The risk factors for chronic cough in children: a meta-analysis covering five continents.

BACKGROUND: This study aimed to explore the risk factors for chronic cough in children and provide a reference for prevention and healthcare measures. METHODS: PubMed, Web of Science, Cochrane, and EMBASE were searched for observational studies published up to April 2024. Outcome included risk factors associated with chronic cough in children. Two investigators independently searched and screened the literature, evaluated the qualities and extracted baseline datas. Results were analyzed using random-effects models with odds ratios and their 95% confidence intervals to address heterogeneity. Subgroup analyses, sensitivity analyses and assessment of publication bias were performed. Stata17 and GRADEwas used for the meta-analysis. RESULTS: 18 studies including 97,462 children were reviewed. Asthma( OR= 4.06, 95%CI: 2.37-6.96, P＜0.01), NO2( OR= 1.19, 95%CI: 1.01-1.39, P= 0.031), Home remodeling history ( OR= 1.82,95% CI: 1.61-2.05, P＜0.01), Environment Tobacco Smoke( OR= 1.41, 95% CI: 1.15-1.73, P=0.001), Pet exposure ( OR= 1.56, 95%CI: 1.25-1.95, P＜0.01), Mould (OR= 1.64,95%CI: 1.45-1.85, P＜0.01), Age＜1 year(OR= 3.19, 95% CI: 1.8-5.63, P＜0.01) were reported as risk factors for chronic cough in children, these results were discussed qualitatively in the study. CONCLUSION: Asthma, NO2, Home remodeling history, Environment Tobacco Smoke( ETS), Pet exposure, Mould, and Age＜1 year are risk factors for chronic coughing in children. Due to the few studies and insufficient evidence, other potential risk factors need to be robustly confirmed by subsequent large-sample and multicenter trials.

Airway Clearance in Neuromuscular Disease.

High-quality respiratory care and airway clearance is essential for people with neuromuscular disease (pwNMD) as respiratory tract infections are a major cause of morbidity and mortality. This review expands on published guidelines by highlighting the role of cough peak flow along with other options for cough evaluation, and discusses recent key research findings which have influenced the practice of respiratory therapy for pwNMD.

[New medical technologies in cough therapy: results of a double-blind randomized placebo-controlled multicenter clinical trial].

AIM: To study the efficacy and safety of Eladis® in comparison with placebo in patients with non-productive cough. MATERIALS AND METHODS: A phase III clinical trial enrolled 250 patients aged 18-65 years with acute respiratory viral infection with upper respiratory tract involvement or acute bronchitis. Patients were randomized into 2 groups of 125 subjects: group 1 received Eladis® (40 mg tablets), group 2 received a matching placebo. The patients received the study drugs 1 tablet BID for 7-14 days. After the treatment, patients were followed up (day 7±2) to assess the effect of therapy on the frequency of coughing attacks, the frequency and severity of daytime and nocturnal cough, the severity of cough, the duration of clinical cough cure, and the effect on the severity of the main acute respiratory viral infection symptoms. RESULTS AND CONCLUSION: The results of the study demonstrate the overall efficacy and statistically significant superiority of Eladis® over placebo: there were significant differences between the study groups in the proportion of patients who decreased the coughing attack frequency by ≥50% by day 5 (p<0.0001). In addition, the clinical cure of cough in the Eladis® group occurred 2 days earlier: the median time was 6 days, vs 8 days in placebo group. There was a decrease in the frequency of cough attacks and a decrease in its severity by more than 3.5 points by day 5 of treatment. All the effects were associated with high safety of the drug.

The validity of single-item measures of health-related quality of life across groups differing in acute respiratory symptom severity.

PURPOSE: Practical considerations precluding health-related quality of life (HRQOL) monitoring in population and clinical research have spawned development of improved items for more brief surveys of frequently measured HRQOL outcomes. The aim of this study was to validate the use of the Quality of Life General (QGEN-8), a shorter 8-item alternative to the longer 36-item short form (SF)-36 Health Survey for measuring the same eight HRQOL domains across groups of adults with varying severity of acute respiratory symptoms, such as cough and sore throat. METHODS: National Opinion Research Center (NORC) representative probability (N = 1,648) and supplemental opt-in (N = 5,915) U.S. adult samples were surveyed cross-sectionally online in 2020. Parallel analyses compared QGEN-8 and SF-36 estimates of group means for each of eight matching profile domains and summary physical and mental scores across groups differing in severity of acute symptoms and chronic respiratory conditions using analysis of covariance (ANCOVAs) controlling for socio-demographics and presence of chronic respiratory conditions. RESULTS: In support of discriminant validity, ANCOVA estimates of QGEN-8 means with SF-36 estimates revealed the same patterns of declining HRQOL with the presence and increasing severity of symptoms and chronic condition severity. CONCLUSION: QGEN-8® shows satisfactory validity and warrants further testing in cross-sectional and longitudinal population and clinical survey research as a more practical method for estimating group differences in SF-36 profile and summary component HRQOL scores.

