Acupoint Herbal Patching for Long-Term Immune Function in Children with Recurrent Respiratory-Tract Infections: A Systematic Review of Real-World Data

Abstract

Objective: Acupoint herbal patching (AHP) has been used for the prevention and treatment of recurrent respiratory-tract infections (RRTIs) in children. some studies have suggested relevance to immune function as AHP's mechanism. This study was conducted to evaluate the long-term effects of AHP on immune function in pediatric patients with RRTIs based on real-world data from more than 1-year of follow-up.

Materials and Methods: Eleven English-, Korean-, and Chinese-language databases were searched comprehensively up to January 2020. Real-world clinical data assessing AHP for children with RRTI and reporting long-term immune function–related biomarkers as outcomes were included. Descriptive analyses of the details of the participants, interventions, and outcomes were conducted. The risk of bias was assessed, using the ROBINS–I [Risk of Bias in Non-randomized Studies—of Interventions] tool.

Results: Four observational studies with 399 pediatric participants were included. Two studies reported salivary secretory immunoglobulin (Ig) A (sIgA) as an immune function–related biomarker and 2 reported serum levels of IgA, IgG, and IgM. sIgA levels showed inconsistent results at 1 year after AHP. However, IgA, IgG, and IgM levels were increased significantly at both 1 and 2 years after AHP. The frequency and duration of respiratory infections were also reduced significantly after AHP. Most studies had high risks of bias, especially lack of consideration of confounding factors.

Conclusions: Current evidence suggested that AHP might be connected to immune function–related biomarker levels and symptoms in pediatric patients with RRTIs in the long-term. Further well-designed, large-size, long-term registries are needed to investigate the effects of AHP on immune function in pediatric patients with RRTIs.

Introduction

Recurrent respiratory tract infections (RRTIs) are common in children and contribute to a global disease burden.¹ Although there are no “gold standard” diagnostic criteria for RRTIs, more than 8 infections per year for children under 3 years of age and more than 6 infections per year for children age 3 years and older, may be considered RRTIs.² A prospective cohort study in Finland found that, on average, each year, children with RRTIs experienced ∼9.6 acute respiratory infections, which were associated with increased antibiotic use and increased use of surgical procedures including tympanostomy and adenoidectomy.³ In addition, 12% of these children were diagnosed with asthma at 24 months of age.³ Therefore, preventing and treating RRTIs in children is of great public-health significance.

While RRTIs in children do not necessarily indicate severe variations in the immune system, they can suggest immature immune systems.⁴ Among strategies to prevent RRTIs, prevention of respiratory infections in children through immunity is considered to be effective.⁵ For example, RRTIs are associated with abnormal immunologic responses, including improper neutrophil responses⁶ and immune deficiency⁷ in children. Moreover, immunostimulants, such as Ribomunyl^® and OM-85 Broncho-Vaxom,^® can reduce the number of episodes, duration, and severity of RRTIs as well as antibiotic use.^8–10

In East Asia, East Asian Traditional Medicine (EATM) has a long history of health promotion, disease prevention, and treatment. Acupoint herbal patching (AHP) is a type of external herbal medicine, which is one of the EATM modalities, with curative effects in patients with respiratory diseases, especially asthma, chronic bronchitis, allergic rhinitis, chronic obstructive pulmonary disease, and RRTIs.^11–13 Furthermore, a clinical practice guideline of the Pediatric Branch of the China Association of Chinese Medicine published in 2008 recommended AHP as a form of external herbal medicine for RRTIs in pediatric patients.¹⁴ In China, many patients with chronic respiratory disease use AHP during their stable stages and are satisfied with the treatment.¹⁵

According to classical theory, AHP can be therapeutic by stimulating acupoints, the local regions of the body that produce therapeutic effects.¹⁶ AHP has also been shown to prevent airway inflammation and collagen deposition, and improve serum inflammation profiles in ovalbumin-induced allergic asthma.¹⁷ Although the findings from strictly designed randomized controlled trials (RCTs) are regarded as the best evidence in evidence-based medicine, the generalizability of research outcomes is limited. Moreover, given the heterogeneity of the causes of RRTIs in children, analysis of the effectiveness and safety of AHP using real-world data may provide the rationale for its use in RRTI.¹⁸ Because a prophylactic approach to RRTI requires observation from a long-term perspective, the long-term effects of AHP on immune function in pediatric patients with RRTIs were analyzed based on real-world data on AHP, including more than 1 year of follow-up data.

