An international, multicentre evaluation and description of Burkholderia pseudomallei infection in cystic fibrosis.

BACKGROUND: Several cases of Burkholderia pseudomallei infection in CF have been previously reported. We aimed to identify all cases globally, risk factors for acquisition, clinical consequences, and optimal treatment strategies. METHODS: We performed a literature search to identify all published cases of B. pseudomallei infection in CF. In addition we hand-searched respiratory journals, and contacted experts in infectious diseases and CF around the world. Supervising clinicians for identified cases were contacted and contemporaneous clinical data was requested. RESULTS: 25 culture-confirmed cases were identified. The median age at acquisition was 21 years, mean FEV1 % predicted was 60 %, and mean BMI was 19.5 kg/m(2). The location of acquisition was northern Australia or south-east Asia for most. 19 patients (76 %) developed chronic infection, which was usually associated with clinical decline. Successful eradication strategies included a minimum of two weeks of intravenous ceftazidime, followed by a consolidation phase with trimethoprim/sulfamethoxazole, and this resulted in a higher chance of success when instituted early. Three cases of lung transplantation have been recorded in the setting of chronic B. pseudomallei infection. CONCLUSION: Chronic carriage of B. pseudomallei in patients with CF appears common after infection, in contrast to the non-CF population. This is often associated with an accelerated clinical decline. Lung transplantation has been performed in select cases of chronic B. pseudomallei infection.

Prevalence of nontuberculous mycobacteria in cystic fibrosis clinics, United Kingdom, 2009.

Incidence of pulmonary infection with nontuberculous mycobacteria (NTM) is increasing among persons with cystic fibrosis (CF). We assessed prevalence and management in CF centers in the United Kingdom and found 5.0% of 3,805 adults and 3.3% of 3,317 children had recently been diagnosed with NTM. Of those, 44% of adults and 47% of children received treatment.

Characteristics and significance of "green snake" bites in Myanmar, especially by the pit vipers Trimeresurus albolabris and Trimeresurus erythrurus.

Snakebite is an important problem in Myanmar. Regionally, bites by Eastern Russell's vipers, Daboia siamensis (Viperidae, Viperinae), and monocled cobras, Naja kaouthia are considered medically important, but those categorised as "green snake" bites are not. However, these may include bites by green pit vipers, Trimeresurus spp. (Viperidae, Crotalinae) for which no antivenom is available in Myanmar. Elsewhere in Southeast Asia, these snakes are reported to cause local and systemic envenoming. As part of the Myanmar Snakebite Project, prospective case data were collected over 3 years from five hospitals in the Mandalay region. These included 3803 snakebite cases reported from Mandalay region. Of these, 355 were listed as bites by a witnessed green-coloured snake. In 22 cases, the snakes responsible were retained and preserved, then expertly identified; 21 were medically important white-lipped pit vipers (Trimeresurus albolabris), and one as an Asian vine snake, Ahaetulla prasina (Colubridae, Ahaetuliinae) which is not of medical importance. Among confirmed Trimeresurus albolabris bites, 15/21 developed swelling of the bitten limb, and 3/21 coagulopathy, defined as a positive 20-min whole blood clotting test (20WBCT). None developed necrosis, blistering, thrombocytopenia or acute kidney injury (AKI). Of the remaining 333 patients bitten by green snakes that were not specifically identified, 241 (72%) developed swelling of the bitten limb, and 62 (19%) coagulopathy. AKI occurred in 21/333 patients, but only one required dialysis. At least 10/21 of the cases with AKI in this study were more likely to represent bites from Trimeresurus spp. than D. siamensis because the snake responsible was brought into the hospital, examined and described by the treating physician as "green-coloured". This study describes a previously unpublished case of AKI from envenoming by T. erythrurus in Yangon, and reviews cases of AKI following bites by this species and T. albolabris in Myanmar. This confirms that, at least on rare occasions, Trimeresurus spp. envenoming can cause AKI. This has important implications for snakebite management in Myanmar as the finding of local swelling, coagulopathy and AKI is generally considered pathognomonic of D. siamensis envenoming. Further collection of confirmed Trimeresurus spp. bites is required in Myanmar in order better to define the syndrome of envenoming and to assess the possible need for antivenom against Trimeresurus spp. in this country.

Community responses to COVID-19 pandemic first wave containment measures: a multinational study.

