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Objectives: Cardiopulmonary exercise testing (CPET) is an integrative assessment of multiple interdependent variables contributing to exercise response. CPET parameters such as maximum or peak oxygen uptake (VO2max/peak) are used to estimate this response. VO2max/peak varies with physiological predictors such as age, sex, body mass index (BMI), and activity level. The existing normative values for Indian subjects have, thus, far been adapted from Western populations who have a different body habitus in terms of these physiological predictors. We aimed to determine the relation and a prediction equation of these variables with VO2peak. Materials and Method: One hundred and twenty-one healthy subjects underwent CPET on a treadmill (Cortex Metalyzer) in a tertiary care hospital and VO2peak was calculated through Metasoft software. Statistical analysis: Student’s t-test and one-way analysis of variance (ANOVA) were used for calculating the between-group difference. Logistic regression with univariate and multivariate ANOVA was used for computing the reference equation. Results: Mean VO2peak (ml/min/kg) was 29.9 ± 7.7. It was higher for males (32.81 ± 7.9 vs. 26.79 ± 6.1 [P < 0.001]) and active individuals (32.8 ± 7 vs. 26.1 ± 6.9 [P < 0.001]). Higher values were observed in younger and non-obese population (P < 0.001). Regression coefficient (r2) was 0.44 and 0.36 for male and female, respectively. Reference equation was then calculated for males and females using the r2 value. Conclusion: VO2peak was higher in males and active individuals, it declined with increasing age and BMI. The values obtained were much lower than the Western population, therefore stressing the need for the development of our own set of reference equations.

Melioidosis is an endemic infection caused byBurkholderia pseudomalleipredominantly reported in the coastal parts of India. A 19-year-old male student with no comorbidities presented with features suggestive of pneumonia. He was initiated on antitubercular treatment empirically elsewhere. However, due to lack of response to therapy diagnosis was revisited. Microbiological investigations were unyielding initially. Despite antitubercular treatment, he presented with complications of pneumonia and was diagnosed to have melioidosis. He was initiated on appropriate antibiotics for the intensive and eradication phase. Obtaining microbiological confirmation is of utmost importance to prevent misdiagnosis and undue morbidity and mortality due to these uncommon infections.

Over the last decade, advances in understanding the pathophysiology, clinical presentation, systemic consequences and treatment responses in obstructive sleep apnea (OSA) have made individualised OSA management plausible. As the first step in this direction, this study was undertaken to identify OSA phenotypes.Patients diagnosed with OSA on level 1 polysomnography (PSG) were included. Clinical and co-morbidity profile, anthropometry and sleepiness scores were compiled. On PSG, apnea-hypopnea index, positional indices, sleep stages and desaturation indices (T90) were tabulated. Cluster analysis was performed to identify distinct phenotypes among included patients with OSA.One hundred patients (66 males) with a mean age of 49.5 ± 13.3 years were included. Snoring was reported by 94% subjects, and 50% were excessively sleepy. Two-thirds of subjects had co-morbidities, the most frequent being hypertension (55%) and dyslipidemia (53%). Severe OSA was diagnosed on PSG in 42%, while 29% each had mild and moderate OSA, respectively. On cluster analysis, 3 distinct clusters emerged. Cluster 1 consisted of older, obese subjects with no gender predilection, higher neck circumference, severe OSA with more co-morbidities and higher T90. Cluster 2 comprised of younger, less obese males with snoring, witnessed apnea, moderate and supine predominant OSA. Cluster 3 consisted of middle-aged, obese males with lesser co-morbidities, mild OSA and lower T90.This study revealed three OSA clusters with distinct demographic, anthropometric and PSG features. Further research with bigger sample size and additional parameters may pave the way for characterising distinct phenotypes and individualising OSA management.

