Prostate cancer (PCa) is the most common non-cutaneous malignancy among men in western countries, and is the third most common cancer among men in Hong Kong.1 Increasing public awareness in the Chinese community, as well as the common use of prostate-specific antigen (PSA) tests by primary health physicians, have led to detection of PCa at an earlier stage, when it is amenable to either radical surgery or radiotherapy (RT).2 Because of recent advancements in operative management, such as robotic-assisted laparoscopic prostatectomy,3 many patients have found radical prostatectomy (RP) the preferred treatment option. Nevertheless, adjuvant radiotherapy (ART) to the prostatic fossa is indicated postoperatively in cases with positive surgical margin (SM), or residual disease from extracapsular extension (ECE). Alternatively, patients may receive salvage radiotherapy (SRT) when there is PSA failure, defined as any detectable and rising PSA level after RP.

Currently, ART is still being compared with SRT in three randomised controlled trials (RADICALS, RAVES, GETUG-AFU 17).4 5 6 While the results of these European and Australasian studies are still pending, the American Society for Radiation Oncology/American Urological Association guidelines recommend that physicians offer SRT to patients with PSA or local recurrence after RP in whom there is no evidence of distant metastasis (DM).7 Patients should be advised that SRT should be administered at the earliest sign of PSA recurrence. Approximately 60% of patients who are treated with SRT before the PSA level rises to >0.5 ng/mL will achieve an undetectable PSA level, providing long-term PSA control in nearly half of them.8

However, after SRT, some patients may still experience further clinical progression, including DM and cancer-related death. The effect of SRT on the long-term outcomes including metastasis-free survival (MFS) and overall survival—especially in Chinese patients—is not well understood. Herein we report the long-term survival data of patients at a single institution in Hong Kong who received SRT to the prostatic fossa using modern RT techniques.

Using the MOSAIQ system (version 2.62, IMPAC Medical Systems, Inc.; Sunnyvale [CA], US), we identified 91 Chinese patients treated with postoperative RT to the prostatic fossa at Tuen Mun Hospital, Hong Kong, between 2006 and 2017. The treatment records and clinical data of these patients were reviewed. Two patients who received ART with undetectable PSA were excluded. Patients who had received androgen deprivation therapy (ADT) prior to SRT were also excluded. These selection criteria yielded 84 evaluable individuals who received SRT to the prostatic fossa alone for PSA failure (defined as detection of PSA concentration at 0.2 ng/mL, with a second confirmatory level detected at 0.2 ng/mL) more than 3 months after RP.

A planning computed tomographic scan was performed for each patient with 3-mm slice thickness, and the clinical target volume was determined with reference to one of the published consensus guidelines.9 10 11 The usual boundaries of the clinical target volume are: inferiorly, 5 mm below the urethral anastomosis; anteriorly, the posterior aspect of the symphysis pubis or the posterior third of the bladder; laterally, the medial border of the obturator internus and levator ani muscles; posteriorly, the anterior mesorectal fascia; and superiorly, 5 mm above the surgical bed. The planning target volume was defined as clinical target volume with a margin of 4 to 5 mm posteriorly and 0.7 to 1 cm in all other directions. Organs at risk, including the rectum, bladder, and bilateral femoral heads were contoured. Conformal radiotherapy or inverse planning techniques with intensity-modulated radiotherapy (IMRT) using seven to nine static beams were used before October 2010. After that, volumetric modulated arc radiotherapy (VMAT) was employed using the Pinnacle treatment planning system (Philips Medical Systems, Fitchburg [WI], US) with treatment delivered through one to two dynamic cone arcs.

Clinical data included age at SRT, time from surgery to RT (≤24 months vs >24 months), SRT dose, pre-SRT PSA level, and post-SRT nadir PSA. Pathological data consisted of pathological T stages (T2a vs T2b vs T2c vs T3a or T3b), ECE, seminal vesicle invasion, SM, and pathological Gleason scores (≤7 or ≥8).

After SRT, patients were followed up with PSA level checks every 3 months in the first 2 years, every 6 months from year 3 to year 5, then annually. A complete response was defined as an undetectable nadir PSA (<0.1 ng/mL). Biochemical progression (PSA failure) was defined as a rise of PSA level by 0.2 ng/mL above the nadir with a second confirmation at least 1 week apart.12 Biochemical progression-free survival (bPFS) was defined as the date from SRT completion to the first date of biochemical progression. Patients who showed biochemical progression or symptoms suggestive of metastasis received imaging studies at the discretion of the oncologist. Metastasis-free survival was defined as the date from SRT completion to the date of occurrence of metastasis on imaging. Patients who showed biochemical progression with or without metastasis were counselled on the use of ADT; ADT-free survival was defined as the date of SRT completion to the first date of ADT administration.

