Post Infectious Bronchiolitis Obliterans: Knowledge, Attitude and Practice survey

Objective: To outline what is commonly understood, perceived and followed at individual institutions across the country on the subject of Post-Infectious Bronchiolitis Obliterans(PIBO) Methods: A 64-item web-based questionnaire with three sections addressing key domains in PIBO was employed. The questionnaire assessed knowledge points, attitudes and practice essentials which were consolidated and analysed. Results: The questionnaire was completed by 40 paediatricians/sub-specialists across 15 cities in India, and 88% of them were paediatric pulmonologists. The knowledge about disease process, clinical presentation, diagnostic modalities and treatment options were consistent with established literature. The prognosis was thought to be favourable by 75% respondents. Considerable heterogenicity was noted in the choice of first-line drugs, their doses, durations and combinations. Similarly, the time of the institution of second-line medication and drug of choice exhibited discrepancies. Conclusions There is a sizeable ambiguity in treatment practices concerning PIBO. This uncertainty calls for a review and consensus among Indian practitioners. TITLE PAGE TITLE: Post Infectious Bronchiolitis Obliterans: Knowledge, Attitude and Practice survey Authorship Priyanka Potti MD 1, Manoj Madhusudan DNB 1, Tejaswi Chandra DcH 2, Srikanta JT DNB 1 1 Department of Pediatric Interventional Pulmonology and Sleep Medicine, Aster CMI Hospital, Bengaluru 2 Department of Pediatric Pulmonology, Aster Whitefield Hospital, Bengaluru PP - Writing - original draft, Validation, Writing - review & editing MM, TC- Writing - review & editing SJT- Conceptualisation, Writing- Review and editing The manuscript has been read and approved by all authors and the requirements for authorship have been met. All the authors firmly believe Corresponding author Dr. Priyanka Potti Address: No. 43/2, New Airport Road NH 7, Outer Ring Rd, Sahakar Nagar, Bengaluru, Karnataka 560092 Email id: [email protected] Conflict of interest: None. There are no financial or other relationships that might lead to a conflict in interest Funding No financial support received Ethical clearance No approval was deemed necessary as the following article does not include patient information Data availability statement Data that supports the findings of the study are available with the corresponding author and will be available on request TITLE: Post Infectious Bronchiolitis Obliterans: Knowledge, Attitude and Practice survey

Objective: To outline what is commonly understood, perceived and followed at individual institutions across the country on the subject of Post-Infectious Bronchiolitis Obliterans(PIBO)

A 64-item web-based questionnaire with three sections addressing key domains in PIBO was employed. The questionnaire assessed knowledge points, attitudes and practice essentials which were consolidated and analysed.

The questionnaire was completed by 40 paediatricians/sub-specialists across 15 cities in India, and 88% of them were paediatric pulmonologists. The knowledge about disease process, clinical presentation, diagnostic modalities and treatment options were consistent with established literature. The prognosis was thought to be favourable by 75% respondents. Considerable heterogenicity was noted in the choice of first-line drugs, their doses, durations and combinations. Similarly, the time of the institution of second-line medication and drug of choice exhibited discrepancies.

There is a sizeable ambiguity in treatment practices concerning PIBO. This uncertainty calls for a review and consensus among Indian practitioners.

Post Infectious Bronchiolitis Obliterans; Children; Survey; Diagnosis; Management

