Delayed diagnosis of tuberculosis: risk factors and effect on mortality among older adults in Hong Kong.

OBJECTIVE: To assess the risk factors and effects of delayed diagnosis on tuberculosis (TB) mortality in Hong Kong. METHODS: All consecutive patients with TB notified in 2010 were tracked through their clinical records for treatment outcome until 2012. All TB cases notified or confirmed after death were identified for a mortality survey on the timing and causes of death. RESULTS: Of 5092 TB cases notified, 1061 (20.9%) died within 2 years of notification; 211 (4.1%) patients died before notification, 683 (13.4%) died within the first year, and 167 (3.3%) died within the second year after notification. Among the 211 cases with TB notified after death, only 30 were certified to have died from TB. However, 52 (24.6%) died from unspecified pneumonia/sepsis possibly related to pulmonary TB. If these cases are counted, the total TB-related deaths increases from 191 to 243. In 82 (33.7%) of these, TB was notified after death. Over 60% of cases in which TB diagnosed after death involved patients aged ≥80 years and a similar proportion had an advance care directive against resuscitation or investigation. Independent factors for TB notified after death included female sex, living in an old age home, drug abuse, malignancy other than lung cancer, sputum TB smear negative, sputum TB culture positive, and chest X-ray not done. CONCLUSIONS: High mortality was observed among patients with TB aged ≥80 years. Increased vigilance is warranted to avoid delayed diagnosis and reduce the transmission risk, especially among elderly patients with co-morbidities living in old age homes.

Angiogenesis in spontaneous tumors and implications for comparative tumor biology.

Blood supply is essential for development and growth of tumors and angiogenesis is the fundamental process of new blood vessel formation from preexisting ones. Angiogenesis is a prognostic indicator for a variety of tumors, and it coincides with increased shedding of neoplastic cells into the circulation and metastasis. Several molecules such as cell surface receptors, growth factors, and enzymes are involved in this process. While antiangiogenic therapy for cancer has been proposed over 20 years ago, it has garnered much controversy in recent years within the scientific community. The complex relationships between the angiogenic signaling cascade and antiangiogenic substances have indicated the angiogenic pathway as a valid target for anticancer drug development and VEGF has become the primary antiangiogenic drug target. This review discusses the basic and clinical perspectives of angiogenesis highlighting the importance of comparative biology in understanding tumor angiogenesis and the integration of these model systems for future drug development.

Aspirin desensitisation for Chinese patients with coronary artery disease.

OBJECTIVE. To assess the efficacy and safety of aspirin desensitisation in Chinese patients with coronary artery disease. DESIGN. Case series. SETTING. A regional hospital in Hong Kong. PATIENTS. Chinese patients with coronary artery disease and a history of a hypersensitivity reaction to aspirin or non-steroidal anti-inflammatory drug, who underwent aspirin desensitisation between February 2008 and July 2012. RESULTS. There were 24 Chinese patients with coronary artery disease who were admitted to our unit for aspirin desensitisation during this period. The majority (79%) were clinical admissions for desensitisation; eight (33%) of them developed a hypersensitivity reaction during desensitisation. Half of the latter had only limited cutaneous reactions and were able to complete the desensitisation protocol and developed aspirin tolerance. Overall, 20 (83%) of the patients were successfully desensitised at the initial attempt. No serious adverse reactions occurred in the cohort. Twelve of the patients had significant coronary artery disease revealed by coronary angiography and received a percutaneous coronary intervention, nine of whom received drug-eluting stents while three received bare metal stents due to financial constraints. All 11 successfully desensitised patients received aspirin and clopidogrel as double antiplatelet therapy after percutaneous coronary intervention. The remaining patient had a bare metal stent implant due to failed aspirin desensitisation. CONCLUSION. Given the potentially different genetic basis of aspirin hypersensitivity in different ethnicities, recourse to desensitisation in the Chinese population has not previously been addressed. This study demonstrated that aspirin desensitisation using a rapid protocol can be performed effectively and safely in Chinese patients. Our results were comparable to those in other reported studies involving other ethnicities. Successful aspirin desensitisation permits patients to pursue long-term double antiplatelet therapy that includes aspirin after percutaneous coronary intervention, and thus allows the use of drug-eluting stents as a feasible option.