The Kaplan-Meier method was used to estimate bPFS, MFS, and ADT-free survival. Log-rank tests and Cox regression analysis were used to test the association between groups and oncologic outcomes. Covariates consisted of continuous variables, including patient age at SRT, SRT dose, and pre-SRT PSA, and discrete variables including post-SRT nadir PSA (detectable vs undetectable), pathological T stages (T2a vs T2b vs T2c vs T3a vs T3b), pathological Gleason score (≤7 vs ≥8), SM (negative vs positive), ECE (negative vs positive), seminal vesicle invasion (negative vs positive), and time of SRT (≤24 months after RP or >24 months after RP). Only variables that were significantly associated with outcomes on univariate analyses were further tested for association in multivariate analyses.

Statistical analyses were performed using IBM SPSS Statistics for Windows, version 24.0 (IBM Corp, Armonk [NY], US), and numerical data were presented according to Cole.13

The median age of the 84 patients was 68 years (range, 52-79 years) when they received SRT. The patients’ median pre-SRT PSA level was 0.4 ng/mL (range, 0.2-7.4 ng/mL). Of the patients, 63 (75%) had positive SM in their prostatectomy specimens. Extracapsular extension was detected in 25 (29.8%) patients. Pelvic lymph nodes of 41 patients were sampled during RP and were all found to be negative for malignancy. These and other pathological characteristics are summarised in Table 1. The median time from surgery to start of SRT was 18.4 months (range, 3.8-121 months).

Before October 2010, one patient was treated with conformal RT and 10 patients were treated with IMRT. Subsequently the other 73 patients were treated with VMAT. The median dose given to the prostatic fossa was 70 Gy (range, 64-76 Gy), with 66 (79%) patients receiving a dose of ≥70 Gy. The mean dose delivered using VMAT (69.5 Gy) was slightly higher than that delivered using IMRT/conformal RT (68.1 Gy) [independent-samples t test, t=2.1; P=0.028].

Of 84 patients, 47 (56%) had undetectable PSA levels (complete response; <0.1 ng/mL) after SRT. After a median follow-up of 48 months (range, 2-120 months), 25 (30%) patients had biochemical progression with an estimated 5-year bPFS of 62.7% (95% confidence interval [CI], 50.1-75.3%) [Fig 1a]. Among the 25 patients who developed biochemical progression after SRT, seven were found to have DM and subsequently received ADT, and five started ADT in the absence of DM, two of whom later developed DM and had their disease became castration-resistant. Overall, 12 patients received ADT and nine (11%) patients developed DM. The 5-year ADT-free survival and MFS were 83.5% (95% CI, 73.7-93.3%) and 86.7% (95% CI, 77.7-95.7%), respectively (Fig 1b, c). Notably, only six patients died, all from causes other than PCa.

On univariate analysis, a post-SRT nadir PSA ≥0.1 ng/mL, positive ECE, and bPFS ≤12 months were significantly associated with a shorter MFS (all P<0.001; Fig 2). Similarly, a post-SRT nadir PSA ≥0.1 ng/mL (P<0.001), positive ECE (P<0.001), negative SM (P=0.045), pathological Gleason score ≥8 (P=0.002), and time from surgery to SRT ≤24 months (P=0.008) were significant predictors of a shorter bPFS (Fig 3). The pre-SRT PSA level, age, and SRT dose were not associated with either MFS or bPFS in this cohort on univariate analysis. On multivariate analysis using the Cox regression method, negative SM (hazard ratio [HR]=2.7; 95% confidence interval [CI], 1.1-6.6), positive ECE (HR=4.6; 95% CI, 1.8-11.7), post-SRT nadir PSA ≥0.1 ng/mL (HR=17.3; 95% CI, 5.3-57.0), and time from surgery to SRT ≤24 months (HR=7.4; 95% CI, 2.2-24.0) retained significant association with a shorter bPFS (Table 2). There was no variable significantly associated with MFS after multivariate analysis.

