Effects of bilateral lung transplantation on cardiac autonomic modulation and cardiorespiratory coupling: a prospective study.

BACKGROUND: Although cardiac autonomic modulation has been studied in several respiratory diseases, the evidence is limited on lung transplantation, particularly on its acute and chronic effects. Thus, we aimed to evaluate cardiac autonomic modulation before and after bilateral lung transplantation (BLT) through a prospective study on patients enrolled while awaiting transplant. METHODS: Twenty-two patients on the waiting list for lung transplantation (11 women, age 33 [24-51] years) were enrolled in a prospective study at Ospedale Maggiore Policlinico Hospital in Milan, Italy. To evaluate cardiac autonomic modulation, ten minutes ECG and respiration were recorded at different time points before (T0) and 15 days (T1) and 6 months (T2) after bilateral lung transplantation. As to the analysis of cardiac autonomic modulation, heart rate variability (HRV) was assessed using spectral and symbolic analysis. Entropy-derived measures were used to evaluate complexity of cardiac autonomic modulation. Comparisons of autonomic indices at different time points were performed. RESULTS: BLT reduced HRV total power, HRV complexity and vagal modulation, while it increased sympathetic modulation in the acute phase (T1) compared to baseline (T0). The HRV alterations remained stable after 6 months (T2). CONCLUSION: BLT reduced global variability and complexity of cardiac autonomic modulation in acute phases, and these alterations remain stable after 6 months from surgery. After BLT, a sympathetic predominance and a vagal withdrawal could be a characteristic autonomic pattern in this population.

Bone involvement in young adults with cystic fibrosis awaiting lung transplantation for end-stage respiratory failure.

Patients with cystic fibrosis awaiting lung transplantation for end-stage respiratory failure have high prevalence of reduced bone mineral density and fragility fracture. Suboptimal 25-hydroxyvitamin D levels could significantly contribute to the development of cystic fibrosis-related bone disease. INTRODUCTION: The assessment of the prevalence of cystic fibrosis-related bone disease (CFBD) and its associated risk factors in young adults with cystic fibrosis (CF) awaiting lung transplantation for end-stage respiratory failure. METHODS: Clinical characteristics, bone mineral density (BMD), the parameters of calcium metabolism, including vitamin D (25OHVitD) levels, and the presence of fragility fractures were evaluated in 42 CF patients (24 females, age 34.0 ± 8.4 years) consecutively referred as lung transplant candidates. RESULTS: Mean 25OHVitD levels (54.9 ± 26.2 nmol/L) were below the reference range and hypovitaminosis D (25OHVitD < 75 nmol/L) was found in 34 patients (81%) and daily calcium intakes (median 550 mg/day) were lower than recommended. A BMD below the expected range for age (Z-score of - 2.0 or lower) and at least one prevalent fragility fracture were found in 22 patients (52.4%) and 18 patients (45.2%), respectively. The coexistence of low BMD and the presence of fracture was observed in 13 patients (31.0%). In these patients, the prevalence of nephrolithiasis was higher than in the remaining ones (p = 0.046). The presence of kidney stones was associated with a worse bone status and with severe vitamin D deficiency. In the whole sample, femoral BMD Z-scores were directly correlated with albumin-adjusted calcium (p < 0.05) and 25OHVitD levels (p < 0.01). CONCLUSIONS: Despite the improvement of CF care, CFBD is still highly prevalent in young adults awaiting lung transplantation for end-stage CF. Suboptimal 25OHVitD levels could significantly contribute to the development of CFBD. The presence of nephrolithiasis could be an additional warning about the need for a careful evaluation of bone health in CF patients.

Drug-induced interstitial lung disease during cancer therapies: expert opinion on diagnosis and treatment.