Materials and Methods

Data Sources and Search Strategy

Database searches were conducted in 5 English-language electronic databases including Medline^® (via PubMed), EMBASE (via Elsevier), the Cochrane Central Register of Controlled Trials, the Allied and Complementary Medicine Database (via the Elton B. Stephens Company [EBSCO]), and the Cumulative Index to Nursing and Allied Health Literature (via EBSCO); 3 Korean-language electronic databases including the Oriental Medicine Advanced Searching Integrated System, the Korean Studies Information Service System, and the Korean Medical Database; and 3 Chinese-language electronic databases including the China National Knowledge Infrastructure, Wanfang data, and Chongqing VIP. The search date was January 8, 2020, and all studies published by the search date were considered. The reference lists of the included studies were also reviewed to include all relevant studies. The search terms in Chinese and Korean databases were adapted with appropriate Chinese and Korean terms. The detailed search strategies for each database are provided in Appendix A1. The study search was performed by 1 author (B.L.). We reported this review according to the PRISMA checklist (Appendix A2).

Inclusion Criteria and Study Selection

Studies that met the following criteria were included in the analysis:

• (1)Data sources: real-world clinical data, including medical-record review, databases, and registries
• (2)Population: pediatric participants less than 18 years of age with RRTIs
• (3)Intervention: AHP regardless of its components
• (4)Outcomes: any biomarkers associated with immune function, with follow-ups of at least 1 year.

There were no restrictions on languages, countries, and participants' sex. Gray literature, including conference abstracts and dissertations, was also allowed. Two independent authors (C.-Y.K. and B.L.) screened and selected the identified studies by first reviewing the titles and abstracts of the searched articles and then reviewing the full texts of the eligible studies for final inclusion. Any discrepancies were resolved through discussion between these 2 authors.

Data Extraction

Using predefined extraction forms, the following data were extracted: publication year; country; study and participant characteristics; use of pattern identifications in inclusion criteria; diagnostic criteria of RRTI; composition, treatment procedure, and frequency of AHP; acupoints treated; outcomes assessed at follow-up after more than 1 year; results; and adverse events. Data extraction was performed by 1 author (C.-Y.K.) and rechecked by another author (B.L.). Any discrepancies were resolved through discussion between these authors.

Quality Assessment

The Risk of Bias in Non-randomized Studies—of Interventions (ROBINS–I) tool, a tool to assess bias in nonrandomized studies of interventions, was used to assess the methodological quality of the included studies.¹⁹ ROBINS–I was developed by members of the Cochrane Bias Methods Group and the Cochrane Non-Randomised Studies Methods Group. The tool categorizes the following 7 bias domains into low, moderate, serious, and critical risks of bias or no information: (1) “bias due to confounding”; (2) “bias in the selection of participants into the study”; (3) “bias in classification of interventions”; (4) “bias due to deviations from intended interventions”; (5) “bias due to missing data”; (6) “bias in the measurement of outcomes”; and (7) “bias in the selection of the reported result.”¹⁹ This risk-of-bias assessment was conducted by 2 independent authors (C.-Y.K and B.L.) and any disagreement between them was resolved through discussion.

Data Analysis

Quantitative synthesis was not performed due to the limited number of included studies and the treatment and outcome heterogeneity. Only descriptive synthesis of the included studies was conducted. This review focused on the analysis of biomarkers associated with immune function.

Results

Description of Studies

The database searches identified 539 citations. After removing 252 duplicates, 225 nonrelevant studies were excluded following abstract and title reviews. The full texts of the remaining 62 articles were reviewed carefully. As a result, 4 uncontrolled before-and-after studies^20–23 finally met the inclusion criteria (Fig. 1). The studies^20–23 were journal articles published between 2013 and 2018. All of these studies were conducted in China and included a total of 399 pediatric participants ages 2–14 years. Three of the 4 studies^20–22 used diagnostic criteria for RRTI derived from those of the Pediatric Branch of the Chinese Academy of Medical Sciences in 2007. The other study²³ used criteria derived from the Criteria from the Chinese Academy of Pediatric Respiratory Diseases published in 1988 (Table 1).

FIG. 1.