Upper respiratory tract infections (URTI) with symptoms such as cough and sore throat are highly prevalent and negatively impact on health-related quality of life (HRQOL). Existing instruments that comprehensively measure HRQOL are lengthy, potentially increasing respondent burden and restricting their use in clinical studies and research. The aim of this study was to evaluate whether eight newly constructed survey items, the QGEN-8®, measure the same HRQOL outcomes as the 36-item SF-36 Health Survey well enough to serve as a more practical alternative for purposes of detecting the physical and mental HRQOL effects on differing severity of acute URTI symptoms, specifically cough and sore throat. The results showed that the QGEN-8® was psychometrically sound and able to differentiate between different levels of URTI symptoms, even in cases where respondents had chronic respiratory conditions. This indicates that the briefer QGEN-8® with 75% shorter response time is able to provide HRQOL measurements comparable to those derived from lengthier instruments thereby lending itself more readily to use in clinical studies and research of URTI symptoms, such as cough and sore throat.

Laryngeal Vibrotactile Stimulation Is Feasible, Acceptable To People With Unexplained Chronic Cough.

OBJECTIVES: Unexplained chronic cough (UCC) is common and has significant impacts on quality of life. Ongoing cough can sensitize the larynx, increasing the urge to cough and perpetuating the cycle of chronic cough. Vibrotactile stimulation (VTS) of the larynx is a noninvasive stimulation technique that can modulate laryngeal somatosensory and motor activity. Study objectives were to assess feasibility and acceptability of VTS use by people with UCC. Secondarily, changes in cough-related quality of life measures were assessed. METHODS: Adults with UCC recorded cough measures at baseline and after completing 2 weeks of daily VTS. Feasibility and acceptability were assessed through participant-reported device use and structured feedback. Cough-related quality of life measures were the Leicester Cough Questionnaire (LCQ) and the Newcastle Laryngeal Hypersensitivity Questionnaire (NLHQ). RESULTS: Nineteen adults participated, with mean age 67 years and cough duration 130 months. Notably, 93% of planned VTS sessions were logged, 94% of participants found the device comfortable to wear, 89% found it easy to operate and 79% would recommend it to others. Pre-post LCQ change achieved a minimal important difference (MID) (mean 1.3 [SD 2.4, p = 0.015]). NLHQ scores improved, but did not reach an MID. CONCLUSIONS: Laryngeal VTS use was feasible and acceptable for use by patients with UCC and was associated with a meaningful improvement in cough-related quality of life. Future studies will include VTS dose refinement and the inclusion of a comparison arm to further assess the potential for laryngeal VTS as a novel treatment modality for UCC. LEVEL OF EVIDENCE: 4 Laryngoscope, 2024.

Retrospective, observational study of different medication regimens and outcome in children with cough variant asthma.

OBJECTIVE: This retrospective longitudinal cohort study aimed to explore the best therapeutic regimen and treatment duration of cough variant asthma (CVA) in children. METHODS: A total of 314 children with CVA were divided into receive inhaled corticosteroids (ICS) combined with long-acting beta2-agonist (LABA) group, ICS combined with leukotriene receptor antagonists (LTRA) group, ICS monotherapy group and LTRA monotherapy group. All clinical data were statistically analyzed. Logistic regression model was used to compare the advantages and disadvantages of different treatment schemes at each follow-up time point and the best treatment scheme. The Cox proportional hazard regression model based on inverse probability weighting was used to compare the effects of different medication regimens on adverse outcomes with asthma recurrence or progression as the end point. RESULTS: (1) After comprehensive analysis, ICS + LABA group was the preferred control regimen for CVA within 8 weeks. After 8 weeks of diagnosis, the efficacy of ICS group or LTRA group was comparable to that of ICS + LABA group and ICS + LTRA group. (2) The ICS + LABA group showed a significant improvement in cough at an early stage, particularly at 4 weeks; the symptoms of ICS + LTRA and ICS groups were significantly improved at 36 weeks. The LTRA group alone showed significant improvement at 20 weeks. CONCLUSION: ICS + LABA, ICS + LTRA, ICS alone and LTRA alone can effectively treat CVA. ICS + LABA could improve the symptoms most quickly within 8 weeks after CVA diagnosis, followed by ICS + LATR group. After 8 weeks, it can be reduced to ICS alone to control CVA for at least 36 weeks based on the remission of symptoms in children.