Obstructive sleep apnoea (OSA) is a disorder characterized by apnoeas and hypopnoeas due to repetitive upper airway collapse during sleep. So far, there are no published data regarding quality of life (QoL) and adherence to CPAP among patients with OSA in India. This study aims to measure sleepiness and QoL of patients before and after effective CPAP use in patients with OSA. Newly diagnosed subjects with OSA were included, and socio-demographic risk factors and anthropomorphic measures were collected. Epworth sleepiness scale (ESS) and short sleep apnoea quality of life index (SAQLI) were administered before and after a minimum of 4 weeks of domiciliary CPAP use. While short SAQLI is a disease-specific questionnaire, ESS measures excessive daytime sleepiness. In 92 subjects age range was 28–74 years, mean age 49.7 ± 11.3 years, and male:female ratio was 70:22. Mean BMI was 32.1 ± 6.4 kg/sq.m; mean neck circumference was 39.4 ± 3.4 cm; 56 subjects had Mallampati score of 3 or 4. One-month follow-up was completed by 34 subjects who reported a mean of 5.8 ± 1.1 hours/night usage of CPAP. Mean ESS score was 11.31 ± 5.6 at baseline vs 6.9 ± 3.3 after 1 month (p = 0.02), and baseline short SAQLI score was at 2.54 ± 1.26 vs 1.38 ± 0.87 after 1 month (p = 0.0001). Subjects reported adequate compliance with CPAP at 1 month, and both ESS and short SAQLI showed a significant improvement in these patients. CPAP compliance improved both QoL and sleepiness in patients with OSA.

Background: Although muscle dysfunction is a major contributor to morbidity in chronic obstructive pulmonary disease (COPD), assessment of skeletal muscle, and diaphragm function is not routinely performed in COPD patients. Objectives: (1) The aim is to assess muscle dysfunction in COPD by measuring the zone of apposition of diaphragm, diaphragm excursion, thickness of diaphragm, and rectus femoris cross-sectional area (RFCSA) with ultrasonography. (2) To correlate the above assessments with spirometric parameters; notably forced expiratory volume in 1 s (FEV1). Methods: Twenty-four consecutive stable COPD patients and 18 controls were included after obtaining written informed consent. Demographic and clinical data, spirometric values, 6-min walk distance, and sonographic parameters mentioned above were compiled for the analysis. Results: All included participants were male with a mean age of 62.5 ± 8.4 years. The mean FEV1 in cases was 1.12 ± 0.4 L versus 2.41 ± 0.5 L in controls. The diaphragm thickness (1.8 ± 0.5 mm vs. 2.2 ± 0.6 mm; P = 0.005) and RFCSA was significantly lower in COPD patients (4.8 ± 1.3 cm2 vs. 6.12 ± 1.2 cm2; P = 0.02). However, diaphragm excursion (5.35 ± 2.8 cm vs. 7 ± 2.6 cm) although lower in COPD patients, was not significantly different between the groups. Correlation between FEV1 and ultrasound diaphragm measurements and RFCSA by Spearman's Rho correlation was poor (ρ = 0.2). Conclusion: Ultrasonographic assessment of the diaphragm and rectus femoris can be used as markers to assess skeletal muscle dysfunction in COPD as diaphragmatic function and RFCSA were lower in COPD patients.

Case Presentation A 51-year-old woman with no comorbidities presented with a 3-month history of cough with mucopurulent expectoration and intermittent fever. Over the past 1 month, she complained of streaky hemoptysis and gave history of expectorating "whitish pellets" in the sputum on two occasions. She had developed progressive breathlessness for a week prior to presentation to our hospital. There was no history of chest pain or loss of weight or appetite. She was a nonsmoker and did not consume alcohol. She had received multiple courses of antibiotics at another center with no relief of symptoms.

Tuberculosis (TB) is the commonest cause of death by a single infectious agent globally and ranks amongst the top ten causes of global mortality. The incidence of TB is highest in Low-Middle Income countries (LMICs). Prompt institution of, and compliance with, therapy are cornerstones for a favourable outcome in TB and to mitigate the risk of multiple drug resistant (MDR)-TB, which is challenging to treat. There is some evidence that adverse drug reactions (ADRs) and hypersensitivity reactions (HSRs) to anti-TB drugs occur in over 60% and 3%-4% of patients respectively. Both ADRs and HSRs represent significant barriers to treatment adherence and are recognised risk factors for MDR-TB. HSRs to anti-TB drugs are usually cutaneous and benign, occur within few weeks after commencement of therapy and are likely to be T-cell mediated. Severe and systemic T-cell mediated HSRs and IgE mediated anaphylaxis to anti-TB drugs are relatively rare, but important to recognise and treat promptly. T-cell-mediated HSRs are more frequent amongst patients with co-existing HIV infection. Some patients develop multiple sensitisation to anti-TB drugs. Whilst skin tests, patch tests and in vitro diagnostics have been used in the investigation of HSRs to anti-TB drugs, their predictive value is not established, they are onerous, require specialist input of an allergist and are resource-dependent. This is compounded by the global, unmet demand for allergy specialists, particularly in low-income countries (LICs)/LMICs and now the challenging circumstances of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic. This narrative review provides a critical analysis of the limited published evidence on this topic and proposes a cautious and pragmatic approach to optimise and standardise the management of HSRs to anti-TB drugs. This includes clinical risk stratification and a dual strategy involving sequential re-challenge and rapid drug desensitisation. Furthermore, a concerted international effort is needed to generate real-time data on ADRs, HSRs, safety and clinical outcomes of these interventions.