Most patients who develop biochemical recurrence after RP for localised PCa remain asymptomatic for many years.14 However, patients with increasing PSA level are at high risk of developing DM. Salvage radiotherapy is effective in terms of biochemical control when it is administered at low PSA level. Stephenson et al12 reported a 6-year progression-free probability of 32% after SRT. In their multi-institutional retrospective cohort of 1603 consecutive patients from 17 North American tertiary referral centres who received SRT after RP for PSA recurrence between 1987 and 2005, the median dose was only 64.8 Gy (interquartile range, 63-66 Gy) delivered using older techniques. The 5-year bPFS of 62.7% in the present study is similar or better than those reported in western countries.12 15 16 This might be due to better selection of patients (most patients started SRT when their PSA level was ≤0.5 ng/mL), or the higher dose of SRT to the prostatic fossa (median 70 Gy). In our cohort, all patients but one were treated using IMRT/VMAT. Intensity-modulated radiotherapy was introduced in the 1990s and it has since enabled radiation oncologists to deliver higher doses of radiation to treat patients with PCa—including patients with residual disease at the prostatic fossa—without causing excessive radiation damage to healthy tissue.17 18 19 Volumetric modulated arc radiotherapy has recently attracted much interest because it can dynamically deliver a radiation dose during rotation of the gantry; this is also superior to IMRT in terms of its plan qualities and efficiency in the treatment of PCa.20 21

Pisansky et al22 reported that SRT doses of ≥66.0 Gy were associated with reduced cumulative incidence of biochemical progression. A systemic review by King23 provides level 2a evidence for escalated SRT dose of at least 70 Gy. A 2% improvement in relapse-free survival can be achieved for each additional Gy from 60 Gy to 70 Gy.23 However, higher SRT dose was not shown to be associated with better bPFS/MFS in our 84 patients by univariate analysis, because most (79%) had been treated with an SRT dose of ≥70 Gy, and the follow-up time may still be too short to demonstrate any further dose-response relationship. We postulated that such high-dose SRT can be delivered safely with modern techniques using VMAT, therefore our current usual prescribed dose is 70 Gy to the prostatic fossa, unless limited by dose constraints of the organ at risk. We have previously shown the efficiency and low toxicities using VMAT for SRT to the prostatic fossa.24 Longer follow-up is necessary to ensure that late complications are within safety limits.

Despite the success of SRT in biochemical control, some patients may develop further biochemical progression. In our present study, patients whose surgical pathology revealed negative margin and positive ECE had a shorter bPFS (HRs of 2.7 and 4.6, respectively). Patients who start SRT within 2 years of RP may also have a shorter PSA doubling time, leading to earlier detection of recurrence. These patients have a greater than 7-fold higher risk of biochemical regression after SRT than those with later recurrence. Salvage radiotherapy to the prostatic fossa alone cannot eradicate cancer that has spread outside the surgical bed after RP. In fact, negative SM, positive ECE, and shorter PSA doubling time are three of the many adverse factors which predict a shorter bPFS after SRT, using the nomogram proposed by Stephenson et al.25 However, we cannot demonstrate the importance of pre-SRT PSA level in our patient cohort because more than 65% of the patients had started SRT when their PSA level was ≤0.5 ng/mL.

Overall, the role of SRT in improving MFS and overall survival is less certain, because the disease can be indolent and mortality due to causes other than PCa is more likely in older patients. Patients also have other complications related to disease progression, such as painful bone metastasis. Efforts have been made to identify surrogate endpoints that can predict further disease progression, metastasis, and even cancer-related death after SRT. In a single institution review, Johnson et al26 reported approximately 50% of men experience further biochemical progression after SRT. Those who have a short interval to biochemical progression of ≤18 months after SRT are most likely to experience DM, PCa-specific mortality, and overall mortality. Bartkowiak et al27 reported on the long-term outcomes of patients with a median follow-up of 7 years (maximum, 14 years) after SRT. They found that a post-SRT nadir PSA <0.1 ng/mL was associated with improved bPFS and overall survival. The results of our univariate analysis support the abovementioned findings27 (Fig 2a, b). On multivariate analysis, we found that undetectable nadir PSA (<0.1 ng/mL) is the most important factor for predicting longer bPFS (Table 2). In the present study, of the 47 patients who achieved biochemical complete response after SRT, none developed DM. In contrast, among the 25 patients who had biochemical progression, nine whose disease progressed within 1 year after SRT eventually developed DM. Although our result of a 5-year MFS of nearly 90% is encouraging, with the median follow-up of only 4 years, we can hypothesise only that better biochemical control is correlated with improvements in other clinical outcomes. For patients whose PSA level does not become undetectable and rapidly rises within 1 year after SRT (bPFS ≤12 months), close monitoring for DM may be needed.