BACKGROUND: Drug-induced interstitial lung disease (DIILD) is a form of interstitial lung disease resulting from exposure to drugs causing inflammation and possibly interstitial fibrosis. Antineoplastic drugs are the primary cause of DIILD, accounting for 23%-51% of cases, with bleomycin, everolimus, erlotinib, trastuzumab-deruxtecan and immune checkpoint inhibitors being the most common causative agents. DIILD can be difficult to identify and manage, and there are currently no specific guidelines on the diagnosis and treatment of DIILD caused by anticancer drugs. OBJECTIVE: To develop recommendations for the diagnosis and management of DIILD in cancer patients. METHODS: Based on the published literature and their clinical expertise, a multidisciplinary group of experts in Italy developed recommendations stratified by DIILD severity, based on the Common Terminology Criteria for Adverse Events. RESULTS: The recommendations highlight the importance of multidisciplinary interaction in the diagnosis and management of DIILD. Important components of the diagnostic process are physical examination and careful patient history-taking, measurement of vital signs (particularly respiratory rate and arterial oxygen saturation), relevant laboratory tests, respiratory function testing with spirometry and diffusing capacity of the lung for carbon monoxide and computed tomography/imaging. Because the clinical and radiological signs of DIILD are often similar to those of pneumonias or interstitial lung diseases, differential diagnosis is important, including microbial and serological testing to exclude or confirm infectious causes. In most cases, management of DIILD requires the discontinuation of the antineoplastic agent and the administration of short-term steroids. Steroid tapering must be undertaken slowly to prevent reactivation of DIILD. Patients with severe and very severe (grade 3 and 4) DIILD will require hospitalisation and often need oxygen and non-invasive ventilation. Decisions about invasive ventilation should take into account the patient's cancer prognosis. CONCLUSIONS: These recommendations provide a structured step-by-step diagnostic and therapeutic approach for each grade of suspected cancer-related DIILD.

Duration of antibiotic therapy in hospitalised patients with community-acquired pneumonia.

Recent guidelines suggest that duration of antibiotic therapy for hospitalized patients with community-acquired pneumonia (CAP) can be reduced by individualising treatment based on patient's clinical response. However, the degree of application of this principle in clinical practice is unknown. Duration of therapy was analysed in patients identified from the Community-Acquired Pneumonia Organization database and evaluated with respect to severity of the disease on admission and time to clinical stability (TCS). Among the 2,003 patients enrolled, mean duration of total antibiotic therapy was 11 days. Neither the pneumonia severity index (r(2) = 0.005) nor the CRB-65 (r(2) = 0.004) scores were related to total duration of therapy. Duration of intravenous antibiotic therapy was related to TCS (r(2) = 0.198). Conversely, TCS was not related to duration of either oral (r(2) = 0.014) or total (r(2) = 0.02) antibiotic therapy. Neither TCS nor other characteristics were found to be significantly associated with duration of total therapy by logistic regression analysis (r(2)<0.09). The individualised approach suggested by recent guidelines has not been adopted in current clinical practice. Duration of therapy is not influenced by either the severity of disease at the time of hospitalisation or the clinical response to therapy.

Non-invasive continuous positive airway pressure in monolateral lung transplant patient with pneumonia and IPF.

Patients who undergo lung transplantation are prone to develop lower respiratory tract infections, leading to severe acute respiratory failure (ARF). Endotracheal intubation may not be indicated in these patients in light of a higher rate of mortality due to infections. The application of non-invasive ventilation could play a role in bridging these patients through the episode of ARF waiting for medical treatment to have effect. We report the evidence of morphological and physiological effects of the application of non-invasive continuous positive airway pressure during ARF sustained by pneumonia in a patient who underwent left lung transplantation because of idiopathic pulmonary fibrosis (IPF). We studied the effects of the application of positive end-expiratory pressure on both the right native lung affected by IPF and the transplanted lung affected by pneumonia.

Epstein-Barr Virus-Related Post-Transplant Lymphoproliferative Disorders in Cystic Fibrosis Lung Transplant Recipients: A Case Series.

