti, 2020).

Diagnostic Findings: The diagnosis was based on the clinical history of recurrent symptoms and physical examination findings. The child exhibited tachypnea, wheezing, and crackles on auscultation. Chest x-rays and blood tests were performed to rule out other underlying conditions (McCallum et al., 2018; Vinaykumar and Maruti, 2020).

Treatment and Outcomes: Management included supportive care with oxygen supplementation and hydration during acute episodes. Antibiotics were not routinely prescribed unless a secondary bacterial infection was suspected. The child was monitored for persistent symptoms and received follow-up care to manage and prevent future episodes. Despite the recurrent nature of the infections, the child showed gradual improvement with appropriate management and preventive measures (McCallum et al., 2018; Vinaykumar and Maruti, 2020).

7 Insights into Treatment and Management

7.1 Key findings from clinical case evaluations

Acute lower respiratory infections (ALRIs) in children, particularly those caused by respiratory syncytial virus (RSV), pose significant clinical challenges. Vinaykumar and Maruti (2020) explored the clinical features, risk factors, and outcomes of ALRIs in children aged 2 to 60 months. The study found that low birth weight, parental education level, household crowding, and immunization status significantly influence the occurrence of ALRIs (Figure 2). Additionally, children with bronchopulmonary dysplasia (BPD) and congenital heart disease (CHD) face a higher risk of severe outcomes. Children with BPD have higher odds of hospitalization, ICU admission, oxygen supplementation, mechanical ventilation, and in-hospital mortality compared to those without BPD (Chaw  et al., 2019a). Similarly, children with CHD face higher risks of severe RSV-ALRI, including increased rates of hospitalization, ICU admission, and mechanical ventilation (Chaw et al., 2019b). These findings underscore the need for targeted interventions and management strategies for high-risk pediatric populations.

Figure 2 Association between nutritional and clinical risk factors and the occurrence of ALRIs (Adopted from Vinaykumar and Maruti, 2020)

Figure 2 shows the relationship between different nutritional and clinical risk factors and the occurrence of ALRIs. The data indicate that malnutrition and anemia significantly increase the incidence of ALRIs. Particularly in cases of severe and very severe pneumonia, the proportion of malnourished children is higher. This suggests that nutritional status is a significant risk factor for ALRIs, and improving children's nutrition can effectively reduce the incidence and severity of ALRIs.

7.2 Best practices in treatment and management

The management of ALRIs in children involves both pharmacological and non-pharmacological strategies. Non-invasive ventilation (NIV) modalities such as continuous positive airway pressure (CPAP) and high-flow nasal cannula (HFNC) have shown promise in reducing the risk of intubation and treatment failure compared to standard oxygen therapy (Wang et al., 2021). However, the evidence is still inconclusive regarding their impact on mortality, indicating the need for further research.

Antibiotic use in children with uncomplicated lower respiratory tract infections (LRTIs) is another area of concern. A randomized controlled trial (ARTIC PC) found that amoxicillin did not significantly reduce the duration of symptoms in children with uncomplicated LRTIs, suggesting that antibiotics should not be routinely prescribed unless pneumonia is suspected (Little et al., 2021). This aligns with the broader public health goal of reducing antibiotic resistance.

7.3 Areas requiring further research and development

Several areas require further research to improve the treatment and management of ALRIs in children. First, there is a need for standardized definitions and guidelines for conditions like BPD to facilitate more consistent and effective management (Chaw et al., 2018). Additionally, more specific studies on RSV infection in children with BPD and CHD, including vaccine development and RSV-specific treatments, are urgently needed (Chaw et al., 2019a; Chaw et al., 2019b).

The development and validation of patient-reported outcome measures (PROMs) for pediatric ALRIs are also critical. Current PROMs lack validation for young children and do not adequately capture the experiences of populations most affected by ALRIs, such as First Nations children (Oakes et al., 2023). Developing robust PROMs will help in assessing treatment outcomes more accurately and tailoring interventions to patient needs.

Finally, further large-scale, multicenter studies are needed to confirm the benefits of various NIV strategies and to explore their impact on mortality and other long-term outcomes (Wang et al., 2021). Research should also focus on identifying and mitigating risk factors for poor outcomes and mortality in children with ALRIs, particularly in low- and middle-income countries where the burden is highest (Sonego et al., 2015).

8 Concluding Remarks

Acute lower respiratory infections (ALRIs) remain a significant cause of morbidity and mortality in children worldwide, especially in developing countries. This study synthesizes findings from multiple studies to provide a comprehensive perspective on the clinical cases and treatment outcomes of ALRIs in children. The study indicates a significant association between specific risk factors such as bronchopulmonary dysplasia (BPD), congenital heart disease (CHD), and respiratory syncytial virus (RSV) infections with higher severity and poorer prognosis. Additionally, the impact of socioeconomic factors, parental smoking, and nutritional status on the severity of ALRIs has been emphasized.

The treatment outcomes for ALRIs in children vary significantly based on underlying conditions and comorbidities. Children with BPD and CHD are at higher risk of severe RSV-ALRI, necessitating more intensive care, including mechanical ventilation and prolonged hospital stays. Standardized case definitions and improved prophylactic measures, such as RSV vaccines, are critical for effectively managing these high-risk groups. Moreover, studies have shown that the use of antibiotics for treating uncomplicated ALRIs is questionable, as antibiotics like amoxicillin do not significantly reduce the duration of symptoms in non-pneumonic lower respiratory tract infections. This calls for more judicious use of antibiotics to combat antibiotic resistance and highlights the importance of providing safety-netting advice for clinicians

Patient-reported outcome measures (PROMs) have been identified as valuable tools for capturing meaningful outcomes in clinical trials involving pediatric ALRIs. However, there is a notable lack of validated PROMs for young children, particularly in populations with the highest burden of ALRIs. Future research should focus on developing and validating PROMs that are culturally and contextually appropriate. Managing ALRIs in children requires a multifaceted approach, including early diagnosis, appropriate use of antibiotics, and targeted interventions for high-risk groups. Improving living standards, promoting exclusive breastfeeding, and educating parents about the hazards of smoking are essential strategies to reduce the burden and severity of ALRIs. Continued research and development of effective vaccines and treatments, along with standardized clinical guidelines, will be crucial in improving outcomes for children with ALRIs.

Acknowledgments

The publisher sincerely thanks the two anonymous peer reviewers for their feedback and suggestions on the manuscript of this study.

Conflict of Interest Disclosure

The author affirms that this research was conducted without any commercial or financial relationships that could be construed as a potential conflict of interest.

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