INTRODUCTION: National strategies to control COVID-19 pandemic consisted mostly of social distancing measures such as lockdowns, curfews, and stay-home guidelines, personal protection such as hand hygiene and mask wearing, as well as contact tracing, isolation and quarantine. Whilst policy interventions were broadly similar across the globe, there were some differences in individual and community responses. This study explored community responses to COVID-19 containment measures in different countries and synthesized a model. This exaplains the community response to pandemic containment measures in the local context, so as to be suitably prepared for future interventions and research. METHODOLOGY: A mutlinational study was conducted from April-June 2020 involving researchers from 12 countries (Japan, Austria, U.S., Taiwan, India, Sudan, Indonesia, Malaysia, Philippines, Myanmar, Vietnam and Thailand). Steps in this research consisted of carrying out open-ended questionnaires, qualitative analyses in NVivo, and a multinational meeting to reflect, exchange, and validate results. Lastly, a commuinty response model was synthesized from multinational experiences. RESULTS: Effective communication is key in promoting collective action for preventing virus transmission. Health literacy, habits and social norms in different populations are core components of public health interventions. To enable people to stay home while sustaining livelihoods, economic and social support are essential. Countries could benefit from previous pandemic experience in their community response. Whilst contact tracing and isolation are crucial intervention components, issues of privacy and human rights need to be considered. CONCLUSIONS: Understanding community responses to containment policies will help in ending current and future pandemics in the world.

Symptomatic pancreatitis in patients with cystic fibrosis.

OBJECTIVES: A small group of cystic fibrosis (CF) patients develop symptomatic pancreatitis. The clinical characteristics of these cases are not well documented in the literature. Most cases are in pancreatic sufficient (PS) patients, but it is not clear whether pancreatitis does occur in pancreatic insufficient (PI) patients. There is no information on how the group with PS and pancreatitis differs from the group with PS that does not develop pancreatitis. METHODS: The Royal Brompton Hospital database of adult CF patients was searched to identify all patients with symptomatic pancreatitis. Clinical details were taken from the case notes. PS pancreatitis patients were then compared with an age- and sex-matched PS control group drawn from the database. RESULTS: Sixteen patients (9 males) had suffered symptomatic pancreatitis, representing 1.6% of the total database. The mean age at CF diagnosis was 18.7 years, and at presentation with pancreatitis it was 28.8 years. Twelve were PS at diagnosis of CF. At presentation with pancreatitis, seven patients were PS and at the most recent follow-up or death, two remained PS. There was a median of three hospital admissions with pancreatitis. Eight cases developed pancreatic or hepatobiliary complications. In the comparison of pancreatitis patients with controls, there was no difference in survival but pancreatitis patients were significantly more likely to develop PI status. Mild CF transmembrane conductance regulator mutations in general, and R117H in particular, were found more often in pancreatitis patients. CONCLUSIONS: Symptomatic pancreatitis is a significant problem in 1-2% of patients with CF. These patients are PS at birth but are more likely to develop late PI status than PS patients without pancreatitis. R117H may be associated with this phenotype.

Hyperglycemia and cystic fibrosis alter respiratory fluid glucose concentrations estimated by breath condensate analysis.

In animals, glucose concentrations are 3-20 times lower in lung lining fluid than in plasma. In humans, glucose concentrations are normally low (<1 mmol/l) in nasal and bronchial fluid, but they are elevated by inflammation or hyperglycemia. Furthermore, elevated bronchial glucose is associated with increased respiratory infection in intensive care patients. Our aims were to estimate normal glucose concentrations in fluid from distal human lung sampled noninvasively and to determine effects of hyperglycemia and lung disease on lung glucose concentrations. Respiratory fluid was sampled as exhaled breath condensate, and glucose was measured by chromatography with pulsed amperometric detection. Dilution corrections, based on conductivity, were applied to estimate respiratory fluid glucose concentrations (breath glucose). We found that breath glucose in healthy volunteers was 0.40 mmol/l (SD 0.24), reproducible, and unaffected by changes in salivary glucose. Breath-to-blood glucose ratio (BBGR) was 0.08 (SD 0.05). Breath glucose increased during experimental hyperglycemia (P < 0.05) and was elevated in diabetic patients without lung disease [1.20 mmol/l (SD 0.69)] in proportion to hyperglycemia [BBGR 0.09 (SD 0.06)]. Breath glucose was elevated more than expected for blood glucose in cystic fibrosis patients [breath 2.04 mmol/l (SD 1.14), BBGR 0.29 (SD 0.17)] and in cystic fibrosis-related diabetes [breath 4.00 mmol/l (SD 2.07), BBGR 0.54 (0.28); P < 0.0001]. These data indicate that 1) this method makes a biologically plausible estimate of respiratory fluid glucose concentration, 2) respiratory fluid glucose concentrations are elevated by hyperglycemia and lung disease, and 3) effects of hyperglycemia and lung disease can be distinguished using the BBGR. This method will support future in vivo investigation of the cause and effect of elevated respiratory fluid glucose in human lung disease.