Temporary Vocal Fold Augmentation Outcomes for Refractory Chronic Cough with Concurrent Nonparalytic Glottic Insufficiency due to Vocal Fold Atrophy.

OBJECTIVE: Determine the effect of temporary vocal fold augmentation on refractory chronic cough (RCC) in patients with glottic insufficiency (GI) due to vocal fold atrophy. METHODS: Retrospective electronic chart review was conducted for patients with a diagnosis of bilateral vocal fold atrophy and RCC undergoing vocal fold augmentation with carboxymethylcellulose (CMC). Patients with vocal fold immobility were excluded, and cough must have been present for at minimum 8weeks. VHI-10, CSI, and RSI scores along with subjective overall patient report of chronic cough improvement were collected. RESULTS: A total of 28 patients underwent 30 vocal fold augmentation procedures with CMC. All had undergone extensive cough work-up and treatment trials prior to their augmentation procedure. From chart review, 13 overall subjectively reported satisfactory improvement in their cough, 5 reported partial improvement, and 7 reported no improvement in their cough. An uncertain effect on cough was documented in 5 (either patient was uncertain or no mention of cough symptom in the interval chart history note). For those subjects with both pre- and post-augmentation data, mean preaugmentation CSI: 22.08± 6.8 (n = 13); VHI-10: 13.6± 8.9 (n = 18); RSI: 22.4± 7.5 (n = 17). Mean postaugmentation CSI was 20.7± 9.2 (n = 13); VHI-10: 15.2± 8.2 (n = 18); RSI: 21.1± 5.8 (n = 17). Mean pre-post change in CSI was -1.4± 5.1 (P = 0.175, n = 13, range -10 to +6). CONCLUSIONS: Vocal fold augmentation seems to provide subjective cough improvement in some patients with concurrent GI due to vocal fold atrophy and RCC. It can be offered as a diagnostic trial, on which further augmentation may be offered, for patients with persistent cough despite prior work-up and treatment trials. Further controlled prospective studies are needed to identify factors that are predictive of successful cough improvement following vocal fold augmentation, as well as the effect of durable augmentation in those patients who had improvement with a diagnostic trial.

Manometric Abnormalities in Patients With and Without Chronic Cough.

PURPOSE: This study examines the relationship between chronic cough and vagal hypersensitivity by measuring baseline esophageal motility, with interest in the upper esophageal sphincter (UES). MATERIALS AND METHODS: Patients undergoing workup for dysphagia were assigned to a chronic cough or control group based on self-reported symptoms. Differences in demographics, medical comorbidities, and high resolution esophageal manometry findings were obtained retrospectively. RESULTS: 62.5% of our cohort had chronic cough (30/48). There were no significant differences between the two groups with respect to sex, age, and race/ethnicity. Laryngopharyngeal reflux (LPR) was the only statistically significant predictor of CC (OR 74.04, p = 0.010). Cough patients had upper esophageal sphincter relaxation duration (734 ms) significantly longer than the non-cough patients (582 ms; p = 0.03), though both groups had similar upper esophageal mean basal pressure, mean residual pressure, relaxation time-to-nadir, and recovery time. No significant difference was found in the median intrabolus pressure and UES motility mean peak pressure between groups. CONCLUSION: Subtle differences in high-resolution manometry between patients with and without cough suggest, in line with previous studies, baseline alterations of upper esophageal function may manifest in patients with chronic cough through an undetermined mechanism that may include underlying vagal hypersensitivity. These findings encourage further manometric study examining the relationship between UES dysfunction and chronic cough.

Characteristics of US Medicare Beneficiaries with Chronic Cough vs. Non-Chronic Cough: 2011-2018.