BACKGROUND: Solid organ transplantation is associated with a higher risk of Epstein-Barr virus (EBV)-related lymphoproliferative disease due to immunosuppressive regimen. Little evidence is currently available on post-transplant lymphoproliferative disorders (PTLDs) in the lung transplant (LuTx) setting, particularly in cystic fibrosis (CF) recipients. METHODS: We retrospectively analyzed all the cases of PTLDs that occurred in our LuTx center between January 2015 and December 2017. We reviewed clinical and radiologic data, donor and recipient EBV serostatus, immunosuppressive therapy, histologic data, and follow-up of these patients. RESULTS: A total of 77 LuTxs were performed at our center in the study period; 39 (50.6%) patients had CF; 4 developed EBV-related PTLDs. They were all young (17-26 years) CF patients with high serum EBV DNA load. Disease onset was within the first 3 months after LuTx. In 3 cases presentation was associated with fever and infection-like symptoms, whereas in 1 case radiologic suspicion arose unexpectedly from a CT scan performed for different clinical reasons. Diagnosis was reached through lung biopsy in all cases. All patients received rituximab, cyclophosphamide, doxorubicin hydrochloride (hydroxydaunomycin), vincristine sulfate (Oncovin), and prednisone with variable response and complications. CONCLUSION: In our experience, the early development of EBV-related PTLD was a highly aggressive, life-threatening condition, which exclusively affected young CF patients in the early post-transplant period. The rate of this complication was relatively high in our population. Diagnosis with lung biopsy is crucial in all suspected cases and regular monitoring of EBV DNA levels is of utmost importance given the high correlation with PTLDs in patients at increased risk.

Lung Allocation Score System: First Italian Experience.

BACKGROUND: Lung transplantation is an established therapeutic option for patients with end-stage pulmonary disease. In May 2005, the lung allocation score (LAS) was introduced in the United States to maximize the benefit to the recipient population and reduce waiting list mortality. The LAS has been applied in a region of Italy since March 2016 on a provisional basis. The aims of the study were describing waiting list characteristics and short-term outcomes after lung transplantation before and after LAS introduction. METHODS: All the patients who received transplants between January 1, 2011, and March 15, 2017, were included in our retrospective study. The study population was divided into 2 cohorts (historical cohort and post-LAS cohort) and a comparison among the main perioperative data was performed. RESULTS: The historical cohort consisted of 415 patients on the waiting list with 91 deaths and 199 lung transplants; the post-LAS cohort consisted of 134 patients with 10 deaths on the waiting list and 51 transplants. Median waiting time and mortality on the list decreased from 223 to 106 days (P = .03) and from 11.2% to 7.5% (P > .05), respectively. The transplantation rate increased from 25% to 38% (P = .001) and the probability to receive a transplant in the first year in the post-LAS era increased significantly (P = .004). CONCLUSIONS: The results of the introduction of the LAS system in our region are encouraging and have not shown any adverse short-term effects. The regional coordination decided to prolong the experimental application of LAS in order to accumulate more data and to evaluate medium-term outcomes.

Surveillance Transbronchial Biopsy Program to Evaluate Acute Rejection After Lung Transplantation: A Single Institution Experience.

BACKGROUND: There is no unanimity in the literature regarding the value of transbronchial biopsies (TBBs) performed at a scheduled time after lung transplantation (surveillance TBBs [SBs]), compared to biopsies performed for suspected clinical acute rejection (clinically indicated TBBs [CIBs]). This study exposes an assessment of our experience over the last 4 years through a retrospective analysis of the data collected. METHODS: In our center, SBs are performed at 3, 6, and 12 months after a transplant. Data from 110 patients who underwent a TBB were collected from January 2013 to November 2017. Clinical and functional data along with the histologic results and complications were collected. RESULTS: Overall 251 procedures were performed: 223 for surveillance purposes and 28 for clinical indications. The SBs diagnostic rate was 84%. A grade 2 acute rejection (AR) was detected in 9 asymptomatic patients, all of whom were medically treated, with downgrading of AR documented in all cases. The rate of medical intervention in the SB group was 8%. The CIBs diagnostic rate was 96%. The rate of AR detected by CIBs was significantly higher than by SBs (36% versus 4%; P < .0001). Overall the major complication rate was 4%; no patients required transfusions and no mortality occurred in the patient cohort. CONCLUSIONS: The surveillance protocol did not eliminate the necessity of CIBs, but in 8% of patients early rejection was histologically assessed. The correlation between histologic and clinical data allows a more careful approach to transplanted patients.