A PRISMA [Preferred Reporting Items for Systematic reviews and Meta-Analyses] flow diagram of the literature screening and selection process. EMBASE; CENTRAL, Cochrane Central Register of Controlled Trials; AMED, Allied and Complementary Medicine Database; CINAHL, Cumulative Index to Nursing and Allied Health Literature; OASIS, Oriental Medicine Advanced Searching Integrated System; KISS, Korean Studies Information Service System; KMbase, Korean Medical Database; CNKI, China National Knowledge Infrastructure; VIP, Vendor Information Pages; CCT, controlled clinical trial; RCT, randomized controlled trial; RRTI, recurrent respiratory-tract infection.

Table 1.

Characteristics of the Included Studies

1st author, year & ref.	Sample size (included→analyzed)	Mean age (range) (yr)	Disease duration (yr)	Diagnostic criteria	Treatment duration
Huo, 201321	120 → 118	NR (2–13)	1–7	Criteria from the Pediatric Branch of the Chinese Academy of Medical Sciences (2007)a	During Dog Daysc (July to August, 6 weeks), 2 sessions/wk, total 12 sessions
Tu, 201322	64 → 64	NR (2–14)	NR	Criteria from the Pediatric Branch of the Chinese Academy of Medical Sciences (2007)a	During the recovery period from the RTI (8 weeks), (1 session/3 days × 7) + 2 weeks of rest period + (1 session/3 days × 7), total 14 sessions
Huo, 201423	120 → 109	NR (2–11)	1–6	Criteria from the Pediatric Branch of the Chinese Academy of Medical Sciences (2007)a	During Dog Daysc (July to August, 6 weeks) & winter (December to January, 6 weeks), 2 sessions/wk, total 24 sessions (12 in summer & 12 sessions in winter)
Huang, 201824	95 → 88 (1-yr f/u) →79 (2-yr f/u)	6.18 ± 2.34 (3–12)	4.05 ± 2.93 (1-8)	Criteria from the Chinese Academy of Pediatric Respiratory Diseases (1988)b	During Dog Daysc (July to August, 10 weeks), 3 sessions/wk, total 30 sessions (10 in 1st yr, 10 in 2nd yr, & 10 in 3rd yr)

^a0–2 years: upper-RTI 7 times/yr, bronchitis 3 times/yr, or pneumonia 2 times/yr; 3–5 years: upper-RTI 6 times/yr, bronchitis 2 times/yr, or pneumonia 2 times/yr; 6–14 years: upper-RTI 5 times/yr, bronchitis 2 times/yr, or pneumonia 2 times/yr, with at least 7 days between infections. If the number of upper-RTIs does not meet the criteria, the numbers of upper- and lower-RTIs can be added together.

^b0–2 years: upper-RTI 7 times/yr or lower-RTI 3 times/yr; 3–6 years: upper-RTI 6 times/yr or lower-RTI 2 times/yr; 7–12 years: upper-RTI 5 times/yr or lower-RTI 2 times/yr, with at least 7 days between infections. If the number of upper-RTIs does not meet the criteria, the number of upper- and lower-RTIs can be added together.

^cAn idiomatic expression in East Asia, meaning the period between early July and early September when the hot sultry weather of summer usually occurs in the northern hemisphere.

yr, year(s); f/u, follow-up; NR, not reported; wk, week(s); RTI, respiratory-tract infection.

A total of 4 immune-related biomarkers were assessed, including salivary secretory immunoglobulin (Ig) A (sIgA) and serum levels of IgA, IgG, and IgM. Three studies^20–22 performed follow-up for 1 year after treatment initiation while the other study²³ performed follow-up for 2 years (Table 2).

Table 2.

