Remarkable clinical improvement with oral nucleoside treatment in a patient with adult-onset TK2 deficiency: A case report.

OBJECTIVES: Thymidine kinase 2 deficiency (TK2d) is a rare autosomal recessive mitochondrial disorder. It manifests as a continuous clinical spectrum, from fatal infantile mitochondrial DNA depletion syndromes to adult-onset mitochondrial myopathies characterized by ophthalmoplegia-plus phenotypes with early respiratory involvement. Treatment with pyrimidine nucleosides has recently shown striking effects on survival and motor outcomes in the more severe infantile-onset clinical forms. We present the response to treatment in a patient with adult-onset TK2d. METHODS: An adult with ptosis, ophthalmoplegia, facial, neck, and proximal muscle weakness, non-invasive nocturnal mechanical ventilation, and dysphagia due to biallelic pathogenic variants in TK2 received treatment with 260 mg/kg/day of deoxycytidine (dC) and deoxythymidine (dT) under a Compassionate Use Program. Prospective motor and respiratory assessments are presented. RESULTS: After 27 months of follow-up, the North Star Ambulatory Assessment improved by 11 points, he walked 195 m more in the 6 Minute-Walking-Test, ran 10 s faster in the 100-meter time velocity test, and the Forced Vital Capacity stabilized. Growth Differentiation Factor-15 (GDF15) levels, a biomarker of respiratory chain dysfunction, normalized. The only reported side effect was dose-dependent diarrhea. DISCUSSION: Treatment with dC and dT can significantly improve motor performance and stabilize respiratory function safely in patients with adult-onset TK2d.

High-Flow Nasal Cannula Therapy as an Adjuvant Therapy for Respiratory Support during Endoscopic Techniques: A Narrative Review.

High-flow nasal cannula (HFNC) is a respiratory support technique that delivers a controlled concentration of oxygen with high flow, heat, and humidity via the nasal pathway. As it has many physiological effects, its use has increased for a variety of clinical indications; however, there is limited guidance on using HFNC as a respiratory support tool during endoscopic procedures. We conducted a narrative review to evaluate the effect of HFNC as an adjuvant tool during fiberoptic bronchoscopy (FOB), upper gastrointestinal tract endoscopy, and surgical procedures in adults. A search of the PubMed and Cochrane databases were performed. Approximately 384 publications were retrieved, and 99 were selected (93 original works and 6 case reports with a literature review). In patients who underwent FOB, HFNC appears to be superior to conventional oxygen therapy (COT) in preventing hypoxaemia. In contrast, for gastrointestinal endoscopy, the current evidence is insufficient to recommend HFNC over COT in a cost-effective manner. Finally, in surgical procedures such as laryngeal microsurgery or thoracic surgery, HFNC has been shown to be a safe and effective alternative to orotracheal intubation. As the results are heterogeneous, we advocate for the need for more quality studies to understand the effectiveness of HFNC during endoscopic procedures.

Metrics of progression and prognosis in untreated adults with thymidine kinase 2 deficiency: An observational study.

This historical cohort study evaluated clinical characteristics of progression and prognosis in adults with thymidine kinase 2 deficiency (TK2d). Records were available for 17 untreated adults with TK2d (mean age of onset, 32 years), including longitudinal data from 6 patients (mean follow-up duration, 26.5 months). Pearson's correlation assessed associations between standard motor and respiratory assessments, clinical characteristics, and laboratory values. Longitudinal data were assessed by linear regression mixed models. Respiratory involvement progressed at an annual rate of 8.16% decrement in forced vital capacity (FVC). Most patients under noninvasive ventilation (NIV) remained ambulant (12/14, 86%), reduced FVC was not associated with concomitant decline in 6-minute walk test (6MWT), and 6MWT results were not correlated with FVC. Disease severity, assessed by age at NIV onset, correlated most strongly at diagnosis with: creatinine levels (r = 0.8036; P = 0.0009), followed by FVC (r = 0.7265; P = 0.0033), mtDNA levels in muscle (r = 0.7933; P = 0.0188), and age at disease onset (r = 0.7128; P = 0.0042). This population of adults with TK2d demonstrates rapid deterioration of respiratory muscles, which progresses independently of motor impairment. The results support FVC at diagnosis, mtDNA levels in muscle, and age at disease onset as prognostic indicators. Creatinine levels may also be potentially prognostic, as previously reported in other neuromuscular disorders.