Reperfusion strategy for ST-segment elevation myocardial infarction: trend over a 10-year period.

OBJECTIVES. To review the 10-year trend of reperfusion strategies in patients with ST-segment elevation myocardial infarction, and the adoption rate of percutaneous coronary interventions as opposed to thrombolytic therapy. Also to explore why some patients did not receive reperfusion therapy, and document changes in reperfusion strategies after the introduction of primary percutaneous coronary intervention programmes. DESIGN. Case series. SETTING. A regional hospital, Hong Kong. PATIENTS. All patients with ST-segment elevation myocardial infarction from January 2000 to December 2009. RESULTS. There were 1835 patients with ST-segment elevation myocardial infarction in that period, of which 1179 (64.3%) received reperfusion therapy (thrombolytic therapy, 46.0%; primary percutaneous coronary intervention, 17.5%; emergency coronary artery bypass graft, 0.7%). After introduction of the primary percutaneous coronary intervention programme, significantly more ST-segment elevation myocardial infarction cases underwent that particular intervention (1.6% in 2000 increasing to 30.6% in 2009), while the proportion receiving thrombolytic therapy declined (57.4% in 2000 decreasing to 35.0% in 2009). Seven reasons for no reperfusion therapy were identified. The commonest ones were delayed presentation (45.1%), succumbed before reperfusion (16.0%), multiple medical co-morbidities (15.2%), and contra-indication to thrombolytic therapy (14.8%). The proportion without reperfusion therapy due to a contra-indication to thrombolytic therapy declined (22.7% in 2000 decreasing to 4.9% to 2009), whilst an increasing proportion received primary percutaneous coronary interventions. CONCLUSIONS. Primary percutaneous coronary intervention is increasingly used as the reperfusion therapy in ST-segment elevation myocardial infarction and is replacing thrombolytic therapy, though the latter still remains a mainstay of therapy. A significant proportion of ST-segment elevation myocardial infarction cases received no reperfusion due to various reasons.

Primary percutaneous coronary intervention for ST elevation myocardial infarction: performance with focus on timeliness of treatment.

OBJECTIVE: To review primary percutaneous coronary interventions performed for patients with ST elevation myocardial infarction with a focus on door-to-treatment time, especially after introduction of a new management programme in November 2003. DESIGN: Retrospective study. SETTING: Regional hospital, Hong Kong. PATIENTS: All patients with ST elevation myocardial infarction who underwent primary percutaneous coronary intervention in our hospital from January 2002 to December 2007. RESULTS: In all, 209 patients with ST elevation myocardial infarction had primary percutaneous coronary interventions between January 2002 and December 2007; 140 of them were admitted within office hours, 125 of whom came directly from Accident and Emergency Department. The mean door-to-balloon time of these patients was 115 minutes, and in 41% the time was less than 90 minutes (as recommended by the American College of Cardiology/American Heart Association guidelines). Since introduction of the new programme, the mean door-to-balloon time has diminished significantly, from 146 to 116 minutes (P=0.047). Delay in diagnosis (28%) and Cardiac Catheterization Laboratory being occupied (20%) were the two most common reasons for prolonged door-to-balloon times. CONCLUSION: We achieved satisfactory performance in our primary percutaneous coronary intervention programme, providing timely reperfusion therapy for patients with ST elevation myocardial infarction. A well-organised and systematic clinical pathway is a prerequisite for a centre that provides a timely and effective primary percutaneous coronary intervention service for patients with ST elevation myocardial infarction. Better public education and greater awareness on the part of medical service providers are needed, so as to facilitate urgent revascularisation and improve outcomes in patients with ST elevation myocardial infarction.