Spirometry is a lung function test used to diagnose and monitor lung diseases like asthma, pneumonia, chronic obstructive pulmonary disease, etc. Spirometry measures forced vital capacity (FVC), forced expiratory volume in 1 sec (FEV1), and their ratio to determine lung health. Spirometry is very time-consuming, strenuous, and requires proper training. Alternate methods based on voice for diagnosis and monitoring of lung health are promising because they are faster, easy to do, and require minimal training. Non-speech sounds, namely, cough and wheeze, have been used to predict spirometry variables, but the role of speech sounds that occur in natural speaking for a similar task has not been explored. In this work, the spirometry variable, FVC has been predicted from sustained phonations of vowel sounds using a convolutional dense neural network (CDNN). Mel-spectrogram has been used as a feature. An experiment conducted using 160 subjects indicates, /i/ is the best sound and /u:/ is worst for the prediction task with an average Mean Absolute Error of 0.67l(±. 07l) and 0.70l(± 0.13l) among all sustained phonations of vowels sounds considered in this work.

Background: Obstructive sleep apnea (OSA) is an eminently modifiable and emerging risk factor for acute stroke. This prospective study was conducted in a tertiary care center to estimate the proportion of OSA in patients presenting with acute stroke.Materials and Methods: Consecutive stable patients with acute stroke were included. Stroke severity, subtype, and anatomical location were classified using standardized scales. Included subjects were screened for OSA with a detailed history (intrusive snoring, witnessed apneas, and excessive daytime sleepiness), quantification of sleepiness (Epworth Sleepiness Scale), clinical examination, and level-3 polysomnography. OSA severity was quantified based on the Apnea–Hypopnea Index.Results: 104 clinically stable stroke patients (67 males and 37 females) were included in the study; mean age was 60.9±13.2 years. Most patients (92 [88.5%]) had ischemic stroke, 9 (8.7%) had hemorrhagic stroke, and 3 (2.9%) had a transient ischemic attack. Intrusive snoring was reported by 37 (35.6%) patients, excessive daytime sleepiness by 32 (30.8%) and witnessed apneas by 19 (18.3%) patients. On level-3 polysomnography, 74 (71.2%) patients were diagnosed to have OSA. Mild OSA was diagnosed in 34 patients, while moderate and severe OSA were diagnosed in 20 patients each.Conclusions: Our study has demonstrated a strong causal relationship between OSA and stroke, thus reinforcing the need to screen all patients with stroke for OSA. Timely institution of nocturnal noninvasive ventilation in stroke patients with OSA would help to reduce the effects of OSA on stroke morbidity and recurrence.

Background Pneumothorax can present as a respiratory emergency and has varied etiology. However, literature available on assessment and management of primary spontaneous pneumothorax (PSP) based on radiological quantitation is scarce. This study was undertaken to compare two different methods of quantitating pneumothorax size with that recommended in American Thoracic Society (ATS) guideline on chest radiogram with respect to possible change in management practices. Patients and methods A prospective cohort of adults presenting with spontaneous pneumothorax (SP) over 3 years to Emergency and Pulmonology Department, St John’s Medical College Hospital, Bangalore, was included. Demographic characteristics and clinical presentation were compiled. Management of SP was based on ATS guidelines. PSP size on chest radiogram was requantitated in the included patients using Light’s index and Collin’s method and was compared with that proposed by the ATS guideline. Results Seventy-six participants with SP were studied; their mean age was 43.7 years, with a preponderance of male patients (84.2%). Twenty-four (31.6%) patients had PSP and 52 (68.4%) patients had secondary spontaneous pneumothorax. In PSP, there was poor agreement between various methods of estimating size of pneumothorax on chest radiogram (Kappa statistic=0.23; ICC of 0.263). Three (12.5%) of the 24 incidences of PSP, which were treated conservatively as per ATS guidelines, would have required invasive intervention if Light’s index or the Collin’s formula were taken into consideration. Conclusion There was poor agreement of radiological pneumothorax size estimation by Collin’s, Light’s, and that proposed in the ATS guidelines. Thus, a unified, standardized method of radiological assessment of PSP is required.