Post-Infectious Bronchiolitis Obliterans(PIBO) is a chronic small airway disease that arises as a sequel to a severe Lower Respiratory Infection(LRI). Microorganisms, especially Adenovirus, Respiratory Syncytial Virus, Influenza, etc., have been implicated in causing significant airway damage [1] . The resulting inflammation and fibrosis of the bronchioles leads to progressive irreversible obstruction and obliteration of the smaller airways. These children present with persistent cough, wheeze, tachypnoea, distress after the initial infection and are eventually diagnosed to have PIBO. Whilst the true prevalence remains unknown, the incidence of PIBO has gradually increased over the last few years. In the light of recent outbreaks of adenoviral respiratory infections throughout India and the subsequent rise in the incidence of PIBO, a critical re-evaluation of our Knowledge, Attitudes and Practices(KAP) becomes necessary [2] . Therefore, this study aims to elicit what is known, believed and done in the context of PIBO Methodology Approximately 70 pediatricians and subspecialists with experience in pediatric pulmonology were contacted via email. A 64-point self-administered web-based questionnaire was employed. The questionnaire included a combination of statements, open ended questions and multiple-choice grids. Under the knowledge section, topics such as etiology, risk factors, clinical presentation, diagnostic and treatment modalities were addressed. The respondents’ attitudes towards mortality, morbidity, prognosis was discussed in a separate section. The third section attempted to comprehensively aggregate current practices in the management of PIBO across the country. Ethical clearance was not sought, as the Institutional policy does not mandate the same for a survey that does not involve patient information. There are many unanswered questions in PIBO. With ongoing research, the gaps continue to be filled. Therefore, this study refrains from scoring the participants on their KAP and remains descriptive in nature.

A total of 40 participants completed the survey, of which 87.5% were pediatric pulmonologists. The survey population was distributed across all major cities of India(Figure 1). Majority(62.5%) of the participants had more than 5 years of experience and 40% had treated >10 children with PIBO. Four participants had a cohort of >30 cases under follow-up. KNOWLEDGE Adenovirus was the most commonly known virus to cause PIBO(Table 1). Persistent cough, wheeze, tachypnoea, distress, prolonged requirement of bronchodilators/systemic steroids after initial LRI were considered as potential markers of PIBO by >75% respondents. About 52% practitioners considered PIBO if symptoms persisted for 4-6 weeks. ATTITUDES The prognosis of PIBO was considered to be favourable by 75% of the participants. Need for mechanical ventilation at initial LRI(77.5%) was strongly perceived to be a prognostic marker of severity(Table 2). About 50% and 32.5% of the practitioners refrained from discussing the possibility of lung transplant and mortality with parents, respectively. PRACTICES A time lag of 1-2 months before diagnosis was noted by 60% respondents. These children underwent recurrent hospitalizations, 1-2 and 3-4 respectively, prior to reaching a conclusive diagnosis by each of the 47.5% respondents respectively. Hypoxia, respiratory distress, tachypnoea and wheezing were the commonest presenting symptoms while cough was noted by 52.5% doctors only at presentation. Room air saturation of <94% was noted by 92.5% of our group at presentation. Majority of the participants(60%) acknowledged that the etiological agent was identifiable in <25% of the children. When etiological diagnosis was available, adenovirus was the commonest offending organism identified according to 80% of the participants. During the course of workup, 95% doctors subjected suspected PIBOs to a High-Resolution Computerised Tomography(HRCT). Other investigations routinely performed by participants included chest-Xray(82.5%), arterial blood gas(55%), spirometry(35%), Forced Oscillation Technique(FOT)(25%), flexible bronchoscopy(32.5%), whereas a lung biopsy was considered by 29.3% respondents. The drug and dosing regimens used as first line, differed greatly between centres(Table 3) dictated primarily by the disease severity. Corticosteroids, either as daily oral(50%) or monthly intravenous(70%) were the most preferred option. Montelukast was used by 40% doctors and half of them choose to add it on at a later date. While 61.5% were aware of combination therapies like Fluticasone(F), Azithromycin(A), Montelukast(M)[FAM]/ Budesonide(B), Azithromycin(A), Montelukast(M)[BAM] therapies, only 48.7% used them. Long term home oxygen and non-invasive ventilation was required in ≤25% and ≤5% children respectively according to majority of the doctors. Second line medications were usually considered after 3 months(47.2%) and 6 months(38.9%) of partial or no response to initial therapy. Up to 10% children went on to require second line drugs as per most(82.5%) practitioners. Azathioprine(50%) followed by Hydrochloroquine(HCQ)(44.7%) were favoured while cyclophosphamide and Mycophenolate mofetil(MMF) were preferred in only 6 centres(15.8%). Most respondents scheduled a follow-up at fortnightly(35%) or monthly(55%) intervals. Compliance(64.9%) and interval infections(58.6%) were the commonly tackled issues during follow up while poor growth, adverse effects of medications were some of the other concerns. Majority(80%) children required 1-3 readmissions/year during follow-up and infection was the commonest reason listed.