Does the Efficacy of High Intensity Ventilation in Stable COPD Depend on the Ventilator Model? A Bench-to-Bedside Study.

PURPOSE: The European Task Force for chronic non-invasive ventilation in stable COPD recommends the use of high pressure-support (PS) level to maximize the decrease in PaCO2. It is possible that the ventilator model can influence the need for higher or lower pressure levels. RESEARCH QUESTION: To determine the differences between ventilators in a bench model with an increased inspiratory demand; and to compare the degree of muscular unloading measured by parasternal electromyogram (EMGpara) provided by the different ventilators in real patients with stable COPD. PATIENTS AND METHODS: Bench: four levels of increasing progressive effort were programmed. The response of nine ventilators to four levels of PS and EPAP of 5 cm H2O was studied. The pressure-time product was determined at 300 and 500 msec (PTP 300/500). CLINICAL STUDY: The ventilators were divided into two groups, based on the result of the bench test. Severe COPD patients with non-invasive ventilation (NIV) were studied, randomly comparing the performance of one ventilator from each group. Muscle unloading was measured by the decrease in EMGpara from its baseline value. RESULTS: There were significant differences in PTP 300 and PTP 500 in the bench study. Based on these results, home ventilators were classified into two groups; group 1 included four models with higher PTP 300. Ten COPD patients were recruited for the clinical study. Group 1 ventilators showed greater muscle unloading at the same PS than group 2. CONCLUSION: The scale of pressure support in NIV for high intensity ventilation may be influenced by the ventilator model. CLINICAL TRIALSGOV: NCT03373175.

Long-Term Effect of Noninvasive Ventilation on Diaphragm in Chronic Respiratory Failure.

PURPOSE: Home non-invasive ventilation (NIV) is recommended in patients with COPD and hypercapnic chronic respiratory failure (HCRF). The mechanism by it can improve alveolar ventilation during spontaneous breathing is not yet completely explained. Our aim is to evaluate the impact of on diaphragm muscle function in a series of patients with HCRF. PATIENTS AND METHODS: Observational, longitudinal, prospective study of a series of patients with very severe chronic obstruction to airflow treated with home high imntensity NIV (HINIV). Patients underwent a baseline and after 12 months assessment including adherence to treatment, quality of life, respiratory function tests and diaphragmatic ultrasound. SPSS v.26 software was used for statistical analysis. RESULTS: We studied 30 patients, 63% male, the mean age was 60.8 (±6.4) years old. Patients had a severe obstructive ventilatory pattern [FEV1 21.8 (±6.1)%] and hypercapnia [pCO2 56.4 (±7.2) mmHg]. After 12 months of HINIV, we observed significant increases in FVC of 9.2% (p = 0.002), FEV1 of 3.5% (p = 0.04), MIP of 9.4% (p = 0.006), and 6-minute-walking test (6MWT) of 31.9 m (p = 0.001), as well as decreases in paCO2 of 12.5 mmHg (p = 0.001), HCO3 of 4.7 mmol/L (p = 0.001) and BODE index from 7 to 6. Diaphragmatic ultrasound demonstrated an increase in the thickening fraction of 14% (p = 0.002). Respiratory symptoms (p = 0.04), physical function (p = 0.03), and sleep (p = 0.04) also improved. CONCLUSION: In patients with HCRF due to very severe chronic obstruction to airflow, long-term HINIV can improve respiratory performance by improving the function of the diaphragmatic musculature. Larger multicenter clinical trials are needed to confirm the results suggested in this study.

Deoxynucleoside therapy for respiratory involvement in adult patients with thymidine kinase 2-deficient myopathy.