The 2001 meningitis epidemic in south Chad.

AIM: Bacterial meningitis is widespread in many areas of tropical countries, has a high mortality rate, and is often devastating. However, epidemiological studies in rural areas are quite rare, especially in Chad. We report data concerning the 2001 meningitis epidemic in the Moyen Chari district, in Southern Chad. METHODS: Five-hundred and ninety-five cases of meningitis were admitted in hospital from January to April 2001. Diagnosis was made on the basis of clinical presentation and/or by cerebrospinal fluid (CSF) specimen analysis. Antimicrobial treatment, time of recovery or death were recorded. Treatments most employed were oily chloramphenicol (CAP) and ampicillin, alone or combined. RESULTS: Two peaks of incidence have been observed: one in children aged below 1 year and the other in 6 year-olds with an overall lethality rate of 8.74%, particularly in children aged below 2 years. Incidence decreased over 13 years of age. Weekly incidence per 1 000 inhabitants, ranged from 0.21 to 1.69. Microbiological data indicated S. pneumoniae as the leading pathogen, but the epidemic nature of the disease suggests that this pathogen was probably overestimated. CONCLUSION: Our data suggest that an incidence of 10 cases per 100 000 appears most useful in predicting an epidemic. CAP was significantly the most effective treatment in terms of lethality, need for second-line treatment, and mean hospital stay, particularly if first administered at a primary health center. In case of lack of response to CAP treatment, the association of ampicillin and gentamicin seems more advisable than ampicillin alone.

A possible association of Chlamydia pneumoniae infection and acute myocardial infarction in patients younger than 65 years of age.

STUDY OBJECTIVES: We conducted a retrospective study on patients with acute myocardial infarction (AMI) and evaluated the incidence and prevalence of Chlamydia pneumoniae infection. METHODS: Sixty-one consecutive patients with AMI aged younger than 65 years were enrolled. Within 24 h of hospital admission, serum samples and pharyngeal swab specimens were obtained from all patients. In 49 of 61 patients, after a mean of 28 days from hospital admission, a second serum sample was drawn. A third serum sample was obtained in 23 of 61 patients. Serologic testing for Chlamydia pneumoniae was performed by a microimmunofluorescence test. We applied a nested-polymerase chain reaction for C pneumoniae DNA detection to pharyngeal swab specimens. Simultaneously, we performed a serologic study for C pneumoniae infection on 61 serum samples obtained from blood donors, matched for age, sex, and smoking habits. RESULTS: Serologic test results for C pneumoniae were consistent with acute reinfection in 12 patients, with chronic infection in 23 patients, and results were negative in 26 patients with AMI. In 3 of 12 patients with acute reinfection pattern and in 3 of 23 patients with chronic infection pattern, C pneumoniae DNA was detected on pharyngeal swab specimens. A significantly higher prevalence of IgG titers was observed in patients with AMI (35/61) compared to blood donors (18/61) (p=0.003). CONCLUSION: Our data confirm the possible role of C pneumoniae infection in coronary heart disease and suggest that reinfection may trigger the onset of AMI.

Clinical efficacy of a vaccine-immunostimulant combination in the prevention of influenza in patients with chronic obstructive pulmonary disease and chronic asthma.

Influenza is a leading cause of morbidity and mortality in patients with chronic respiratory diseases. This study compares two influenza prevention schemes in patients with chronic obstructive pulmonary disease and chronic asthma. We enrolled 66 patients, distributed as follows: Group A: 32 subjects treated with influenza vaccine; Group B: 34 patients treated with influenza vaccine and bacterial immunostimulant. The rate of influenza episodes was recorded. Hemoagglutination inhibiting antibody titers for vaccine strains H1N1, H3N2, and B were determined at time 0 (prior to vaccination), and on days 30 and 90 following vaccination. We observed a lower rate of influenza episodes in Group B patients (8.82%) compared to Group A (31.25%) (p < 0.05). At day 90 Group B patients presented higher geometric mean antibody titers for strains H1N1 (p = 0.07) and H3N2 (p = 0.08). Bacterial immunostimulants appear as possible adjuvants in the prevention of influenza episodes, and may prolong antibody response to influenza vaccine strains.