Outcomes and Results of the Included Studies

1st author, year & ref.	Outcomes at f/u more than 1 yr	Results reported
Huo, 201321	At 1-yr f/u 1. TERa (based on RTI frequency and disease score) 2. Disease score 3. RTI frequency 4. RTI duration 5. Medication administration (infection timeperiod) 6. TCM symptom score 7. Salivary sIgA (μg/mL)	1. Markedly improved: 22; improved: 55; no improvement: 41 2. Significantly reduced (P < 0.001) 3. Significantly reduced (all, P < 0.001) 4. Significantly reduced (P < 0.001) 5. Significantly reduced on IV administration; significantly increased on oral administration (both P < 0.001) 6. Significantly improved sweating (P < 0.001), but not cough, sputum, poor appetite, stool, enuresis, sleep, face color, throat, tongue substance, and tongue coating (P > 0.05) 7. Significantly reduced from 116.0 to 100.0 (P < 0.001); SD value was not presented
Tu, 201322	At 1-yr f/u 1. TERa (based on RTI frequency) 2. Serum IgA (g/L) 3. Serum IgG (g/L) 4. Serum IgM (g/L)	1. Cured: 21; markedly improved: 34; improved: 5; no improvement: 4 2. Significantly increased from 0.63 ± 0.14 to 1.25 ± 0.17 (P < 0.05) 3. Significantly increased from 6.21 ± 1.03 to 8.26 ± 1.42 (P < 0.05) 4. Significantly increased from 1.49 ± 0.22 to 2.81 ± 0.23 (P < 0.05)
Huo, 201423	At 1-yr f/u 1. TERa (based on RTI frequency & disease score) 2. Disease score 3. RTI frequency 4. RTI duration 5. Medication administration (infection timeperiod) 6. TCM symptom score 7. Salivary sIgA (μg/mL)	1. Markedly improved: 39; improved: 46; no improvement: 24 2. Significantly reduced (P < 0.001) 3. Significantly reduced upper-RTI (P = 0.003) & bronchitis (P < 0.001), no significant difference in pneumonia (P = 0.580) 4. Significantly reduced (P < 0.001) 5. Significantly reduced on IV administration, significantly increased on oral administration (both, P < 0.001) 6. Significantly improved sweating (P = 0.004), sleep (P = 0.012), face color (P = 0.022), tongue substance (P = 0.005), & tongue coating (P = 0.021) but not cough, sputum, poor appetite, stool, enuresis, and throat (P > 0.05). 7. Significantly increased from 97 to 119 (summer to summer; P < 0.001) and 104 to 132 (winter to winter; P < 0.001) SD value not presented
Huang, 201824	At 1-yr f/u (2nd year) 1. TERa (based on RTI frequency) At 2-yr f/u (3rd year) 1. TERa (based on RTI frequency) 2. Serum IgA (g/L) 3. Serum IgG (g/L) 4. Serum IgM (g/L)	At 1-yr f/u (2nd year) 1. Cured: 6; markedly improved: 45; improved: 28; no improvement: 9 At 2-yr f/u (3rd year): 1. Cured: 10; markedly improved: 49; improved: 18; no improvement: 2 2. Significantly increased from 0.65 ± 0.26 to 0.91 ± 0.32 (P < 0.05) 3. Significantly increased from 7.38 ± 1.09 to 8.93 ± 1.43 (P < 0.05) 4. Significantly increased from 0.90 ± 0.31 to 1.18 ± 0.29 (P < 0.05)

Note: Bold indicates significance.

^aAn outcome measure that is processed secondarily according to certain evaluation criteria such as clinical symptom improvement, or the improvement rates of other quantified outcomes. In the assessment of TER, participants are generally classified as: “cured”; “markedly improved”; “improved”; or “non-responder” after treatment. TER is calculated using the following formula: TER = N1 + N2 + N3 / N, where N1, N2, N3, and N are the numbers of patients who are cured, markedly improved, improved, and the total sample size, respectively

yr, year(s); f/u, follow-up; TER, total effective rate; RTI, respiratory-tract infection; TCM, Traditional Chinese Medicine; sIgA, secretory immunoglobulin A; Ig, immunoglobulin; IV, intravenous; SD, standard deviation.

Risk of Bias Assessment

Bias due to confounding. Given that 3 studies^{20, 21,23} did not analyze potential confounding factors, the risk of bias for confounding items was assessed as critical. The other study²² performed logistic regression analysis by adjusting for factors such as sex, age, disease duration, and disease classification. However, because few variables were considered, residual confounding was possible, which could have affected the variables associated with immune status. Therefore, the confounding item of that study²² was rated as moderate.

Bias in selection of participants into the study. Two studies^21,23 were unclear regarding whether or not they performed prospective or retrospective analyses. In the other 2 prospective studies,^{20, 22} the intervention initiation and follow-up began in most patients at the same time, so the risk of selection bias was assessed as low.

Bias in classification of interventions. Two studies^21,23 defined the interventions clearly. However, given that the studies did not describe if they were prospective or retrospective assessments clearly, the content of some interventions may have been affected retrospectively. Therefore, the risk of bias in measurement classification of interventions was assessed as moderate. The definitions of the interventions used in the other 2 prospective studies^20,22 were described clearly and the risks of bias were rated as low as the interventions were defined before the interventions.