BACKGROUND: Recessive mutations in the thymidine kinase 2 (TK2) gene cause a rare mitochondrial myopathy, frequently with severe respiratory involvement. Deoxynucleoside therapy is currently under investigation. RESEARCH QUESTION: What is the impact of nucleosides in respiratory function in patients with TK2-deficient myopathy? STUDY DESIGN AND METHODS: Retrospective observational study of patients treated with deoxycytidine and deoxythymidine. Evaluations were performed every 3 to 4 months after treatment during approximately 30 months. Forced vital capacity (FVC), maximuminspiratory and expiratory pressures (MIP/MEP), sniff nasal inspiratory pressure (SNIP), cough peak flow (CPF), arterial blood gas and nocturnal pulse oximeter (SpO2) were collected. RESULTS: We studied six patients, five of which were women, with a median age at onset of symptoms was 35.8 (range 5 to 60) years old. Patients presented a restrictive ventilatory pattern (median FVC of 50 (26 to 71)%) and severe neuromuscular respiratory weakness (MIP 38 (12 to 47)% and SNIP 14 (8 to 19) cmH2O). Four patients required ventilatory support before starting the treatment. FVC improved by 6%, proportion of sleep time with SpO2 <90% diminished from 14% to 0%, CPF increased by 23%, MEP increased by 73%, production and management of bronchial secretions improved and respiratory infections diminished. INTERPRETATION: Early detection of respiratory involvement requires an active search, even in asymptomatic patients. The nucleosides therapy may improve respiratory function, and stabilise the loss of respiratory capacity.

The addition of a humidifier device to a circuit and its impact on home ventilator performance: a bench study.

INTRODUCTION AND OBJECTIVES: Humidification and non-invasive ventilation are frequently used together, despite the lack of precise recommendations regarding this practice. We aimed to analyse the impact of active external and built-in humidifiers on the performance of home ventilators, focusing on their pressurization efficacy and their behaviour under different inspiratory efforts. METHODS: We designed a bench study of a lung simulator programmed to emulate mechanical conditions similar to those experienced by real respiratory patients and to simulate three different levels of inspiratory effort: five different commonly used home NIV devices and active humidifiers attached to the latter (internal or "built-in") or to the circuit (external). To test ventilator pressurization under different humidification and effort settings, pressure-time products in the first 300ms and 500ms of the respiratory cycle were calculated in the 45 situations simulated. Inferential statistical analysis was performed. RESULTS: A significant reduction of PTP 300 and PTP 500 was observed with the external humidifier in three of the devices. The same pattern was noted for another device with an internal humidifier, and only one device showed no significant changes. This impact on pressurization was commonly higher under high inspiratory effort. CONCLUSIONS: These results indicate the need to monitor pressure changes in the use of external humidification devices in some home NIV ventilators.

Late-onset thymidine kinase 2 deficiency: a review of 18 cases.

BACKGROUND: TK2 gene encodes for mitochondrial thymidine kinase, which phosphorylates the pyrimidine nucleosides thymidine and deoxycytidine. Recessive mutations in the TK2 gene are responsible for the 'myopathic form' of the mitochondrial depletion/multiple deletions syndrome, with a wide spectrum of severity. METHODS: We describe 18 patients with mitochondrial myopathy due to mutations in the TK2 gene with absence of clinical symptoms until the age of 12. RESULTS: The mean age of onset was 31 years. The first symptom was muscle limb weakness in 10/18, eyelid ptosis in 6/18, and respiratory insufficiency in 2/18. All patients developed variable muscle weakness during the evolution of the disease. Half of patients presented difficulty in swallowing. All patients showed evidence of respiratory muscle weakness, with need for non-invasive Mechanical Ventilation in 12/18. Four patients had deceased, all of them due to respiratory insufficiency. We identified common radiological features in muscle magnetic resonance, where the most severely affected muscles were the gluteus maximus, semitendinosus and sartorius. On muscle biopsies typical signs of mitochondrial dysfunction were associated with dystrophic changes. All mutations identified were previously reported, being the most frequent the in-frame deletion p.Lys202del. All cases showed multiple mtDNA deletions but mtDNA depletion was present only in two patients. CONCLUSIONS: The late-onset is the less frequent form of presentation of the TK2 deficiency and its natural history is not well known. Patients with late onset TK2 deficiency have a consistent and recognizable clinical phenotype and a poor prognosis, due to the high risk of early and progressive respiratory insufficiency.

Obstructive sleep apnea-hypopnea syndrome in patients with severe chronic respiratory insufficiency. / Síndrome de apnea-hipopnea durante el sueño en pacientes con insuficiencia respiratoria crónica grave.