In this study, we present the findings of the first ever survey conducted to appraise the KAP of PIBO. Respiratory viruses were commonly recognised as etiological agents by >50% respondents while atypical infections were less frequently incriminated. Majority of the practitioners identified Adenovirus as the culprit agent, which is consistent with other studies [3] . A study of 109 PIBO cases by Colom et al noted adenoviral aetiology and need for mechanical ventilation to be the only significant risk factors [4] . A meta-analysis by Liu et al concluded that hypoxemia, mechanical ventilation, tachypnoea, and wheezing to be strong risk factors while use of glucocorticoids, co-infection of bacteria, a history of wheezing and being male may also play a role [1] . The knowledge of our participants was consistent with their findings with up to 75% in agreement on survey. Larger cohorts of Yazan et al reported persistent cough, wheezing and respiratory distress etc in >90% of their children which is similar to the clinical profile reported by our participants [5] . The exception being persistent cough, which was reported only by 52% of our group. Most centres defined PIBO at 4 or 6 weeks after onset of symptoms, as did centres under our study [6][4] . Contrary to studies by Yalcin et al and others who noted a mean lag of 6 months between onset and diagnosis, most of our participants had noted a lag of 1-2 months only [7] . This could potentially be due to the knowledge of the disease resulting from the adenoviral outbreak throughout the country, as well as the ease of access to specialist care in larger cities. Over time, there has been a de-emphasis on histopathological diagnosis and shift towards HRCT for diagnosis [8] . Our findings reflect this, as most respondents opted for HRCT(95%) over a lung biopsy(30%). Knowledge in our cohort regarding radiological findings were comparable with features described by radiological studies on PIBO [5] . Spirometry plays an important role in diagnosis, gauging severity, and long-term follow-up, however, it was less known and used as per our findings [9] . Flexible bronchoscopy was performed by 32.5% doctors, similar to other studies where mucosal inflammation was the usual finding [3] . Treatment strategies have largely been extrapolated from research on bronchiolitis obliterans syndrome(BOS) and focuses on optimal combination of supportive care and anti-inflammatory therapy. Steroids in their various forms are the commonest first line medications employed by our study participants and remain the cornerstone of therapy as in other studies [3][6] . Isolated reports where oral steroids were utilised as an add on, employed prednisolone at 1-2mg/kg/day for a variable duration of up to 4 weeks followed by slow taper over 6-9 months [7] . However, standalone daily oral steroids at a dose and duration needed to sufficiently suppress inflammation in PIBO may cause side effects and is seldom preferred over intravenous(IV) pulse. A study by Tomikawa et al employed IV pulse methylprednisolone(MPS) at 30mg/kg/day for 3 days at monthly intervals for 6-20 cycles and reported clinical improvement, improved oxygenation and fewer hospitalisations with fewer side effects [10] . Their study concluded that pulse corticosteroids could be an effective and safer alternative to prolonged oral steroids. In our study, most doctors used either 10mg/kg or 30 mg/kg MPS for 3 days on a monthly basis for ≤6 cycles(Table 3). Azithromycin is known to combat neutrophilic inflammation and has proven efficacy as an immunomodulator in PIBO [11] . Most studies describe a regimen of 3 days a week but the dosing differs from study to study, between 5-10 mg/kg/day [11][3] . In our study, 10mg/kg/day, three times a week was the preferred practice. Regimens that combine azithromycin, budesonide and montelukast(BAM) demonstrated improvement in clinical symptoms and pulmonary function [12] . In our current study, while many were aware of BAM therapy, only 48.7% used it in practice. PIBO is known to have poor response to bronchodilators, however, tiatropium bromide was proven to significantly relieve airway obstruction and 20% of our respondents routinely used tiatropium [13] . Upto 10% children were observed to need second-line treatment by our respondents, but the choice of drug and time of institution remained controversial. While several immunosuppressants including biologicals are tried in BOS, only isolated case reports exist in PIBO supporting use of HCQ and azathioprine [14][6] . The prognosis was overall opined to be favourable by our group. During follow up, 1-3 admissions were commonplace according to most of our doctors and interval infections were the quoted reason. Age at initial LRI, need for mechanical ventilation at initial LRI, delay is starting treatment and number of exacerbations per year were thought to be prognostic by >70% of our cohort. However, no clinical or radiological factors except a decline in FEV1, FVC, FEF25-75 on spirometry were proven to be statistically significant [15] .