Background: Chronic cough (CC), characterized as a cough lasting >8 weeks, is a common multi-factorial syndrome in the community, especially in older adults. Methods: Using a pre-existing algorithm to identify patients with CC within the 2011-2018 Medicare beneficiaries, we examined trends in gabapentinoid use through repeated cross-sectional analyses and identified distinct utilization trajectories using group-based trajectory modeling (GBTM) in a retrospective cohort study. Individuals without CC but with any respiratory conditions related to cough served as a comparator group. Results: Among patients with CC, gabapentinoid use increased from 18.6% in 2011 to 24.1% in 2018 (p = 0.002), with a similar upward trend observed in the non-CC cohort but with overall lower usage (14.7% to 18.4%; p < 0.001). Patients with CC had significantly higher burdens of respiratory and non-respiratory comorbidities, as well as greater healthcare service and medication use compared to the non-CC cohort. The GBTM analyses identified three distinct gabapentinoid utilization trajectories for CC and non-CC patients: no use (77.3% vs. 84.5%), low use (13.9% vs. 10.3%), and high use (8.8% vs. 5.2%). Conclusions: Future studies are needed to evaluate the safety and effectiveness of gabapentinoid use in patients with refractory or unexplained CC in real-world settings.

Granulomatous lobular mastitis treated by a combined internal and external treatment of traditional Chinese medicine: A case report.

BACKGROUND: Granulomatous lobular mastitis (GLM) is a rare benign inflammatory disease of the breast and is classified under comedo mastitis in traditional Chinese medicine (TCM). The etiology of this disease is unknown, and it mainly occurs in women of childbearing age. The diagnosis depends on histopathological biopsy. At present, there is no systematic and standardized treatment plan for GLM. In the absence of evidence supporting an infectious etiology, affected patients might continue to receive multiple courses of antibiotics and unnecessary surgery. CASE SUMMARY: A 37-year-old Chinese woman with a history of coronavirus disease 2019 infection presented with swelling and pain in the left breast. She also had erythema, nodules in the lower extremities, arthritis in both knees, cough, and headache. In the early stage of GLM, the mass was not significantly reduced by conservative treatment with internal application of TCM; hence, surgical treatment was carried out. The aim of postoperative treatment was to drain the pus, eliminate the necrosed tissue, and expand the muscles; fumigation and washing using TCM was applied. CONCLUSION: Combined internal and external treatment with TCM, following the principle of "Prioritize internal treatment before ulceration and emphasize external treatment after ulceration" was effective in our patient with GLM. The prognosis was good. We believe that TCM offered valuable therapeutic benefits in this disease.

Detection of active SARS-CoV-2 in cough aerosols from COVID-19 patients.

BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is an airborne pathogen, but detection of infectious SARS-CoV-2 in air and in particular the introduction of the virus into the environment by different human expiratory manoeuvres is not well studied. OBJECTIVES: The aim of this study was to investigate the presence of SARS-CoV-2 in cough from coronavirus disease of 2019 (COVID-19) in-patients and to study contamination of the virus in the patient's environment. METHODS: Detection of SARS-CoV-2 in cough was analyzed by PCR, culture and imaging. Detection in cough was compared to presence of the virus in air and on surfaces from patient rooms. RESULTS: Twenty-five patients in 21 rooms were included in the study. SARS-CoV-2 RNA was found in cough aerosols from 16 out of 22 patients that produced voluntary cough. As demonstrated by plaque-forming unit assays, active virus was isolated from 11 of these 16 patients. Using mainly molecular detection, the virus was also found in air, on high-contact surfaces, and no-touch surfaces from the room of the COVID-19 patients. CONCLUSIONS: These results show that infectious SARS-CoV-2 circulating in air can originate from patient cough and should be considered against the risk of acquiring COVID-19 through inhalation.

Acute Appendicitis in the Setting of Infectious Mononucleosis: A Case Report.

Infectious mononucleosis (IM) is a viral illness caused by the Epstein-Barr virus that typically manifests with pharyngitis, lymphadenopathy, and fatigue. In rare cases, IM can cause acute appendicitis. We present the case of an 18-year-old female who arrived at the emergency department with worsening abdominal pain and an ongoing cough. Initial imaging showed a questionably dilated appendix, and a follow-up examination revealed cervical lymphadenopathy. She later returned to the ED with severe abdominal pain, clinical signs of acute appendicitis, and a positive monospot test, which led to an appendectomy. This case illustrates the need for complete history taking and thorough physical examination in patients with acute appendicitis, as their condition may be due to an atypical underlying cause.