Bias due to deviations from intended interventions. In all 4 studies,^20–23 deviations from the intended intervention seemed to reflect usual practice. Therefore, the risk of bias due to deviations from intended interventions was assessed as low.

Bias due to missing data. Two studies^20,22 had few dropouts (less than 10% of all participants); most of the reasons for drop-outs were not thought to affect the outcomes because they were not related to treatment outcomes. Therefore, the risk of bias due to missing data was assessed as low. One study did not report dropout data, so the risk of bias could not be assessed.²¹ In the remaining study,²³ more than 10% of participants dropped out; no reasons were provided for participant drop-outs and no analysis was performed to resolve this. Therefore, the risk of bias was rated as serious.

Bias in measurement of outcomes. As the main focus of this review and the key outcomes measured in the included studies^20–23 were biomarkers from salivary or serum, participant perception or nonblinding by the evaluator likely did not affect the results. Therefore, the risk of bias in the measurement of outcomes was rated as low.

Bias in selection of the reported results. Given that the preregistered protocols of the included studies^20–23 were not found, confidence in the selection bias could not be established. However, the outcomes were defined clearly and appropriate outcomes were reported. Therefore, the risk of bias in the selection of the reported result was assessed as moderate (Table 3).

Table 3.

Risk of Bias in the Included Studies (ROBINS–I)

1st author, year & ref.	1. Bias due to confounding	2. Bias in selection of participants into the study	3. Bias in classification of interventions	4. Bias due to deviations from intended interventions	5. Bias due to missing data	6. Bias in measurement of outcomes	7. Bias in selection of the reported result
Huo, 201321	Critical	Low	Low	Low	Low	Low	Moderate
Tu, 201322	Critical	No information	Moderate	Low	No information	Low	Moderate
Huo, 201423	Moderate	Low	Low	Low	Low	Low	Moderate
Huang, 201824	Critical	No information	Moderate	Low	Serious	Low	Moderate

ROBINS–I, Risk of Bias in Non-randomized Studies—of Interventions tool.

Effects of AHP on Immune Function and Respiratory Infection

Huo et al. (2013)²⁰ conducted 12 AHP sessions for 118 children with RRTIs from July to August (6 weeks) and followed-up for 1 year. These researchers reported significantly decreased salivary sIgA levels at 1 year. The total effective rate based on the frequency of respiratory infections and disease score was 65.25%. Moreover, the disease score and respiratory infection frequency and duration decreased significantly.

Tu and Xie (2013)²¹ conducted 14 AHP sessions in 64 children with RRTIs during the recovery timeperiods from respiratory infections (8 weeks) and followed-up for 1 year. These researchers reported significantly increased serum levels of IgA, IgG, and IgM at 1 year. The total effective rate based on respiratory infection frequency was 93.75%.

Huo et al. (2014)²² conducted 24 AHP sessions in 109 children with RRTIs from July to August (6 weeks) and December to January (6 weeks) and followed-up for 1 year. These researchers reported significantly increased salivary sIgA levels at 1 year. The total effective rate based on the frequencies of respiratory infections and disease scores was 77.98%. Moreover, disease score, frequency of upper-respiratory infection, and bronchitis but not pneumonia, or duration of respiratory infection were reduced significantly.

Huang (2018)²³ conducted 30 AHP sessions in 95 children with RRTIs from July to August for 3 years (10 weeks each year) and followed-up for 2 years. Serum levels of IgA, IgG, and IgM in this population were increased significantly at 2 years. The total effective rates based on the frequencies of respiratory infections at 1 and 2 years of follow-up were 89.77% and 97.47%, respectively (Fig. 2 and Table 2).

FIG. 2.

Changes in immune function biomarker levels after acupoint herbal patching (AHP) in pediatric patients with recurrent respiratory-tract infections. *P < 0.05; **P < 0.01. sIGA, secretory immunoglobulin A; Ig, immunoglobulin.

Safety of AHP

No studies reported adverse events associated with the use of AHP.