The improvement in overall survival and MFS of adjuvant ADT with SRT has been demonstrated by Shipley et al28 in a phase III study. However, ADT is not routinely recommended to our patients because of the known metabolic and cardiovascular toxicities and the negative impact on patients’ quality of life. In addition, most of our patients have fewer adverse features than those reported by Shipley et al.28 For patients with biochemical regression alone after SRT, we suggest monitoring for any site of disease recurrence such that further SRT could still be feasible. Nonetheless, we applied positron emission tomography with 68 Ga-labelled prostate-specific membrane antigen (PET-PSMA) to identify the site of recurrence in four of our patients when their PSA levels increased to ≥2.2 ng/mL (Table 3). All four patients were found to have DM which was not amenable to further local treatment and ADT had become their only option. It remains unclear whether PET-PSMA or other imaging studies at lower PSA levels are sensitive or useful enough to alter the management decision.29 Further research to study the use of novel radiological examinations in this situation is needed.

This is the first report to demonstrate the therapeutic effects in terms of bPFS and MFS of SRT in Chinese patients in a Hong Kong centre. Salvage radiotherapy is an effective local treatment that can prevent DM and avoid the need for ADT in most patients who have PSA failure after RP in Chinese patients. Our results appear to be better than those of some studies in western countries, in which older radiotherapy techniques and lower radiation doses were used. The limitations of our study include the retrospective design with lack of evaluation of patients’ reported outcome, small sample size, and short duration of follow-up. A multi-institutional study is recommended to collect more local data and experiences.

Concept or design: EKC Lee, Y Tung.
Acquisition of data: EKC Lee, AW Chan.
Analysis or interpretation of data: EKC Lee.
Drafting of the article: EKC Lee, WH Mui, FCS Wong.
Critical revision for important intellectual content: EKC Lee, WH Mui, FCS Wong.

This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

All authors have no conflicts of interest to disclose. All authors had full access to the data, contributed to the study, approved the final version for publication, and take responsibility for its accuracy and integrity. An earlier version of this paper was presented as poster presentation at the 9th European Multidisciplinary Meeting on Urological Cancers, 16-19 November 2017, Barcelona, Spain.

The study was conducted with approval from the New Territories West Cluster Clinical and Research Ethics Committee.

1. Hospital Authority, HKSAR Government. Leading cancer sites in Hong Kong in 2014. Available from: http://www3.ha.org.hk/cancereg/pdf/top10/rank_2014.pdf. Accessed Jul 2017.

2. Poon DM, Chan SL, Leung CM, et al. Efficacy and toxicity of intensity-modulated radiation therapy for prostate cancer in Chinese patients. Hong Kong Med J 2013;19:407-15. Crossref

3. Ng AT, Tam PC. Current status of robot-assisted surgery. Hong Kong Med J 2014;20:241-50. Crossref

4. Parker C, Clarke N, Logue J, et al. RADICALS (Radiotherapy and Androgen Deprivation In Combination After Local Surgery). Clin Oncol (R Coll Radiol) 2007;19:167-71. Crossref

5. Richaud P, Sargos P, Henriques de Figueiredo B, et al. Postoperative radiotherapy of prostate cancer [in French]. Cancer Radiother 2010;14:500-3. Crossref

6. Trans Tasman Radiation Oncology Group. RAVES trial: radiotherapy—adjuvant versus early salvage. Available from: http://www.clinicaltrial.gov/ct2/show/NCT00860652. Accessed Jul 2017.