Background Chronic pulmonary aspergillosis (CPA) is a severe form of post tuberculosis lung disease (PTBLD). Considering the high burden of TB in India, it can be concluded that the prevalence of CPA is also high. Chest x-ray though most feasible, interpretation is subjective. Therefore, decision on evaluation for CPA cannot be based on x-ray alone. Objective Present study evaluated an x-ray score as a marker for extent of lung damage in patients with PTBLD presenting with hemoptysis and its utility to predict Aspergillus serum IgG levels. Methods We used a modified scoring system developed by Anna Ralph et al. X-ray score cut-offs of >71 and 40, with or without history of massive hemoptysis, were compared with serum IgG levels. Results With a chest x-ray score cut-off of 71, specificity was 88%. With an x-ray score of >71 combined with history of massive hemoptysis; 86% cases were found to be IgG positive. The specificity of this combination was 96%. Conclusion This study concluded that a simple chest x-ray scoring system in addition to the symptom of massive hemoptysis helped in the decision on further evaluation of the subject for CPA, especially in resource constrained settings.

The diverse clinicopathological spectrum of pulmonary aspergillosis is a consequence of varying levels of invasiveness of this ubiquitous fungus, which largely depends on the host immune response and pre-existing lung disease. The clinical presentation of pulmonary aspergillosis spans a wide spectrum from hypersensitivity to life threatening angio-invasive and disseminated disease. We report the case of a young immunocompetent male with no underlying lung disease, who presented with an incidentally detected ‘infective mass’ lesion in the lung associated with minimal respiratory symptoms. The diagnostic challenges posed by the unusual clinical, radiological and histological picture as well as the therapeutic dilemmas faced are discussed in this report.

Obstructive sleep apnoea (OSA) is a disorder characterized by apnoeas and hypopnoeas due to repetitive upper airway collapse during sleep. So far, there are no published data regarding quality of life (QoL) and adherence to CPAP among patients with OSA in India. This study aims to measure sleepiness and QoL of patients before and after effective CPAP use in patients with OSA.Newly diagnosed subjects with OSA were included, and socio-demographic risk factors and anthropomorphic measures were collected. Epworth sleepiness scale (ESS) and short sleep apnoea quality of life index (SAQLI) were administered before and after a minimum of 4 weeks of domiciliary CPAP use. While short SAQLI is a disease-specific questionnaire, ESS measures excessive daytime sleepiness.In 92 subjects age range was 28-74 years, mean age 49.7 ± 11.3 years, and male:female ratio was 70:22. Mean BMI was 32.1 ± 6.4 kg/sq.m; mean neck circumference was 39.4 ± 3.4 cm; 56 subjects had Mallampati score of 3 or 4. One-month follow-up was completed by 34 subjects who reported a mean of 5.8 ± 1.1 hours/night usage of CPAP. Mean ESS score was 11.31 ± 5.6 at baseline vs 6.9 ± 3.3 after 1 month (p = 0.02), and baseline short SAQLI score was at 2.54 ± 1.26 vs 1.38 ± 0.87 after 1 month (p = 0.0001).Subjects reported adequate compliance with CPAP at 1 month, and both ESS and short SAQLI showed a significant improvement in these patients. CPAP compliance improved both QoL and sleepiness in patients with OSA.