AHP Components and Treatment Procedures

The AHP components included 8 herbs. Among them, the most frequently used were Sinapis semen (4/4, 100%), Asari herba cum radix (4/4, 100%), and juice of Zingiberis succus (4/4, 100%), followed by Thujae resina (2/4, 50.00%) and Euphorbiae kansui radix (2/4, 50.00%). Except for 1 study²¹ using individual acupoints to improve the function of Spleen, Lung, and Kidney using pattern identification, the remaining studies^20,22,23 used the same acupoints across participants. The most frequently used acupoint was BL 13 (4/4, 100%), followed by CV 17 (3/4, 75.00%), Ex-B 1 (3/4, 75.00%), and BL 43 (3/4, 75.00%). Huang (2018)²³ performed AHP by simple attachment for 2–4 hours while Huo et al. (2013)²⁰ and Huo et al. (2014)²² applied 5 minutes of electrical stimulation over the attached AHP. Tu et al. (2013)²¹ did not describe the AHP procedure (Table 4).

Table 4.

AHP Components and Procedures

1st author, year & ref.	Pattern identification	AHP components	Acupoints used	AHP procedures
Huo, 201321	NA	Sinapis semen, Asari herba cum radix, Thujae resina 5–10 g (respectively), juice of Zingiberis succus	CV 17, bilateral BL 13, Ex-B 1, BL 43	Wrap herbs in gauze and place them on acupoints, then apply electrical stimulation for 5 minutes at 5–10 mA.
Tu, 201322	Acupoint use according to pattern identification	Sinapis semen, Corydalis (tuber) rhizoma, Euphorbiae kansui radix, Asari herba cum radix, Cinnamomi cortex spissus (ratio of 4:4:2:2:1), juice of Zingiberis succus	To improve the functions of the Spleen (BL 20, BL 25, ST 36, CV 8); Lung (BL 13, Ex-B 1, BL 43, CV 17); & Kidney (BL 23, GV 4, KI 1, GV 14)	NR
Huo, 201423	NA	Sinapis semen, Asari herba cum radix, Thujae resina 5–10 g (respectively), juice of Zingiberis succus	CV 17, bilateral BL 13, Ex-B 1, BL 43	Wrap herbs in gauze and place them on acupoints, then apply electrical stimulation for 5 minutes at 5–10 mA.
Huang, 201824	NA	Sinapis semen, Polygalae radix, Euphorbiae kansui radix, Asari herba cum radix, juice of Zingiberis succus	Bilateral BL 13, BL 15, BL 17	Attach AHP with tape for 2–4 hours (specific time depending on the child's condition).

AHP, acupoint herbal patching; NA, not applicable; NR, not reported.

Discussion

This systematic review sought to synthesize the long-term effects of AHP on immune function in pediatric patients with RRTIs based on real-world data with more than 1-year of follow-up. Through comprehensive searches, 4 uncontrolled before-and-after studies^20–23 were included.

Summary of Findings

The 4 included studies^20–23 reported levels of biomarkers of immune function including salivary level of sIgA and serum levels of IgA, IgG, and IgM. Huo et al. (2013)²⁰ reported significantly decreased salivary sIgA levels after 1 year of AHP but not at 6 months, suggesting that AHP's sIgA maintenance effect could last for 6 months. This research team applied the same AHP procedure in both summer and winter in their subsequent study and reported significantly increased salivary sIgA levels after both 6 months and 1 year of treatment.²²

Tu et al. (2013)²¹ and Huang (2018)²³ assessed serum levels of IgA, IgG, and IgM at 1 and 2 years of follow-up, respectively, reporting significantly increased levels at both timepoints after AHP.^21,23 In the included studies, total effective rates based on the frequencies of respiratory infections were 65.25–93.75% and 97.47% at 1 and 2 years after AHP, respectively. The 2 studies reporting the frequencies and durations of respiratory infections indicated significantly reduced levels of both after AHP.^20,22

Huo et al. (2014)²² reported that frequencies of upper-respiratory infections and bronchitis decreased, while pneumonia was not affected significantly. Two studies,^20,22 reported decreased intravenous (IV) administration of medication in the infection timeperiod but increased oral administration after AHP. These results might indicate a decreased occurrence of more-severe conditions requiring IV administration and an increasing occurrence of more-mild conditions requiring oral administration. Assessment of the risk of bias using the ROBINS–I tool showed an overall poor methodological quality of the included studies. In particular, all studies showed moderate or critical risks of bias in the confounding-factors domain, suggesting that the effectiveness of the interventions in these studies might differ significantly from the intervention effects in a well-controlled trial.