7. Valicenti RK, Thompson I Jr, Albertsen P, et al. Adjuvant and salvage radiation therapy after prostatectomy: American Society for Radiation Oncology/American Urological Association guidelines. Int J Radiat Oncol Biol Phys 2013;86:822-8. Crossref

8. Wiegel T, Lohm G, Bottke D, et al. Achieving an undetectable PSA after radiotherapy for biochemical progression after radical prostatectomy is an independent predictor of biochemical outcome—results of a retrospective study. Int J Radiat Oncol Biol Phys 2009;73:1009-16. Crossref

9. Michalski JM, Lawton C, El Naqa I, et al. Development of RTOG consensus guidelines for the definition of the clinical target volume for postoperative conformal radiation therapy for prostate cancer. Int J Radiat Oncol Biol Phys 2010;76:361-8. Crossref

10. Poortmans P, Bossi A, Vandeputte K, et al. Guidelines for target volume definition in post-operative radiotherapy for prostate cancer, on behalf of the EORTC Radiation Oncology Group. Radiother Oncol 2007;84:121-7. Crossref

11. Sidhom MA, Kneebone AB, Lehman M, et al. Post-prostatectomy radiation therapy: consensus guidelines of the Australian and New Zealand Radiation Oncology Genito-Urinary Group. Radiother Oncol 2008;88:10-9. Crossref

12. Stephenson AJ, Scardion PT, Kattan MW, et al. Predicting the outcome of salvage radiation therapy for recurrent prostate cancer after radical prostatectomy. J Clin Oncol 2007;25:2035-41. Crossref

13. Cole TJ. Too many digits: the presentation of numerical data. Arch Dis Child 2015;100:608-9. Crossref

14. Pound CR, Partin AW, Eisenberger MA, Chan DW, Pearson JD, Walsh PC. Natural history of progression after PSA elevation following radical prostatectomy. JAMA 1999;281:1591-7. Crossref

15. Geinitz H, Riegel MG, Thamm R, et al. Outcome after conformal salvage radiotherapy in patients with rising prostate-specific antigen levels after radical prostatectomy. Int J Radiat Biol Oncol Phys 2012;82:1930-7. Crossref

16. Fossati N, Karnes RJ, Boorjian SA, et al. Long-term impact of adjuvant versus early salvage radiation therapy in pT3N0 prostate cancer patients treated with radical prostatectomy: results from a multi-institutional series. Eur Urol 2017;71:886-93. Crossref

17. Goldin GH, Sheets NC, Meyer A, et al. Patterns of intensity modulated radiation therapy (IMRT) use for the definitive and postoperative treatments of prostate cancer: a SEER-medicare analysis. Int J Radiat Oncol Biol Phys 2011;81(2 Suppl):S408. Crossref

18. Nath SK, Sandhu AP, Rose BS, et al. Toxicity analysis of postoperative image-guided intensity-modulated radiotherapy for prostate cancer. Int J Radiat Oncol Biol Phys 2010;78:435-41. Crossref

19. Ost P, De Troyer B, Fonteyne V, Oosterlinck W, De Meerleer G. A matched control analysis of adjuvant and salvage high-dose postoperative intensity-modulated radiotherapy for prostate cancer. Int J Radiat Oncol Biol Phys 2011;80:1316-22. Crossref

20. Kopp RW, Duff M, Catalfamo F, Shah D, Rajecki M, Ahmad K. VMAT vs. 7-field-IMRT: assessing the dosimetric parameters of prostate cancer treatment with a 292-patient sample. Med Dosim 2011;36:365-72. Crossref

21. Palma D, Vollans E, James K, et al. Volumetric modulated arc therapy for delivery of prostate radiotherapy: reduction in treatment time and monitor unit requirements compared to intensity modulated radiotherapy. Int J Radiat Oncol Biol Phys 2008;72(1 Suppl):S312. Crossref

22. Pisansky TM, Agrawal S, Hamstra DA, et al. Salvage radiation therapy dose response for biochemical failure of prostate cancer after prostatectomy—A multi-institutional observational study. Int J Radiat Oncol Biol Phys 2016;96:1046-53. Crossref

23. King CR. The dose-response of salvage radiotherapy following radical prostatectomy: a systemic review and meta-analysis. Radiother Oncol 2016;121:199-203. Crossref

24. Lee EK, Yuen KK, Mui WH, et al. Salvage radiotherapy to the prostatic fossa using volumetric-modulated arc therapy: early results. Hong Kong J Radiol 2013;16:191-7. Crossref

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26. Johnson S, Jackson W, Li D, et al. The interval to biochemical failure is prognostic for metastatic, prostate cancer-specific mortality, and overall mortality after salvage radiation therapy for prostate cancer. Int J Radiat Oncol Biol Phys 2013;86:554-61. Crossref

27. Bartkowiak D, Bottke D, Thamm R, Siegmann A, Hinkelbein W, Wiegel T. The PSA-response to salvage radiotherapy after radical prostatectomy correlates with freedom from progression and overall survival. Radiother Oncol 2016;118:131-5. Crossref