Effects of thiabendazole in Mansonella perstans filariasis.

Mansonella perstans is a human filarial parasite distributed across the center of Africa and equatorial America. Although M. perstans infection is asymptomatic in most individuals, a variety of symptoms have been described, including angioedema, pruritus, fever, ocular involvement, and serous cavities pain. Eosinophilia is found in many cases. Treatment with diethyl-carbamazine or mebendazole is often ineffective. We present a study on the effects of thiabendazole in the treatment of symptomatic M. perstans filariasis. Twenty-five patients were treated with thiabendazole at a single dose of 50 mg/kg for children and 3 g for adults. Sixteen out of 25 subjects repeated a second dose a week later. Parasite density, eosinophilia, and symptoms were significantly reduced after both one and two-step therapy in most patients. This study shows that thiabendazole may be effective in M. perstans infection. More studies are needed to determine a more effective dosage, or a putative combination treatment.

Transfusional Mansonella perstans microfilariasis.

Mansonella perstans filariasis is widely distributed across the center of Africa and equatorial America. We describe a case of post-transfusional M. perstans microfilariasis in a young child, affected with severe Plasmodium falciparum malaria, admitted in Goundi Hospital in South of Chad. A decrease of M. perstans microfilariasis in the patient's blood was observed, with no subsequent development of either clinical symptoms or eosinophilia. We suggest that, in endemic areas, transfused M. perstans microfilariae may be cleared from the blood over relatively short periods of time. It is likely that only adult worms are responsible for symptoms and eosinophilia, whereas microfilariae in the bloodstream are unable to give clinical manifestations.

Effect of atropine on ciliary beat in human upper respiratory tract epithelial cells.

The mucociliary apparatus is a fundamental element among the defensive mechanisms of the airways. In man, average ciliary beat frequency (CBF) has been reported to be between 600 and 1,000 beats/min and does not vary significantly at different sites along the respiratory tract. Ciliary function is altered by numerous factors, including temperature, pH, cigarette smoke, drugs, and alcohol. The aim of the present study was to evaluate whether intravenous (i.v.) infusion of atropine alters CBF. We studied nine patients (six females and three males, mean age 42.9 years) with otosclerosis, a nonrespiratory disease. All patients were scheduled for surgical stapedectomy. In all patients, nasal brushing was performed before and 20 min following i.v. injection of 0.5 mg atropine sulphate. The cellular samples, maintained viable in tissue medium, were observed under a microscope and filmed. A quantitative evaluation of ciliary activity was obtained by playing the film back in slow motion. The mean CBF value prior to atropine infusion in the nine patients studied was 588.12 (+/- 53.29 SD) beats/min. After infusion of atropine, mean CBF was 442.33 (+/- 52.82 SD) beats/min. The mean percentage drop in CBF following atropine infusion was 24.79% (t = 5.82, p < 0.001). Our data show a drop in in vitro CBF following atropine infusion which, presumably, reflects a fall in the in vivo efficacy of mucociliary transport. Atropine treatment determined a loss in CBF that was inversely correlated with increasing age.

Community-acquired pneumonia: role of atypical organisms.