Clinical Implications

Ig tests are used to evaluate the body's ability to fight multiple antigens with 5 isotypes; namely, IgA, IgG, IgM, IgE, and IgD. Among them, IgA, IgG, and IgM are often evaluated together and can be used as indicators of the body's immune function against infections or immune diseases. Some studies have investigated the association between Ig levels and pediatric RRTIs. Deficiencies in IgA, IgG, and IgM have been observed in pediatric patients with RRTIs, while IgE levels remained normal.²⁴ In addition, as the first-line defense at the mucosa, sIgA plays an important role in mucosal immunity. Therefore, the results of this review suggest that AHP might be associated with improved immune function and might be useful for this purpose in children in clinical settings.

Strengths and Limitations

To the best of the current authors' knowledge, this is the first systematic review of the long-term effects of AHP on immune function in pediatric patients with RRTIs, based on real-world data. An endeavor was made to provide the most-current evidence, using a comprehensive search strategy; nevertheless, only 4 studies were included and their methodological qualities were generally poor. In addition, given that only real-world observational studies were analyzed, these review findings might only show a correlation between AHP and immune function in pediatric patients with RRTIs.

Suggestions for Further Studies

The frequency of AHP or the presence of accompanying electrical stimulation may be important parameters for treatment. Thus, a consensus is needed to identify the optimal AHP protocol, including procedure timing and method. Moreover, there is a need to establish a long-term registry to investigate the exact effects of AHP on immune markers and the number and frequency of respiratory infections in pediatric patients with RRTIs. From the initial stages of registry construction, it is necessary to control for various confounding factors through expert consensus and literature reviews, and to recruit a large sample size to achieve the required effect size. Furthermore, mechanism and experimental studies are also needed to determine how AHP produces effects in pediatric patients with RRTIs. Finally, a clear and universal definition of childhood RRTI is required.

Conclusions

Current evidence suggests that AHP might be associated with immune function–related biomarker levels and symptoms in pediatric patients with RRTIs in the long-term. However, prospective, well-designed, large-scale, and long-term studies are required in the future considering the small number and low methodological quality of the included studies.

Appendix

Appendix A1. Supplemental Digital Content 1. Search Strategies for Each Database

Medline^® via PubMed

	Searches	Results
#1	respiratory tract infections[MH] OR “recurrent respiratory tract infection”[TIAB] OR “recurrent respiratory infection”[TIAB] OR RRTI[TIAB]	350232
#2	“acupoint application”[TIAB] OR “local application”[TIAB] OR “acupuncture application”[TIAB] OR “acupuncture point application”[TIAB] OR “acupoint sticking”[TIAB] OR “acupoint herbal patching”[TIAB] OR “acupoints herbal patching”[TIAB] OR sanfutie[TIAB] OR sanfujiu[TIAB]	5264
#3	child[MH] OR pediatrics[MH] OR infant[MH] OR adolescent[MH] OR child*[TIAB] OR pediatric*[TIAB] OR infant[TIAB] OR neonate[TIAB] OR newborn[TIAB] OR adolescent[TIAB] OR baby[TIAB]	3976084
#4	#1 AND #2 AND #3	23

EMBASE via Elsevier

	Searches	Results
#1	‘respiratory tract infection’/exp OR ‘respiratory tract infection’:ab,ti OR ‘recurrent respiratory tract infection’:ab,ti OR ‘recurrent respiratory infection’:ab,ti OR RRTI:ab,ti	449314
#2	‘acupoint application’:ab,ti OR ‘local application’:ab,ti OR ‘acupuncture application’:ab,ti OR ‘acupuncture point application’:ab,ti OR ‘acupoint sticking’:ab,ti OR ‘acupoint herbal patching’:ab,ti OR ‘acupoints herbal patching’:ab,ti OR sanfutie:ab,ti OR sanfujiu:ab,ti	6550
#3	(‘pediatrics'/exp OR ‘pediatric’:ab,ti OR ‘infant’/exp OR ‘infant’:ab,ti OR ‘neonate’:ab,ti OR ‘newborn’/exp OR ‘newborn’:ab,ti OR ‘child’/exp OR ‘child’:ab,ti OR ‘adolescent’/exp OR ‘adolescent’:ab,ti OR ‘baby’/exp OR ‘baby’:ab,ti)	3970439
#4	#1 AND #2 AND #3	14