28. Shipley WU, Seiferheld W, Lukka HR, et al. Radiation with or without antiandrogen therapy in recurrent prostate cancer. N Engl J Med 2017;376:417-28. Crossref

29. Perera M, Papa N, Christidis D, et al. Sensitivity, specificity, and predictors of positive 68Ga-prostate-specific membrane antigen positron emission tomography in advanced prostate cancer: a systemic review and meta-analysis. Eur Urol 2016;70:926-37. Crossref

Elderly patients have multiple co-morbidities and they are consequently prone to multiple medication use. Inappropriate medication use is common among hospitalised older adults. The number of drugs taken is one of the important determinants of risk for receiving an inappropriate medication.1 There is a high prevalence of unnecessary drug use in frail older people. In one hospital study, 44% of patients were prescribed at least one unnecessary drug, with the most common reason being lack of indication.2 The most commonly prescribed unnecessary drug classes were gastrointestinal, central nervous system, and therapeutic nutrients/minerals.2 Appropriate use of drugs is particularly important in the frail older people who are especially at risk of adverse drug reactions.3 It has been shown that implementation of a clinical pharmacist service has a positive effect on medication use and health care service utilisation among hospitalised patients.4 5 A local study in a geriatric hospital demonstrated the effectiveness of a drug rationalisation programme with involvement of a clinical pharmacist in reducing the incidence of polypharmacy and inappropriate medications.6 Interacting with the health care team on patient rounds, interviewing patients, reconciling medications, and providing patient discharge counselling and follow-up all resulted in improved outcomes.7 It is for this reason that patient safety strategies encourage the use of medication reconciliation and clinical pharmacists in health care systems to reduce adverse drug events.8 9 10

There is not much information about the effectiveness of a medical review programme among hospitalised elderly patients in Hong Kong. Two recent local reports that examined the effects of a clinical pharmacist–led medication review on hospital readmissions showed conflicting results and did not specifically address elderly patients.11 12 We therefore conducted a prospective controlled study to investigate the effectiveness of a comprehensive pharmacist intervention on medication use and hospital readmission among a group of geriatric in-patients in Hong Kong.

This prospective controlled study was conducted in the geriatric unit of a regional hospital in Hong Kong. The unit has 38 in-patient beds and admits older people aged 65 years or above who are transferred from an acute hospital after initial stabilisation of medical and/or geriatric problems. The unit admits more than 1000 patients per year and provides medical treatment, rehabilitation, and discharge planning services by a multidisciplinary team composed of a geriatrician, residents, nurses, physiotherapists, occupational therapists, and medical social workers. All patients admitted to the unit during December 2013 to September 2014 were included. Patients were excluded if they refused to participate, were terminally ill with a life expectancy of less than 3 months, or if they had already received pharmacist intervention in another hospital prior to this admission. Eligible subjects were assigned to an intervention or control group according to the admission day of the week. Those who were admitted on Monday through Thursday were assigned to the intervention group, and those admitted on Friday through Sunday to the control group. This arrangement was to ensure that pharmacist intervention could be initiated promptly within 48 hours of patient admission. Demographic data, functional status, co-morbidities, and number of drugs on admission were collected at admission.

The intervention was conducted by a pharmacist who was present in the unit from Monday to Saturday. The pharmacist provided pharmaceutical care from admission to discharge. Interventions performed by the pharmacist consisted of the following:

(1) Medication reconciliation on admission to identify unintended discrepancies between medications prescribed on admission and the usual medications prior to admission—sources to assist medication reconciliation included: electronic patient record; patient’s ward case notes; interview with patient and/or patient carer. The number and type of unidentified discrepancies were recorded.

(2) Medication review to check for medication appropriateness on admission and also at discharge—medication appropriateness was assessed by the Medication Appropriateness Index (MAI).13 There are 10 criteria to assess for appropriateness, namely indication, effectiveness, dosage, correct direction, practical direction, drug-drug interaction, drug-disease interaction, duplication, duration, and expense. For a drug item coded as ‘inappropriate’, relative weights for each criterion would apply. A sum of MAI scores could then be calculated to give a score ranging from 0 to 18. The higher the score, the more inappropriate the drug. Recommendations from the pharmacist after the reconciliation and medication review in the intervention group were then communicated to the in-charge doctor via a written note in the medical records. Recommendations were reinforced verbally if deemed appropriate by the pharmacist.