M. pneumoniae infection occurs world-wide and is the most common cause of community-acquired pneumonia (CAP) in the 5 to 20 year-old age group. The most reliable diagnostic test is enzyme immunoassay that allows immunoglobulin (Ig)G and IgM titration and presents 92% sensitivity and 95% specificity on paired samples. Potentially active drugs are tetracyclines, macrolides, ketolides, lincosamides, streptogamines, chloramphenicol, and fluoroquinolones. The incidence of Legionella infection, in spite of its world-wide diffusion, is highly variable in different studies, ranging from 1% to 27% of CAP. The most likely mode of transmission is direct inhalation from Legionella-contaminated water-supply systems. Extrapulmonary manifestations are relatively common but nonspecific. However, some signs and symptoms may raise the suspicion of Legionella infection: a sputum Gram stain with a high number of neutrophils without any organism, hyponatremia, and diarrhea in a critically ill patient. Urinary radioimmunoassay (RIA) antigen detection is the method of choice for L. pneumophila serogroup 1. The best treatment regimen is a full three-week treatment with a macrolide (erythromycin, clarithromycin, azithromycin). An alternative treatment regimen may be the association of second generation fluoroquinolones with tetracyclines. A notable improvement in most of the new fluoroquinolones is their activity against Legionella, so that their use as single agent may be hypothesised even if clinical data are still insufficient for a definitive indication. Chlamydia pneumoniae account for 6-20% of CAP depending on several factors such as setting of the studied population, age group examined, and diagnostic methods used. The current gold standard for serological diagnosis of acute infection is microimmunofluorescence testing. Tetracyclines and erythromycin show good in vitro activity and so far have been the most commonly employed drugs in the treatment of C. pneumoniae infection. New macrolides, ketolides, and new fluoroquinolones are other potentially effective drugs.

Atypical pathogens and asthma: can they influence the natural history of the disease?

The association between respiratory infections and asthma exacerbations was first observed in the early '70s. In particular, the role of viral upper respiratory tract infections has been evaluated both in pediatric and adult populations. More recently, evidence of Mycoplasma and Chlamydia pneumoniae involvement in asthma attacks has been reported. These pathogens are also involved in chronic asthma, and both in vitro and animal model studies indicate that atypical agents may play a role in the pathogenesis of the disease. Further research is required to determine whether specific antibiotic treatment may alter the natural history of asthma.

Utility of monitoring breathing during night hours in COPD patients undergoing long-term oxygen therapy.

We investigated the occurrence of nocturnal respiratory disorders during air and supplemental oxygen breathing in 16 patients with chronic obstructive pulmonary disease (COPD) undergoing long-term home oxygen therapy (LTOT). Following a first night of acclimatization, non-attended continuous nocturnal monitoring was performed for two successive nights in a randomized order. During one night patients breathed room air ("Air night"), and during the other they underwent LTOT ("O2 night") at the same protective O2 nasal flow rate set during waking hours in a resting state. O2 was administered from liquid reservoirs. On both occasions, the patients were monitored during the night for oxygen saturation by pulse finger oximetry (Sp,O2), chest-abdomen impedance, mouth-nasal thermistor flow rate, electrocardiogram (ECG), body position, eye movements, and leg movements. During the O2 night, compared to the Air night, mean (+/- SD) desaturation time decreased from 46 +/- 29 to 13 +/- 25%, while obstructive apnoea-hypopnoea duration increased from 6 +/- 8 to 9 +/- 7%, both expressed as percentage of total sleep time. The sleep apnoea/hypopnoea syndrome (SAHS) rate during the Air-night was 2 out of 16, both SAHS patients showing a reduction of apnoea-hypopnoea number.h-1 during the O2 night; whilst SAHS was noted in a further two patients during the O2 night. We conclude that Sp,O2 together with monitoring of breathing during the night, is potentially useful in patients with chronic obstructive pulmonary disease undergoing long-term oxygen therapy, not only when evaluating the O2 flow rate to be used during the night, but also for an understanding of the pathogenesis of nocturnal arterial oxyhaemoglobin desaturations, which may or may not be related to respiratory events.

Understanding the burden of pneumococcal disease in adults.

Streptococcus pneumoniae causes different types of acute, invasive and non-invasive clinical infections, being the most frequently detected pathogen responsible for community-acquired pneumonia. Pneumococcal pneumonia is accompanied by bacteraemia in 10-30% of cases. Streptococcus pneumoniae is gaining resistance to the in vitro activity of several antimicrobial agents and, even if questions remain regarding the clinical impact of this phenomenon, more and more reports indicate that antibiotic resistance can lead to more treatment failures if not higher mortality. Use of the 23-valent anti-pneumococcal vaccine appears to offer subpotimal protection against pneumococcal disease, particularly among high-risk adult populations. Vaccination against S. pneumoniae with new conjugate vaccines seems to be the most promising field for real improvement in the management of pneumococcal infections in adults.