Analyses of fluoroquinolones and Clostridium difficile-associated diarrhoea in tuberculosis patients.

SETTING: Systematic studies of fluoroquinolones (FQs) and Clostridium difficile-associated diarrhoea (CDAD) are scarce among tuberculosis (TB) patients, in whom fluoroquinolones (FQs) are increasingly used. OBJECTIVE: To evaluate the relationship between FQs and CDAD among TB patients. DESIGN: Retrospective cohort and nested case-control analyses were conducted among 3319 hospital patients on anti-tuberculosis treatment from 1999 to 2005. Each case of CDAD was matched by three sex- and age-matched controls randomly selected from the rest of the cohort. Not every case was confirmed by C. difficile cytotoxins. RESULTS: Among 38 cases studied, the incidence of CDAD, which was 28.2 (95%CI 20.3-38.3) per 100 000 patient-days overall, increased from 12.9 (95%CI 5.8-25.3) for patients aged <60 years to 26.6 (95%CI 15.5-42.8) for those aged between 60 and 79 years, and 66.9 (95%CI 39.8-106.1) for those aged >79 years. Univariate analysis showed a significant association between CDAD and age, FQs, non-FQ antibiotics, serum albumin level, duration of hospital stay and nasogastric feeding. Only duration of hospital stay and nasogastric feeding remained significant on multivariable analysis. CONCLUSION: The risk of CDAD due to FQs among TB patients is probably modest after controlling for sex, age, non-FQ antibiotics, serum albumin level, duration of hospital stay and nasogastric feeding.

Chondroitinase ABC enhances axonal regrowth through Schwann cell-seeded guidance channels after spinal cord injury.

Grafting of Schwann cell-seeded channels into hemisected adult rat thoracic spinal cords has been tested as a strategy to bridge the injured cord. Despite success in guiding axonal growth into the graft, regeneration across the distal graft-host interface into the host spinal cord was limited. We hypothesized that chondroitin sulfate (CS) glycoforms deposited at the gliotic front of the interface constitute a molecular barrier to axonal growth into the host cord. Because CS glycoforms deposited by purified astrocytes in vitro were removable by digestion with chondroitinase ABC, we attempted to achieve likewise by infusion of the enzyme to the host side of the interface. By 1 month post-treatment, significant numbers of regenerating axons crossed an interface that was subdued in macrophage/microglia reaction and decreased in CS-immunopositivity. The axons extended as far into the caudal cord as 5 mm, in contrast to nil in vehicle-infused controls. Fascicular organizations of axon-Schwann cell units within the regenerated tissue cable were better-preserved in enzyme-treated cords than in vehicle-infused controls. We conclude that CS glycoforms deposited during gliosis at the distal graft-host interface could be cleared by the in vivo action of chondroitinase ABC to improve prospects of axonal regeneration into the host spinal cord.

Outcomes of patients with multidrug-resistant pulmonary tuberculosis treated with ofloxacin/levofloxacin-containing regimens.