Prevalence and disease burden of chronic cough in nine cities of China: an observational study.

BACKGROUND: Chronic cough (CC) is common in the general population of China, creating a difficult-to-ignore public health burden. However, there is a lack of research on the nationwide prevalence and disease burden of CC in the Chinese population. We aim to use an insurance claims database to assess the prevalence and the corresponding economic burden owing to CC in China. METHODS: This was a retrospective observational study based on an administrative medical insurance database in 2015, 2016 and 2017, from nine cities in North, South, East, South-West, and North-West regions of China. The study population was Chinese adults (≥ 18 years old) who had been identified as CC patients. Descriptive data analyses were used in statistical analysis. RESULTS: A total of 44,472, 55,565, and 56,439 patients with mean ages of 53.2 (16.3) years were identified as patients with CC in 2015, 2016, and 2017, respectively. Of these, 55.24% were women. In addition, 8.90%, 9.46%, and 8.37% of all patients in 2015, 2016, and 2017, who had applied for medical insurance, had CC, respectively, with a three-year average probability of 8.88%. The median number of outpatient visits within a calendar year was 27 per year due to any reason during the period of 2015-2017. The median medical cost of each patient per year increased from 935.30 USD to 1191.47 USD from 2015 to 2017. CONCLUSION: CC is common among medical insurance users, with a substantial utilization of medical resources, highlighting the huge burden of CC in China.

An observational study to understand burden and cost of care in adults diagnosed with refractory chronic cough (RCC) or unexplained chronic cough (UCC).

BACKGROUND: Refractory and unexplained chronic cough (RCC and UCC) necessitate frequent referral for specialist evaluations, but data on healthcare resource utilisation and costs are lacking. METHODS: This observational study enrolled adults with RCC or UCC attending a specialist cough clinic and included a control cohort, both from North West England, matched 1:5 for age, gender and smoking history. Primary and secondary care data were obtained for the 5 years prior to and 2 years post initial clinic visit (index). The primary endpoint was the total 5-year healthcare cost to the UK NHS pre-RCC or UCC diagnosis compared to the control cohort. RESULTS: Mean age at index for the 200 RCC or UCC consented patients was 62.2 ± 11.4 years; 71% were female, and 68% had never smoked. Mean duration of symptoms pre-diagnosis was 8.0 ± 9.4 years. Mean cough severity score was 63.7 ± 23.2 mm at index on a Visual Analog Scale, and Leicester Cough Questionnaire total score was 10.9 ± 4.1. GP data were available for 80 patients and mean total cost over the 5 years pre-diagnosis (index date) was 3.0-fold higher (95% CI 2.3, 3.9) than in the control cohort (p < 0.001). Most excess costs were related to visits and procedures carried out in secondary care. RCC- or UCC-associated costs decreased post-diagnosis, but remained higher than those of controls. CONCLUSION: Diagnosis of RCC or UCC requires significant health resource utilisation in the 5 years prior to a specialist clinic diagnosis. Resource utilisation was less after diagnosis, but remained higher than in a matched control cohort.

The Effect of Long-Term Azithromycin on Objective and Subjective Cough in Chronic Respiratory Disease: A Systematic Review and Meta-analysis of Randomised Controlled Trials and Noncomparative Studies.

INTRODUCTION: Azithromycin is an effective treatment for various respiratory conditions but its effect on cough is poorly understood. We synthesised data from randomised controlled trials (RCTs) and noncomparative studies (NCT) examining its effect on objective and subjective cough. METHODS: After prospective registration on PROSPERO, we searched MEDLINE, EMBASE, and CENTRAL for both RCTs and NCT trials examining the effect azithromycin on cough in respiratory disease. RESULTS: We identified 1240 studies of which 6 (4 RCTs and 2 NCT studies) were included in the meta-analysis, with a total of 275 patients. Azithromycin was associated with significant improvement in Leicester Cough Questionnaire scores at follow-up when compared to baseline scores (SMD = 0.62 [95% CI 0.12 to 1.12], p = 0.01). However, when only RCTs were synthesised, no significant effect was observed (SMD = 0.12 [95% CI - 0.36 to 0.60], p = 0.62). There was no significant reduction in cough severity VAS score (SMD = - 0.39 [95% CI - 0.92 to 0.14], p = 0.15). There was no significant reduction in objective cough count (SMD = - 0.41 [95% CI - 1.04 to 0.32], p = 0.09). CONCLUSION: Azithromycin therapy improves cough-related quality of life in various chronic respiratory diseases; however, there was no significant effect on cough outcomes when only data from RCTs were synthesised. We believe that to accurately identify which patients whose cough would benefit from azithromycin a large-scale clinical trial of patients with a broad spectrum of respiratory diseases, with sufficiently severe cough, should be undertaken with subgroup analysis of individual disease areas.