Airway glucose concentrations and effect on growth of respiratory pathogens in cystic fibrosis.

BACKGROUND: Pulmonary decline accelerates in cystic fibrosis-related diabetes (CFRD) proportional to severity of glucose intolerance, but mechanisms are unclear. In people without CF, airway glucose (AG) concentrations are elevated when blood glucose (BG)> or =8 mmol L(-1) (airway threshold), and are associated with acquisition of respiratory infection. METHODS: To determine the relationship between BG and AG, 40 CF patients underwent paired BG and AG (nasal) measurements. Daily time with BG>airway threshold was compared in 10 CFRD, 10 CF patients with normal glucose tolerance (CF-NGT) and 10 healthy volunteers by continuous BG monitoring. The effect of glucose at airway concentrations on bacterial growth was determined in vitro by optical densitometry. RESULTS: AG was present more frequently (85%-vs.-19%, p<0.0001) and at higher concentrations (0.5-3 mmol L(-1)-vs.-0.5-1 mmol L(-1), p<0.0001) when BG was > or =8 mmol L(-1)-vs.-<8 mmol L(-1). Daily time with BG> or =8 mmol L(-1) was CFRD (49+/-25%), CF-NGT (6+/-5%), healthy volunteers (1+/-3%), p<0.0001. Staphylococcus aureus growth increased at > or =0.5 mmol L(-1) (p=0.006) and Pseudomonas aeruginosa growth above 1-4 mmol L(-1) glucose (p=0.039). CONCLUSIONS: BG> or =8 mmol L(-1) predicted elevated AG concentrations in CF, at least in nasal secretions. CFRD patients spent approximately 50% day with BG>airway threshold, implying persistently elevated AG concentrations. Further studies are required to determine whether elevated airway glucose concentrations contribute to accelerated pulmonary decline in CFRD.

Pregnancy in cystic fibrosis lung transplant recipients: case series and review.

A single centre experience of four pregnancies in four cystic fibrosis (CF) lung transplant recipients is reported. Six more cases were identified from the literature review and combined data analysis on 10 pregnancies in 10 CF lung transplant recipients was performed to determine maternal, foetal and graft outcome. There were nine live births and one therapeutic abortion. Three required caesarean sections. Five babies were premature but all nine children were well at follow-up. Five recipients who had a long, stable interval (i.e. at least three years) between transplant and pregnancy had a favourable outcome. Three recipients developed rejection during the pregnancy and one already had obliterative bronchiolitis before pregnancy. All showed progressive decline in lung function and subsequently died of chronic rejection within 38 months of delivery. Pregnancy in CF lung transplant recipients is feasible but should still be regarded as a risky undertaking.

Temocillin in the treatment of Burkholderia cepacia infection in cystic fibrosis.

BACKGROUND: Infections due to Burkholderia cepacia complex (Bcc) strains increase morbidity and mortality in cystic fibrosis (CF). Some transplant centres reject Bcc infected patients. We reviewed the results in patients treated with i.v temocillin. METHODS: Twenty-three patients who received 38 courses of temocillin (1988-1998) were identified from the CF database at Royal Brompton Hospital. In three patients' data were inadequate; therefore analysis was done in 20. Outcome was measured as improvement, deterioration or no change (compared to admission) in the following categories: clinical (temperature, dyspnoea, sputum volume, chest pain), physiological (FEV1, FVC, oxygen saturation) and inflammatory markers (WBC, ESR, CRP). Patients who improved in two categories were classified as having improved. Antibiotic sensitivities and outcome were recorded. RESULTS: In 18 of 32 courses (56.25%) improvement occurred. The organism (Bcc) in eight patients' sputum became resistant (three died). The antibiotics was changed in five patients with Bcc strains sensitive to temocillin because of no improvement and one patient due to allergy (rash). The average time to the next i.v antibiotic was 41 days. Eight patients died (in three the Bcc strain was resistant to temocillin). Fourteen patients with Bcc were transplanted and eight patients survived. Another patient who developed Bcc infection post-operatively, failing to respond to temocillin. CONCLUSIONS: These results suggest the potential benefit of i.v temocillin in CF patients with Bcc for exacerbations and at the time of transplantation.

Relationship between glycosylated haemoglobin and mean plasma glucose concentration in cystic fibrosis.