This study highlights the disparities in knowledge, attitudes, and practices among Indian pediatricians, reaffirming the requirement of a consensus regarding PIBO.

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KNOWLEDGE | Knowledge about etiological agents | Number of respondents (%) | | Adenovirus | 40(100%) | | Influenza virus | 32(80%) | | Parainfluenza | 24(60%) | | Respiratory Syncytial virus(RSV) | 28(70%) | | Measles | 23(57.5%) | | Mycoplasma | 28(70%) | | Knowledge about risk factors for PIBO | Number of respondents (%) | | Gender | 17(42.5%) | | Age at initial LRI | 33(82.5%) | | Wheezing and tachypnoea during the initial LRI | 27(67.5%) | | Hypoxemia during the LRI | 36(40%) | | Need for mechanical ventilation | 31(77.5%) | | Prolonged oxygen support | 40(100%) | | Need for steroids | 32(80%) | | Coinfection with bacteria | 16(40%) | | Duration of hospital stay | 30(75%) | | Past history of wheezing | 21(52.5%) | | Investigation of choice for establishing diagnosis | Number of respondents (%) | | HRCT chest | 38(95%) | | Lung biopsy | 12(30%) | | Pulmonary function test | 5(12.5%) | | Forced Oscillometry Technique | 5(12.5%) | | Findings of ancillary investigations and their supportive role in diagnosis of PIBO | Number of respondents (%) | | Normal bronchoscopy | 29(72.5%) | | Peribronchial fibrosis on lung biopsy | 32(80%) | | Obstructive pattern of PFT with poor reversibility | 36(90%) | | Reduced DLCO | 17(42.5%) | | HRCT findings associated with PIBO | Number of respondents (%) | | Mosaic attenuation | 40(100%) | | Air trapping | 40(100%) | | Patchy atelectasis | 34(85%) | | Ground glass opacities | 32(80%) | | Bronchial wall thickening | 34(85%) | | Central bronchiectasis | 19(47.5%) | | Centrilobular opacities | 18(45%) | | Mucous plugging | 24(60%) | | Chest X ray findings consistent with PIBO | Number of respondents (%) | | Hyperinflation | 38(95%) | | Peribronchial thickening | 38(95%) | | Interstitial infiltration | 21(52.5%) | | Atelectasis | 28(70%) | | Consolidation | 17(42.5%) | | Markers of disease severity | Number of respondents (%) | | Respiratory distress | 25(62.5%) | | Hypoxia | 36(90%) | | Pulmonary function tests | 6(15%) | | Atelectasis and bronchiectasis on CT | 15(37.5%) | Table1: Knowledge points and their responses. PIBO- Post infectious Bronchiolitis Obliterans; LRI- Lower Respiratory Infection; CT- Computerised tomography; DLCO- Diffusion capacity of Lung for Carbon Monoxide ATTITUDES | Children who significantly improve with treatment | Number of respondents (%) | | Upto 25% | 10(25%) | | 26-50% | 11(27.5%) | | 51-75% | 9(22.5%) | | 75-90% | 8(20%) | | >90% | 2(5%) | | Prognostic factors | Number of respondents (%) | | Need for mechanical ventilation at initial LRI | 31(77.5%) | | Age at initial LRI | 28(70%) | | Gender | 10(25%) | | Etiology | 16(40%) | | Delay in starting therapy | 28(70%) | | Low FEV1, FVC, FEF25-75 | 21(52.5%) | | Number of exacerbations per year | 28(70%) | | Atopic history | 9(22.5%) | Table2: Attitudes towards prognosis among participants; LRI- Lower Respiratory Infection FIRST LINE MEDICATIONS | Drugs | Number of respondents (%) using these drugs for first line treatment | | Intravenous steroids | 28(70%) | | Oral steroids | 20(50%) | | Inhaled corticosteroids | 28(70%) | | Azithromycin | 29(72.5%) | | Montelukast | 16(40%) | | Muscarinic agents | 8(20%) | | Hydrochloroquine(HCQ) | 11(27.5%) | | INTRAVENOUS STEROID DOSING REGIMEN | INTRAVENOUS STEROID DOSING REGIMEN | | Dosing regimen for pulse MPS | Number of respondents using the regimen, (%) | | 10mg/kg/day | 20(50%) | | 20mg/kg/day | 4(10%) | | 30mg/kg/day | 15(37.5%) | | Other regimens(2mg/kg/day) | 1(2.5%) | | DURATION OF IV PULSE MPS | DURATION OF IV PULSE MPS | | Number of monthly cycles | Number of respondents using the regimen (%) | | ≤3 cycles | 15(37.5%) | | 4-6 cycles | 20(50%) | | >6 cycles | 3(7.5%) | | Others | 2(5%) | | STANDALONE ORAL STEROIDS | STANDALONE ORAL STEROIDS | | Duration for which 2mg/kg oral steroid is given | Number of respondents using the regimen (%) | | 2 weeks | 19(47.5%) | | 4 weeks | 12(30%) | | 4 weeks to 3 months | 3(7.5%) | | Until symptomatically better | 5(12.5%) | | Total duration of standalone oral steroids | Number of respondents using the regimen (%) | | ≤6 weeks | 18(45%) | | 6 weeks to 3 months | 15(37.5%) | | 3-6 months | 4(10%) | | >6 months | 3(7.5%) | | INHALED CORTICOSTEROIDS(ICS) | INHALED CORTICOSTEROIDS(ICS) | | ICS/ ICS-LABA combinations | Number of respondents using these drugs, (%) | | Budesonide | 32(80%) | | Fluticasone | 4(10%) | | Budesonide + Formoterol | 10(25%) | | Fluticasone + Salmeterol | 3(7.5%) | | Tiatropium bromide | 5(12.5%) | | Duration of ICS therapy | Number of respondents using the regimen (%) | | 1 year | 12(30%) | | AZITHROMYCIN | AZITHROMYCIN | | Dosing regimen | Number of respondents using the regimen (%) | | 10mg/kg/day daily | 2(5%) | | 10mg/kg/day, 3 days a week | 26(65%) | | 10mg/kg stat followed by 5 mg/kg/day, daily | 1(2.5%) | | 10mg/kg stat followed by 5 mg/kg/day,3 days/week | 11(27.5%) | Table 3: Treatment practices amongst participants. IV- Intra Venous; MPS- Methyl Prednisolone; ICS- Inhaled Cortico Steroids; LABA- Long Acting Beta Agonist Figure 1: Geographical distribution of participants Legends for Illustrations Figure 1: Geographical distribution of participants Table1: Knowledge points and their responses. PIBO- Post infectious Bronchiolitis Obliterans; LRI- Lower Respiratory Infection; CT- Computerised tomography; DLCO- Diffusion capacity of Lung for Carbon Monoxide Table2: Attitudes towards prognosis among participants; LRI- Lower Respiratory Infection Table 3: Treatment practices amongst participants. IV- Intra Venous; MPS- Methyl Prednisolone; ICS- Inhaled Cortico Steroids; LABA- Long Acting Beta Agonist Information & Authors Information Version history Copyright This work is licensed under a Non Exclusive No Reuse License.

Authors Metrics & Citations Metrics Article Usage 295views 206downloads Citations Download citation Priyanka Potti, Manoj Madhusudan, Tejaswi Chandra, et al. Post Infectious Bronchiolitis Obliterans: Knowledge, Attitude and Practice survey. Authorea. 16 March 2024. DOI: https://doi.org/10.22541/au.171063076.60692350/v1 DOI: https://doi.org/10.22541/au.171063076.60692350/v1 If you have the appropriate software installed, you can download article citation data to the citation manager of your choice. Simply select your manager software from the list below and click Download. For more information or tips please see 'Downloading to a citation manager' in the Help menu.