Transient reemergence of Bordetella parapertussis in France in 2022.

Between March and October 2022, a peak of detection of Bordetella parapertussis by qPCR, real-time PCR was observed in France.Hypothesis/Gap Statement. Whether this peak was due to resurgence from previous circulating lineages or reintroduction into the country was unknown.Objective. The objective of this study is to understand B. parapertussis-transient increase observed in France in 2022 whereas it had virtually stopped being reported since the start of the COVID-19 pandemic in 2020.Methods. We analysed real-time PCR (qPCR) data from the two largest French outpatient laboratories performing whooping cough diagnosis and characterized all B. parapertussis isolates collected in the 2016-2022 period by the French National Reference Centre for Whooping Cough.Results. Microbiological analyses reveal that 13 of 18 bacterial isolates collected in 2022 produce the vaccine antigen pertactin, whereas none of the 22 isolates collected in the 2016-2021 period did.Conclusion. We hypothesize a re-introduction of B. parapertussis from regions of the world where whole-cell vaccines are still in use.

Two-year survival after scheduled extubation in patients with pneumonia or ARDS: a prospective observational study.

PURPOSE: To report two-year survival after scheduled extubation in patients with pneumonia or acute respiratory distress syndrome (ARDS). METHODS: This was a prospective observational study performed in a respiratory ICU of a teaching hospital. Pneumonia or ARDS patients who successfully completed a spontaneous breathing trial were enrolled. Data were collected before extubation. Patients were followed up to two years by phone every 3 months. RESULTS: A total of 230 patients were enrolled in final analysis. One-, 3-, 6-, 12-, and 24-month survival was 77.4%, 63.8%, 61.3%, 57.8%, and 47.8%, respectively. Cox regression shows that Charlson comorbidity index (hazard ratio: 1.20, 95% confidence interval: 1.10-1.32), APACHE II score before extubation (1.11, 1.05-1.17), cough peak flow before extubation (0.993, 0.986-0.999), and extubation failure (3.96, 2.51-6.24) were associated with two-year mortality. To predict death within two years, the area under the curve of receiver operating characteristic was 0.79 tested by Charlson comorbidity index, 0.75 tested by APACHE II score, and 0.75 tested by cough peak flow. Two-year survival was 31% and 77% in patients with Charlson comorbidity index ≥ 1 and < 1, 28% and 62% in patients with APACHE II score ≥ 12 and < 12, and 64% and 17% in patients with cough peak flow > 58 and ≤ 58 L/min, respectively. CONCLUSIONS: Comorbidity, disease severity, weak cough and extubation failure were associated with increased two-year mortality in pneumonia or ARDS patients who experienced scheduled extubation. It provides objective information to caregivers to improve decision-making process during hospitalization and post discharge.

Solid-phase extraction followed by gas chromatography-mass spectrometry for the quantitative analysis of small molecule N-nitrosamine impurities in antitussive syrups.

A quantitative testing method was developed for the analysis of low molecular weight (small molecules) nitrosamine impurities in cough syrups using solid phase extraction (SPE) on strong cation-exchange functionalized polymeric sorbent cartridges followed by gas chromatography-mass spectrometry. The matrix spike recoveries of the nitrosamine impurities from the cough syrup samples was observed to be within the range of 90 %-120 %. Limit of detection (LOD) achieved for NNitrosodimethylamine (NDMA) and NNitroso morpholine (NMOR) was about 0.1 ng/mL while the LOD for NNitrosodiethylamine (NDEA), NNitrosodiisopropylamine (NDIPA) and NNitrosoisopropylethylamine (NIPEA) impurities was about 0.02 ng/mL. The method was evaluated and found to meet the acceptable criteria as per the ICH Q2 guidelines for a working concentration range of 0.02 ng/mL to 1.2 ng/mL for the analyzed impurities. The selectivity of the nitrosamine impurities against the presence of drug product was established using multiple reaction monitoring (MRM) transitions during analysis.