Cochrane Central Register of Controlled Trials

	Searches	Results
#1	MeSH descriptor: [Respiratory Tract Infections] explode all trees	13254
#2	(“recurrent respiratory tract infection” OR “recurrent respiratory infection” OR RRTI):ti,ab,kw	57
#3	(“acupoint application” OR “local application” OR “acupuncture application” OR “acupuncture point application” OR “acupoint sticking” OR “acupoint herbal patching” OR “acupoints herbal patching” OR sanfutie OR sanfujiu):ti,ab,kw	946
#4	MeSH descriptor: [Child] explode all trees	1209
#5	MeSH descriptor: [Pediatrics] explode all trees	651
#6	MeSH descriptor: [Infant] explode all trees	15756
#7	MeSH descriptor: [Adolescent] explode all trees	102003
#8	(child* OR pediatric* OR infant OR neonate OR newborn OR adolescent OR baby):ti,ab,kw	261491
#9	[(#1 OR #2) AND #3 AND (#4 OR #5 OR #6 OR #7 OR #8)] in Trials	8

Allied and Complementary Medicine Database via the Elton B. Stephens Company (EBSCO)

	Searches	Results
#1	“respiratory tract infections”[SU] OR “recurrent respiratory tract infection”[TX] OR “recurrent respiratory infection”[TX] OR RRTI[TX]	220
#2	“acupoint application”[TX] OR “local application”[TX] OR “acupuncture application”[TX] OR “acupuncture point application”[TX] OR “acupoint sticking”[TX] OR “acupoint herbal patching”[TX] OR “acupoints herbal patching”[TX] OR sanfutie[TX] OR sanfujiu[TX]	45
#3	child[SU] OR pediatrics[SU] OR infant[SU] OR adolescent[SU] OR child*[TX] OR pediatric*[TX] OR infant[TX] OR neonate[TX] OR newborn[TX] OR adolescent[TX] OR baby[TX]	30458
#4	#1 AND #2 AND #3	0

Cumulative Index to Nursing and Allied Health Literature via EBSCO

	Searches	Results
#1	“respiratory tract infections”[MH] OR “recurrent respiratory tract infection”[TX] OR “recurrent respiratory infection”[TX] OR RRTI[TX]	7507
#2	“acupoint application”[TX] OR “local application”[TX] OR “acupuncture application”[TX] OR “acupuncture point application”[TX] OR “acupoint sticking”[TX] OR “acupoint herbal patching”[TX] OR “acupoints herbal patching”[TX] OR sanfutie[TX] OR sanfujiu[TX]	1011
#3	child[MH] OR pediatrics[MH] OR infant[MH] OR adolescent[MH] OR child*[TX] OR pediatric*[TX] OR infant[TX] OR neonate[TX] OR newborn[TX] OR adolescent[TX] OR baby[TX]	1469401
#4	#1 AND #2 AND #3	1

Oriental Medicine Advanced Searching Integrated System

	Searches	Results
#1	(삼복첩 OR 혈위첩부) AND 호흡기	0

Korean Studies Information Service System

	Searches	Results
#1	(삼복첩 OR 혈위첩부) AND 호흡기	1

Korean Medical Database

	Searches	Results
#1	(삼복첩 OR 혈위첩부) AND 호흡기	1

China National Knowledge Infrastructure

	Searches	Results
#1	(SU = '反复呼吸道感染'+'复感'+'RRTI') AND (SU = '三伏贴'+'穴位敷贴'+'穴位贴敷'+'穴位帖敷'+'穴位敷帖'+'冬病夏治'+'伏九敷贴') AND (SU = '小儿'+'儿童'+'儿')	151

Wanfang data

	Searches	Results
#1	(主题:(“反复呼吸道感染” + “复感” + “RRTI”) * 主题:(”三伏贴” + ”穴位敷贴” + ”穴位贴敷” + ”穴位帖敷” + ”穴位敷帖” + ”冬病夏治” + ”伏九敷贴”) * 主题:(”小儿” + ”儿童” + ”儿”))	222

Chongqing VIP

	Searches	Results
#1	(M = (反复呼吸道感染 OR 复感 OR RRTI) AND M = (三伏贴 OR 穴位敷贴 OR 穴位贴敷 OR 穴位帖敷 OR 穴位敷帖 OR 冬病夏治 OR 伏九敷贴) AND M = (小儿 OR 儿童 OR 儿))	118

Appendix A2. PRISMA 2009 Checklist

Author Disclosure Statement

No financial conflicts of interest exist.

Funding Information

This research did not receive any specific grant from any funding agencies in the public, commercial, or not-for-profit sectors.