Introduction Restless legs syndrome (RLS) is characterized by an irresistible urge to move, with or without paraesthesia occurring or worsening at rest and relieved by activity. Only a few reports of prevalence of RLS with type 2 diabetes are available in India. Aims To estimate the occurrence and risk factors of RLS among Indian patients with type 2 diabetes mellitus. Method This cross-sectional study was done in consecutive adult patients with type 2 diabetes. Demographic and comorbidity profile were collected. RLS diagnosis was made based on revised international RLS study group (IRLSSG) criteria. Results Two hundred and ten diabetic patients were interviewed. Mean age was 56 ± 13.5 years. Male-female ratio was 139: 71. Mean duration of diabetes was 8.3 years. Treatment received for diabetes included oral hypoglycaemic agents (153 patients) and insulin (85 patients). Forty-five patients had polyneuropathy, 18 had retinopathy and 22 had nephropathy. Majority (103) of subjects reported their bedtime as 9–10 pm. Average sleep duration was 8.4 h per night. RLS was diagnosed in 17 (8%) subjects. Mean sleep onset in subjects with RLS was 56 min versus 29 min in diabetics without RLS (p-0.01). The mean Pittsburgh Sleep Quality Index score was 5 in RLS and 3.3 in non-RLS patients (p-0.01). Discussion and conclusions RLS resulted in poor sleep quality and affected overall quality of life in diabetics. As poor sleep is a known risk factor for uncontrolled diabetes, early identification and treatment of RLS would help improve glycaemic control and quality of life in these patients.

Electronic nicotine delivery systems were developed over a decade ago to simulate the experience of smoking, although with a lower exposure to toxins than in conventional smoking. However, they have their own unique profile of side effects, some of which can be life threatening. We report the case of a young male, who in a desperate bid to de-addict himself from smoking developed a serious adverse effect related to the e-cigarettes.

Background: Administration of local airway anesthesia is the principal determinant of procedural comfort during flexible bronchoscopy. However, the ideal method of administration is still unknown. In this study, we compared lignocaine administration using a spray catheter (SC) with “spray-as-you-go” technique. Methods: Patients undergoing bronchoscopy were randomized to receive airway anesthesia with 2% lignocaine through the SC (SC group) or “spray-as-you-go” technique through the working channel (WC group). The primary outcome parameter was cough count, and the secondary outcome parameters compared were need for sedation, operator-rated procedural satisfaction and cough, and patient-rated comfort on a Visual Analog Scale (VAS). Results: One hundred and thirty patients were randomized with comparable baseline parameters. The median (interquartile range [IQR]) cough count was 28 (19, 37) in the WC group and 15 (9, 23) in the SC group (P < 0.001). Requirement for sedation was lower in the SC group (5 vs. 18; P = 0.003). The mean (standard deviation [SD]) VAS score for operator-rated satisfaction was 66.5 (16.8) in the WC group and 80.6 (14.2) in the SC group; P < 0.001. The median (IQR) VAS score for operator-rated cough was 35 (23, 44) in the WC group and 18 (11, 28) in the SC group; P < 0.001. However, there was no difference in the patient-rated comfort VAS (mean [SD] of 66.4 [14.5] in the WC group and 69.9 [13.0] in the SC group; P = 0.07). Conclusion: Lignocaine instillation using the SC during bronchoscopy reduced cough, need for sedation, and improved operator satisfaction.

In this work, we consider the task of automatic classification of asthmatic patients and healthy subjects using voice stimuli. Cough and wheeze have been used as voice stimuli for this classification task in the past. In this work, we focus on sustained phonations, namely /aː/, /iː/, /uː/, /eɪ/, /o℧/ and compare their classification performances with the cough and wheeze. Classification experiments using 35 asthmatic patients and 36 healthy subjects show that sustained vowel /iː/ achieves the highest classification accuracy of 80.79% among five vowels considered. However, it is found to be higher and lower than the classification accuracies of 78.72% and 90.25% obtained using cough and wheeze respectively. This suggests that for speech-based asthma classification, /iː/ would be a better choice compared to other vowels considered in this work. However, when non-speech sounds are included for classification, wheeze is a better choice than sustained /iː/.

We consider the task of automatically predicting spirometry readings from cough and wheeze audio signals for asthma severity monitoring. Spirometry is a pulmonary function test used to measure forced expiratory volume in one second (FEV1) and forced vital capacity (FVC) when a subject exhales in the spirometry sensor after taking a deep breath. FEV1%, FVC% and their ratio are typically used to determine the asthma severity. Accurate prediction of these spirometry readings from cough and wheeze could help patients to non-invasively monitor their asthma severity in the absence of spirometry. We use statistical spectrum description (SSD) as the cue from cough and wheeze signal to predict the spirometry readings using support vector regression (SVR). We perform experiments with cough and wheeze recordings from 16 healthy persons and 12 patients. We find that the coughs are better predictor of spirometry readings compared to the wheeze signal. FEV1%, FVC% and their ratio are predicted with root mean squared error of 11.06%, 10.3% and 0.08 respectively. We also perform a three class asthma severity level classification with predicted FEV1% and obtain an accuracy of 77.77%.