OBJECTIVE: To analyze outcomes of patients with multidrug-resistant tuberculosis (MDR-TB) treated with ofloxacin/levofloxacin-containing regimens. MATERIALS AND METHODS: From February 1990 through June 1997, 63 MDR-TB patients (with bacillary resistance to at least isoniazid and rifampin in vitro) were analyzed retrospectively. Twenty-two patients (34.9%) had had no previous antituberculosis chemotherapy. Each patient received either ofloxacin (53) or levofloxacin (10) even though 13 patients had bacilli resistant to ofloxacin in vitro. The other accompanying drugs mainly included aminoglycosides, cycloserine, ethionamide/prothionamide, and pyrazinamide. Sputum smear and culture examinations for acid-fast bacilli (AFB) were performed monthly for the initial 6 months and then at 2- to 3-month intervals until the end of treatment. Comparison was made between clinical successes and failures using univariate and multiple logistic regression analyses for the following variables: age, sex, presence of cavitation, extent of disease, sputum smear positivity, in vitro resistance to ofloxacin, in vitro resistance to streptomycin and/or ethambutol, treatment adherence, and the number of drugs per regimen. RESULTS: Fifty-one patients (81.0%) were cured, nine patients (14.3%) failed, and three patients (4.7%) died. For the entire group, the mean duration of treatment was 14.0 months, and the mean number of drugs was 4.7. Mean durations of chemotherapy in successful and failed patients were 14.5 and 14.2 months, respectively. Mean time for sputum smear and culture conversions were 1.7 and 2.1 months, respectively. Only cavitation, resistance to ofloxacin, and poor adherence were found to be variables independently associated with adverse outcomes (p < 0.05; odds ratios = 15.9, 13.5, 12.8, respectively). Negative sputum cultures after 2 and 3 months of therapy were 100% predictive of cure. Positive sputum cultures after 2 and 3 months were 52.3% and 84.6% predictive of failure, respectively. One patient (2.1%) relapsed after apparent cure. Twenty-five patients experienced adverse drug reactions, but only 12 of them needed drug modifications. CONCLUSION: Most MDR-TB patients can be treated effectively with ofloxacin/levofloxacin-containing regimens. Presence of cavitation, resistance to ofloxacin in vitro, and poor adherence to therapy portend treatment failure. Monitoring monthly sputum culture for AFB in the initial months of chemotherapy helps predict clinical outcomes.

Comparison of MB/BacT system and agar proportion method in drug susceptibility testing of Mycobacterium tuberculosis.

The drug susceptibilities of 105 isolates/strains of Mycobacterium tuberculosis (101 clinical isolates and four control strains from the American Type Culture Collection) were assessed by the MB/BacT system and conventional agar proportion method. The agreement rates between the two methods were 99.0% for streptomycin, 95.2% for isoniazid and 100% for rifampin. The mean times to detection for drug-resistant isolates were 4.7 days (range: 2.5-13.7 days) using the MB/BacT system and 14.8 days (range: 14-21 days) using the agar proportion method. For drug-susceptible isolates, the times to detection were 10.8 days (mean) and 21 days respectively. Thus, these data have demonstrated that the automated, non-radiometric MB/BacT system is an efficient, accurate and reliable method for assessing drug susceptibilities of M. tuberculosis compared with the conventional agar proportion method.

Smoking and tuberculosis in Hong Kong.

OBJECTIVE: To study the relationship between smoking and tuberculosis in Hong Kong. METHOD: Indirect sex and age adjustment was used to compare the prevalence of ever smokers between a sample of 851 patients from the 1996 tuberculosis notification registry and the general population. The clinical characteristics of smokers and non-smokers were compared by stratified univariate analysis and multiple logistic regression. RESULTS: Tuberculosis patients were more likely to have smoked than population controls. The respective odds ratios for ever smoking between tuberculosis patients and population controls were 2.44 and 2.08 for males and females aged 16-64 (Mantel-Haenszel weighted OR = 2.40, P < 0.001), and 2.09 and 2.83 for males and females aged > or = 65 (Mantel-Haenszel weighted odds ratio = 2.19, P < 0.001). Male sex, age > or = 65, working at onset of illness, regular alcohol use, drug abuse and absence of contact history were associated with ever smokers (all P < 0.05). Ever smokers were more likely to have cough (OR 1.69), dyspnoea (OR 1.84), upper zone involvement (OR 1.67), cavity (OR 1.76), miliary lung involvement (OR 2.77), positive sputum culture (OR 1.43), but less isolated extrathoracic involvement (OR 0.31), even after controlling for the confounding background variables (all P < 0.05). CONCLUSION: There was a consistent association between smoking and tuberculosis. More aggressive lung involvement was also found among ever smokers.