BACKGROUND: HbA(1c) is recommended for monitoring glycaemic control in people with cystic fibrosis-related diabetes (CFRD). However the relationship between HbA(1c) and mean plasma glucose concentration (MPG) has not been established in CFRD, as in other forms of diabetes mellitus. METHODS: 20 people (13 male, 29.7+/-8.8 years, 10 CFRD) with cystic fibrosis (CF) underwent HbA(1c) measurement and 48 h continuous glucose monitoring for estimation of MPG. The relationship between HbA(1c) and MPG was established and compared to the reported relationship for type 1 diabetes. RESULTS: HbA(1c) was strongly correlated with MPG (R(2)=0.888, p<0.0001) in CF. The relationship of MPG to HbA(1c) was described by the equation MPG=(1.47xHbA(1c))-1.15, giving a 1.47 mmol L(-1) change in MPG per 1% change in HbA(1c). This equation predicts that MPG in people with CF and HbA(1c) <7.0% will be similar to MPG in people with type 1 diabetes who achieve the same HbA(1c) target. CONCLUSIONS: These results imply that HbA(1c)<7.0% will predict good blood glucose control in CF as in type 1 diabetes. However, although HbA(1c) predicts complications in type 1 diabetes, further studies are required to establish the relationship between HbA(1c) and diabetic complications in people with CFRD.

HbA1c as a screening tool for cystic fibrosis related diabetes.

AIMS: Early diagnosis of cystic fibrosis (CF) related diabetes (CFRD) is important to improve outcomes. International guidelines recommend an oral glucose tolerance test (OGTT) for all CF patients aged ≥10 years - this approach is controversial. The aim of this study was to develop an effective screening tool and reduce the need for a universal OGTT. METHODS: Adult CF patients (without CFRD) attending an annual review assessment were recruited prospectively (March 2009-July 2012) into two sequential studies - a primary investigative study followed by validation study. All patients underwent an OGTT and were simultaneously screened by predetermined biochemical/clinical criteria to identify their risk of CFRD. A sensitivity/specificity analysis was performed using the World Health Organisation diabetes criteria as gold standard; modifications were made to improve the screening tool's accuracy and determine the optimal screening thresholds. This was tested in the validation study. RESULTS: 429 patients (primary, n=94; validation, n=335: mean age=31.7 ± 10.4(SD), 43% female, 77% on pancreatic supplements). Primary study: in predicting a positive OGTT, the test sensitivity was 66.7% and specificity 60%. HbA1c was carried over to the validation study as it was the most discriminative (optimal threshold ≥5.8% (40 mmol/mol); receiver operating curve, ROC, score 0.60). Validation study: the number of patients with a normal, impaired and diabetic OGTT was 268(80%), 51(15.2%) and 16(4.8%), respectively. HbA1c provided a test sensitivity, specificity and ROC score of 93.8%, 53.0% and 0.73, respectively. CONCLUSIONS: The use of HbA1c ≥ 5.8%(40 mmol/mol) is an effective tool for CFRD screening and reduced the need for an OGTT by 50.7%.

Clinical importance of cystic fibrosis-related diabetes.

The prevalence of cystic fibrosis-related diabetes (CFRD) and glucose intolerance (IGT) has risen dramatically over the past 20 years as survival has increased for people with cystic fibrosis (CF). Diabetes is primarily caused by pancreatic damage, which reduces insulin secretion, but glucose tolerance is also modified by factors that alter insulin resistance, such as intercurrent illness and infection. CFRD not only causes the symptoms and micro and macrovascular complications seen in type 1 and type 2 diabetes in the general population, but also is associated with accelerated pulmonary decline and increased mortality. Pulmonary effects are seen some years before the diagnosis of CFRD, implying that impaired glucose tolerance may be detrimental. Current practice is to screen for changes in glucose tolerance by regular measurement of fasting blood glucose, by oral glucose tolerance test or a combination of these approaches with symptom review and measurement of HbA1C. Treatment is clearly indicated for those with CFRD and fasting hyperglycaemia to control symptoms and reduce complications. As nutrition is critical in people with CF to maintain body mass and lung function, blood glucose should be controlled in CFRD by adjusting insulin doses to the requirements of adequate food intake and not by calorie restriction. It is less clear whether blood glucose control will have clinical benefits in the management of patients with CFRD without fasting hyperglycaemia or with impaired glucose tolerance and further studies are required to establish the best treatment for this patient group.

Effect of acute exacerbations on skeletal muscle strength and physical activity in cystic fibrosis.