Electroencephalogram (EEG) based sleep stage analysis considered to be the gold standard method for assessment of sleep architecture. Of importance, transition between the first two stages, wake-sleep stage 1 found to be reliable quantitative tool for drowsiness and fatigue detection. The selection of appropriate feature pattern for EEGs is a quite challenging task due to its non-linear and non-stationary nature of the EEG signals. This research work attempts to provide a comparative study of time influence of time domain feature, relative spike amplitude (RSA) with entropy feature, fuzzy entropy(FE) for recognizing the transition between wake and sleep stage 1. EEGs extracted from offline polysomnography database is used and the extracted RSA and FE wake-sleep stage 1 derived EEG features are further classified using a feedback recurrent Elman neural network (REN) classifier. EEGs are segmented into 1s pattern. Simulation of the REN classifier revealed that the FE feature with REN yields a CA of 99.6% compared to that of with RSA feature.

Background: Sleep disruption and excessive sleepiness are the known consequences of shift work. The recent spate of night-time road and air accidents, with some being directly attributed to driver sleepiness prompted us to undertake this study. Aims: To screen for excessive sleepiness, coping practices, and post-shift sleep hygiene in night bus drivers. Settings and Design: This prospective study was carried out on night bus drivers of a public transport organization in Bengaluru, Karnataka, India. Materials and Methods: Bus drivers driving for ≥8 h at night were screened with the Epworth Sleepiness Scale (ESS) and a prevalidated shift work questionnaire. Statistical Analysis: Descriptive statistics were used to analyze the compiled data using Statistical Package for the Social Sciences (SPSS) version 20. Results: One hundred and eighty bus drivers aged 22-63 years were screened. Excessive Sleepiness: Although only 2 (1.1%) drivers scored above the cutoff on ESS, 10 (5.6%) and 103 (57.2%) drivers admitted to feeling sleepy during daytime and night driving respectively. None of the drivers admitted to causing accidents related to sleepiness. The coping strategies for nocturnal sleepiness included consuming coffee/tea (16.7%), chewing tobacco (12.8%), smoking (6.1%), and walking (3.9%). Post-Shift Sleep Practices: Post-shift sleep duration ranged between 1 h and 10 h. Twenty-six (14.4%) and 16 (8.9%) drivers had difficulty initiating and maintaining sleep, respectively, while 9 (5%) reported frequent awakening during daytime sleep. Conclusion and Implications: This study has demonstrated a high incidence of nocturnal sleepiness and daytime sleep disruption among night bus drivers, thus necessitating the need for education about shift work and alertness testing among shift workers in critical professions.

Background. Rituximab-induced lung disease (R-ILD) is a rare entity that should be considered in patients treated with rituximab who present with dyspnea, fever, and cough but no clear evidence of infection. Aim. The aim of this prospective longitudinal study is to describe the clinical presentation, management, and response to rechallenge in patients diagnosed with rituximab induced ILD over a period of one year. Results. Out of sixteen patients with CD20 positive non-Hodgkin’s lymphoma who received rituximab along with standard chemotherapy, six patients developed features suggestive of R-ILD. Four (66.6%) of these patients had diffuse large B cell lymphoma. The median time of presentation of R-ILD was after the 3rd cycle of chemotherapy. Three patients (50%) presented with acute onset of high fever, dyspnea, and dry cough while the remaining three presented with insidious onset of dyspnea and dry cough. An infectious etiology for the respiratory illness was ruled out in all patients with an exhaustive work-up. Four patients (66.6%) responded to corticosteroid treatment and supplemental oxygen. One patient required mechanical ventilation and succumbed to ILD while another required prolonged supplemental oxygen. Two (33.3%) of patients were successfully rechallenged with rituximab under cover of corticosteroids. Conclusions. Rituximab induced lung disease is a rare but potentially fatal pulmonary toxicity which requires a high index of suspicion for early diagnosis and treatment.