Future directions in the development of new antitubercular drugs. Where do we go from here?

The global resurgence of tuberculosis and rampant drug resistance have rekindled the need for and interest in the development of new antitubercular drugs. Delineation of the possible drug targets furnished by the various mycobacterial cell components might result in rational approaches to the development of such agents. In the future, molecular genetics might help both in the bioengineering and rapid screening of the activity of new compound. Collaboration is anticipated between the pharmaceutical industry and academic institutions in these areas.

Laparoscopic exploration of common bile duct in difficult choledocholithiasis.

BACKGROUND: This review investigated the role played by laparoscopic exploration of the common bile duct (LECBD) in the management of difficult choledocholithiasis. METHODS: This retrospective study reviewed a prospective database of LECBD for difficult choledocholithiasis during the period 1995 to 2003. RESULTS: Of the 97 LECBDs performed in the authors' center from 1995 to 2003, 25 were performed for difficult choledocholithiasis. Difficult choledocholithiasis was defined as failure of endoscopic stone retrieval for the following reasons: access and cannulation difficulty, the difficult nature of common bile duct (CBD) stones, and the presence of endoscopic retrograde cholangiopancreatography (ERCP)-related complications. There were seven unsuccessful cannulations because of previous gastrectomy (n = 5) and periampullary diverticulum (n = 2). Among the 18 patients with failed endoscopic extraction, there were 10 impacted stones, 2 incomplete stone clearances after multiple attempts, 2 type 2 Mirizzi syndromes, 1 proximal stent migration, 1 repeated post-ERCP pancreatitis, 1 situs inversus, and 1 stricture at the distal common bile duct. There were 14 male and 11 female patients with a mean age of 67.8 +/- 15 years. Initial presentations included cholangitis (n = 14, 56%), biliary colic (n = 3, 12%), jaundice/deranged liver function ( n = 5, 20%), cholecystitis (n = 2, 8%), and pancreatitis (n = 1, 4%). Regarding the approach for LECBD, there were 2 transcystic duct explorations and 23 choledochotomies. The mean operative time was 149.4 +/- 49.3 min, and there were three conversions (12%). The stone clearance rate was 100%, and no recurrence was detected during a mean follow-up period of 16.8 months. Five complications were encountered, which included bile leak (3 patients) and wound infection (2 patients). When the results were compared with the remaining 72 LECBDs for nondifficult stones during the same period, the complication rate, conversion rate, and rate of residual stones were similar despite a longer operation time (149.4 +/- 49.4 min vs 121.6 +/- 50.5 min). CONCLUSION: When ERCP is impossible or stone retrieval is incomplete, LECBD is the solution to difficult CBD stones.

Sudden death presenting as massive haemoptysis due to ruptured intrapulmonary aortic aneurysm.

We report a case of a saccular atherosclerotic aneurysm of the thoracic aorta which was incorporated almost entirely within the upper lobe of the right lung. The aneurysm ruptured into the lung causing massive haemoptysis and sudden death. We have been unable to find a similar case reported in the literature.

Is inhaled corticosteroid useful as adjunctive management in tuberculous pyrexia?

Systemic corticosteroid is currently the standard adjunctive therapy for tuberculous pyrexia. A preliminary prospective open study to examine the efficacy of inhaled budesonide at a dose of 2,400 micrograms daily in the management of this condition was performed. Out of nine non-HIV infected patients with tuberculous pyrexia studied, four patients succeeded to achieve defervescence at a mean of 3.25 days (range = 2 to 5 days), while the rest of the patients failed to do so within 7 days. None of the patients had unwanted side effects of systemic corticosteroid and patients' acceptance of such therapy was high. The potential usefulness of inhaled corticosteroid in some patients with tuberculous pyrexia might warrant further evaluation.

Low-dose methotrexate in the management of Chinese patients with steroid-dependent asthma.