BACKGROUND: Skeletal muscle weakness is an important complication of chronic respiratory disease. The effect of acute exacerbations on strength in patients with cystic fibrosis is not known. METHODS: Quadriceps (QMVC) and respiratory muscle strength were measured in patients at the time of acute admission, at discharge and one month later. Patients wore an activity monitor during admission and at one month. Convalescent values were compared to the stable clinic population. RESULTS: Data were available for 13 acute admissions and 25 stable CF outpatients. Strength and other parameters including daily step count did not differ significantly between the stable and one month post-admission groups. At admission, QMVC was 16.7 (8.3)% lower than at convalescence, whereas inspiratory muscle strength did not change significantly. Reduction in QMVC did not correlate with activity levels or with markers of systemic inflammation. CONCLUSION: Further research is needed to identify the mechanisms responsible for the reduction in QMVC.

Predicting survival in end-stage cystic fibrosis.

The natural history of cystic fibrosis (CF) is unpredictable and the optimal timing for lung transplantation in end-stage disease uncertain. Predicting survival based on FEV1 alone remains controversial and therefore the aim of this study was to assess the value of walk test performance in pre-transplant assessment. Retrospective review of adult patients with end-stage CF who underwent transplant assessment between 1988 and 2004 including a documented walk test on room air, but who died before transplant. The six-minute walk test (6MWT) was used between 1988 and 1993 and the shuttle walk test (SWT) thereafter, the two cohorts were therefore individually assessed. A total of 121 patients were identified. The median (IQR) survival in patients performing SWT (n=77) and 6MWT (n=44) was 363 days (226, 566) and 433 days (232, 844), respectively, with survival in both cohorts significantly associated with pre-test (resting) heart rate (HR) (p<0.03), but not distance walked, pre-test SpO2, FEV1 or BMI. It was predicted that 85% of patients performing SWT with a resting HR of 120 bpm, 70% of those with a HR of 109 bpm (cohort median) but only 25% with a HR of 72 bpm would die within 500 days. Distance walked in the SWT was significantly related to pre-test HR (p<0.01), SpO2 (p<0.01) and Borg score (p=0.016) when performing linear regression. Only pre-test HR remained significant when performing multiple regression. Resting heart rate was the only consistent parameter in this study at predicting a high risk of dying on the transplant waiting list.

A woman with cystic fibrosis, severe hypoxaemia, an atrial thrombus and a patent foramen ovale: a case report.

INTRODUCTION: Cystic fibrosis is usually associated with chronic pulmonary sepsis and frequent infective exacerbations. We report a very unusual cause of severe hypoxaemia in a woman with cystic fibrosis caused by thrombus formation in the right atrium. CASE PRESENTATION: A 21-year-old Caucasian woman with cystic fibrosis and a totally implantable venous access device presented with severe hypoxaemia. This was initially treated with antibiotics but her oxygen levels did not improve significantly. Subsequently, a transient ischaemic attack occurred. Further investigations, including a contrast echocardiogram and a cardiac magnetic resonance scan, revealed the presence of a large right atrial thrombus and right-to-left intracardiac shunt through a patent foramen ovale. CONCLUSION: This case highlights the need to consider a right-to-left shunt in chronic respiratory diseases when hypoxaemia is out of proportion to the degree of lung function impairment. Totally implantable venous access devices should always be considered as a source of thrombus formation.

Variceal hemorrhage and cystic fibrosis: outcomes and implications for liver transplantation.

Autopsy and imaging studies show that liver involvement is common in cystic fibrosis. However, complications of chronic liver disease including portal hypertension and variceal bleeding are infrequently encountered, and the degree to which variceal hemorrhage affects prognosis in cystic fibrosis is unclear. This uncertainty has lead to debate as to whether liver transplantation is indicated in these patients. We describe a case series of 18 patients and compare their survival with a control group of cystic fibrosis patients without liver disease. The median age at first bleed was 20.0 years (range 9.7-30.9). The median survival after first bleed was 8.4 years, compared to 13.0 years in the control group (P = 0.15). A total of 14 patients have died, 9 from respiratory disease with no discernable contribution from their liver disease. Liver disease contributed to 4 deaths. Only 1 patient suffered a fatal hemorrhage, which may have been either variceal or bronchial in origin. Long-term survival is a frequent occurrence in patients with cystic fibrosis who suffer variceal hemorrhage, and age at death is comparable to the general cystic fibrosis population. In conclusion, this suggests that liver transplantation is not indicated in these patients without additional features of liver decompensation.