INTRODUCTION AND OBJECTIVE: Although sleep disordered breathing is common in patients with a severe chronic respiratory insufficiency (SCRI), there is few information on its prevalence. Our aim was to describe the prevalence and characteristics of the obstructive sleep apnea-hypopnea syndrome (OSAHS) in these patients. MATERIAL AND METHODS: Prospective and observational study carried out on patients with a SCRI included in a waiting list for a lung transplantation and who had undergone a standard polysomnography. RESULTS: A total of 105 patients were examined, of which 85 met the study's inclusion criteria. The prevalence of the OSAHS was 24.7%, with 19% of cases being severe. The most common underlying respiratory condition was COPD (62%). The OSAHS was linked to the male gender (P=.002), weight (P=.013), BMI (P=.034) and neck circumference (P=.01). Although most patients experienced symptoms suggestive of an OSAHS, the average score obtained in the Epworth Sleepiness Scale was low. CONCLUSIONS: We observed a high prevalence of OSAHS in patients with a SCRI but without clinical data suggestive of its diagnosis; hence, we believe that sleep studies should be carried out in these patients given the low pre-test clinical suspicion of the disease.

Videolaryngoscopy With Noninvasive Ventilation in Subjects With Upper-Airway Obstruction.

BACKGROUND: Noninvasive ventilation (NIV) titration may be difficult when dynamic airway obstruction episodes persist, even with high expiratory positive airway pressure (EPAP). We aimed to determine the usefulness of videolaryngoscopy during NIV for identifying mechanisms and sites of obstruction and for providing a guide for their resolution in difficult-to-titrate subjects. METHODS: When obstructions during NIV were present in the built-in software, EPAP was raised to 12 cm H2O. If obstructions persisted, a polygraphy during NIV was performed; if the events occurred with effort, a videolaryngoscopy with nasal and oronasal masks in awake subjects was performed. RESULTS: In a population of 208 subjects in whom NIV was initiated, 13 were identified as difficult to titrate with persistent obstructions during NIV despite an EPAP of 12 cm H2O. Videolaryngoscopy during NIV was able to identify the mechanism and the site of obstruction in all cases. The obstruction under oronasal mask ventilation was due to soft-palate (velum) collapse in 4 subjects, to epiglottic backward movement in 5 other subjects, and to tongue-base obstruction reducing the retroglossal space in 3 more. Videolaryngoscopy during NIV demonstrated improvement in 9 subjects (69%) upon changing to nasal mask and suggested a possible surgical approach in 2 (15%); in one of these 2 subjects, a successful uvulopalatopharyngoplasty was performed. CONCLUSIONS: The use of videolaryngoscopy during NIV in difficult-to-titrate patients may help to identify the sites and mechanisms of obstruction and in some cases may improve quality of ventilation.

[Diagnostic value of respiratory polygraphy in patients with low probability of obstructive sleep apnea syndrome]. / Valor diagnóstico de la poligrafía respiratoria en pacientes con baja probabilidad de síndrome de apneas e hipopneas durante el sueño.

INTRODUCTION AND OBJECTIVE: Polysomnography (PSG) is the gold standard technic for the diagnosis of obstructive sleep apnea syndrome (OSAS). It is an expensive, complex and not always available technic, meaning that respiratory polygraphy (RP) has become usual. Although RP is not validated in low probability patients, Spanish guidelines recommend conservative treatment in patients with negative RP. We intended to study the prevalence and severity of OSAS through PSG in a sample of patients with low probability and negative RP. MATERIAL AND METHODS: Retrospective, observational, descriptive and analytic study of low probability OSAS patients with negative RP in whom a PSG was performed. Anthropometric, clinical and sleep data were collected. RESULTS: Eighty-two patients were included. After PSG, a greater number of hypopneas (137.8±70.1 vs. 51.2±38.4 [P<.05]) and apnea hypopnea index (27.8±15.6 vs. 11.7±7.1 [P<.05]) was observed, as well as an increment in OSAS prevalence of 17%, which was 35% in severe OSAS. In mild OSAS, there was a decrement of 41%. CONCLUSION: According with the results of this study, RP significantly underestimates the prevalence and severity of OSAS in low probability patients. While it is necessary to adequately stratify the OSAS probability in order to correctly indicate diagnosis tests, we recommend performing a PSG in low probability patients with negative RP.

Sleep-Related Breathing Disorders and Lung Transplantation.