Nine Chinese patients with severe asthma who were dependent on a systemic oral steroid for control were given oral methotrexate at a dose of 7.5 mg on alternate days for two weeks, followed by 15 mg once weekly. Only six patients were evaluable; they had received methotrexate for 6 to 24 months. All six patients could have reduction of daily oral prednisolone dosage by 5-15 mg (mean: 10.4 mg). Only four patients, however, had > or = 15% improvement of their best peak expiratory flow rates compared with baseline levels, though all six patients had symptomatic improvement. These beneficial effects were, however, transient and persisted only during methotrexate therapy. Four patients had liver enzyme changes and discontinuation of therapy was required in one patient. One patient also had infective spondylitis secondary to Salmonella bacteremia. Thus low-dose oral methotrexate may be useful in selected patients with severe steroid-dependent asthma with careful monitoring for response and drug toxicity.

Oral fluconazole in the treatment of pulmonary cryptococcosis in non-AIDS patients.

Four non-AIDS patients with pulmonary cryptococcus infection who could not tolerate amphotericin B treatment were given oral fluconazole at a dose of 600 mg once daily for 4-5 weeks followed by 400 mg once daily for 10-12 weeks resulting in cure. All patients did not have relapse of disease when followed-up for 8-24 months after cessation of treatment. The very good tolerance of oral fluconazole by these patients suggests that such effective monotherapy should be evaluated further in non-AIDS patients with pulmonary cryptococcosis.

Ciprofloxacin in the management of pulmonary tuberculosis in the face of hepatic dysfunction.

Twenty-five patients who had extensive pulmonary tuberculosis and hepatitis induced by antituberculosis drugs were treated with ciprofloxacin together with other relatively non-hepatotoxic drugs, either during the interim phase awaiting recovery of liver function in some, or as definitive therapy as required by the compromised hepatic status of others. Only 22 patients were assessable. All tolerated ciprofloxacin well during the phase of hepatic dysfunction. All patients improved with these ciprofloxacin-containing regimens, but the optimal dosage, specific efficacy and long-term safety of the drug in such cases require further evaluation.

Primary closure versus T-tube drainage after laparoscopic choledochotomy for common bile duct stones.

BACKGROUND/AIMS: To demonstrate the safety and feasibility of primary closure of the common bile duct (CBD) after laparoscopic choledochotomy in patients with CBD stones. Traditionally, the CBD is closed with T-tube drainage after choledochotomy and removal of CBD stones. However, the insertion of a T-tube is not without complication and the patients have to carry it for several weeks before removal. In the laparoscopic era, surgery is performed with minimally invasive techniques in order to reduce the trauma inflicted on patients, hasten their recovery and hence reduce the hospital stay. T-tube insertion seems to negate these benefits and we believe that primary closure can be as safe as closure with T-tube drainage. METHODOLOGY: This is a retrospective analysis of patients who underwent primary closure of the CBD after successful laparoscopic choledochotomy for ductal stones between January 2000 and December 2003. A concurrent control group of patients who underwent T-tube drainage was used for comparison. RESULTS: Of the 64 patients that underwent laparoscopic exploration of the CBD, 24 (37%) underwent transcystic duct approach and 40 (63%) underwent choledochotomy. There were three open conversions (5%). Stone clearance was achieved in all patients with successful laparoscopic choledochotomy (100%). Of the 38 successful laparoscopic choledochotomies, 12 had primary closure of the CBD and 26 had closure with T-tube drainage. There was no mortality in both groups. One patient in the primary closure group suffered from paralytic ileus and small subhepatic collection which was treated conservatively. The median operative time (90 vs. 120 minutes, p=0.002) and postoperative stay (5 vs. 8.5 days, p=0.003) were shorter in the primary closure group when compared with the T-tube group. CONCLUSIONS: Primary closure of the CBD is feasible and as safe as T-tube insertion after laparoscopic choledochotomy for stone disease.