AIM: Sleep-related breathing disorders (SRBD) are common in patients with lung transplantation (LT); however, there are few data about its prevalence, and none about its pathogenesis or evolution. The SRBD events consist mainly obstructive, central, and mixed apnea, as well as hypopneas. The aim of this study was to describe the prevalence of SRBD before the LT, and its evolution after a period of 1 year follow-up. METHODS: Prospective, observational, descriptive, and analytical study of the SRBD and its evolution in 20 LT patients. The group was studied before and at 6 and 12 months after the LT; in each phase, standard polysomnography was performed, and anthropometric, pathologic, clinical, and pharmacological data were collected. RESULTS: Prevalence of obstructive sleep apnea syndrome was 38% before the LT, 86% at 6 months, and 76% at 12 months after LT. There was a significant increase of weight, body mass index, neck circumference, blood pressure during the first year of follow-up, especially at 6 months after LT. We also observed an increase in the number of central and mixed apneas during the follow-up, although not as remarkable as obstructive apneas. There was no correlation between immunosuppressant studied drugs and any of the studied variables. CONCLUSIONS: We have observed a significant prevalence of obstructive sleep apnea syndrome in patients in waiting list for LT, and LT has an important influence in the evolution of the disorder. In our series, LT has somehow affected the stability of upper airway and ventilatory mechanics.

Adherence with national guidelines in hospitalized patients with community-acquired pneumonia: results from the CAPO study in Venezuela.

INTRODUCTION: The Community-Acquired Pneumonia Organization (CAPO) is an international observational study in 130 hospitals, with a total of 31 countries, to assess the current management of hospitalized patients with community-acquired pneumonia (CAP). 2 Using the centralized database of CAPO was decided to conduct this study with the aim of evaluate the level of adherence with national guidelines in Venezuela, to define in which areas an intervention may be necessary to improve the quality of care of hospitalized patients with CAP. METHODS: In this observational retrospective study quality indicators were used to evaluate the management of hospitalized patients with CAP in 8 Venezuelan's centers. The care of the patients was evaluated in the areas of: hospitalization, oxygen therapy, empiric antibiotic therapy, switch therapy, etiological studies, blood cultures indication, and prevention. The compliance was rated as good (>90%), intermediate (60% to 90%), or low (<60%). RESULTS: A total of 454 patients with CAP were enrolled. The empiric treatment administered within 8 hours of the patient arrival to the hospital was good (96%), but the rest of the indicators showed a low level of adherence (<60%). CONCLUSION: We can say that there are many areas in the management of CAP in Venezuela that are not performed according to the national guidelines of SOVETHORAX.1 In any quality improvement process the first step is to evaluate the difference between what is recommended and what is done in clinical practice. While this study meets this first step, the challenge for the future is to implement the processes necessary to improve the management of CAP in Venezuela.

Evolution and complications of chest trauma.

OBJECTIVE: To describe the clinical characteristics and risk factors of patients with chest trauma, and to evaluate their correlation with the development of complications. METHODS: Descriptive, prospective and analytical study of a patient cohort with chest trauma who underwent follow-up for a period of 30 days. Excluded from the study were those patients with moderate to severe traumatic brain injury, long-bone fractures, abdominal trauma and patients requiring mechanical ventilation. RESULTS: A total of 376 patients met the inclusion criteria, 220 of whom were males (58.5%). The most frequent causes of trauma were falls (218 cases; 57.9%) and motor vehicle accidents (57 cases; 15.1%). The most frequent type of trauma was rib contusion (248 cases; 65.9%) and rib fractures (61 cases; 16.2%). Complications were observed in 43 patients (11.4%), mainly hemothorax (13 cases), pneumothorax (9 cases), pneumonia (6 cases) and acute renal failure (4 cases). Four patients died due to pneumonia and hemothorax. Thirty-three patients were hospitalized (8.7%) and 10 (2.6%) required later re-admittance. The risk for complications increased significantly in patients with more than 2 rib fractures, in those over the age of 85 and in the presence of certain comorbidities, such as COPD and pathologies requiring anticoagulation therapy. The risk for re-admittance is higher in patients over the age of 60. CONCLUSIONS: Patients with chest trauma who present certain comorbidities, are over the age of 85 and have more than 2 rib fractures may present more complications. These factors should be contemplated in the evaluation, management and follow-up of these subjects.