(3) Pharmacist counselling on admission and also at discharge was provided to improve patients’ drug knowledge to ensure proper use of drugs and compliance after discharge. A discharge counselling service was provided for all patients who returned home. The counselling included any changes to drug regimen; an explanation of each drug’s indication; any untoward effects that might occur and when to seek medical advice; and drug storage and administration instructions. To ensure patient understanding, written information such as patient information leaflets were given to patients and their carers to remind them of the correct drug regimen. If the patient was illiterate, a simple diagram was drawn on drug labels to demonstrate the time of day and number of tablets to be taken. If necessary, individualised pictorial schedules with drug images and administration instructions could be produced for patients and their carers. The assistance of a family member or external care services such as a community nurse was enlisted if the patient was found to have compliance issues.

The control group received routine clinical services. Records of the control group were retrospectively reviewed by the pharmacist after patient discharge to check for medication appropriateness on admission and also at discharge. The primary outcome measure was the appropriateness of prescription as measured by the MAI. Secondary outcomes included the acceptance rate by physicians, number of subjects with unintended discrepancies, patient satisfaction with the programme (for those home-living only), and unplanned hospitalisations 1 and 3 months after discharge.

A sample size of 98 patients per group was required to have 85% power to detect an effect size of 0.9 on the MAI. Our sample size was finally set at 210 patients to account for loss of participants due to dropout or death. This sample size was comparable with a study by Spinewine et al14 in which MAI was used as one of the tools to assess appropriateness of prescribing in an acute geriatric care unit and 203 patients were recruited. Our study included 212 patients and was expected to have adequate statistical power to detect differences between groups. Descriptive analyses were performed and included the number and types of unintended discrepancies, MAI score upon admission and at discharge, types of drug-related problems, number of interventions made by pharmacists, and number of recommendations accepted by doctors and implemented. Outcomes for the two groups before and after the programme were compared using the t test and Chi squared test. The Statistical Package for the Social Sciences (Windows version 17.0; SPSS Inc, Chicago [IL], United States) was used and a P value of <0.05 was regarded as statistically significant. The study was approved by the Cluster Research Ethics Committee of the Hospital Authority Hong Kong West Cluster. Written consent was obtained from the patient or their caregiver. The absence of pharmacist intervention in the control group was considered acceptable because a pharmacy service was not a part of routine care at the institution.

Figure 1 summarises the patient flow from recruitment to hospital discharge, the components of the medication review programme, and the planned outcome measures. A total of 212 patients were recruited. There were 108 subjects in the intervention group and 104 in the control group (Fig 2). There were no statistical differences in the baseline characteristics of patients (Table 1).

On admission, 51.9% (56/108) of the intervention group and 58.7% (61/104) of the control group had at least one drug classified as inappropriate (P=0.319). Overall, 1996 drug items were reviewed by a pharmacist on admission of which 1020 were from the intervention group and 976 from the control group. Among them, 9.3% and 11.1% of the drugs, respectively, were classified as inappropriate (P=0.282). In the intervention group, 93 recommendations were made by the pharmacist of which 60 (64.5%) were accepted by the physicians and implemented. The mean (standard deviation) MAI score per patient was 2.19 (3.03) in the intervention group and 2.28 (3.09) in the control group (P=0.841). The mean MAI score per drug was 0.23 (0.30) in the intervention group and 0.25 (0.31) in the control group (P=0.628) [Table 2].

After the program and at discharge, the proportion of subjects with inappropriate medications in the intervention group was significantly lower than that in the control group (28.0% vs 56.4%; P<0.001). Among the 1999 drug items reviewed by the pharmacist on patient discharge, 3.5% (37 of 1048) of the intervention group and 9.7% (92 of 951) of the control group were classified as inappropriate (P<0.001). The intervention group also had a significantly lower MAI score per patient (0.95 (2.02) vs 2.02 (2.53); P<0.001) and MAI score per drug (0.09 (0.17) vs 0.24 (0.30); P<0.001) implying a significant reduction in medication inappropriateness after the pharmacist medication review (Table 2).

Types of inappropriateness according to the MAI in the two groups are illustrated in Figure 3. In both the intervention and control groups, the common causes were indication, effectiveness, dosage, practical direction, duration, and expense. After the programme, there was a significant reduction in the number of these drug-related problems in the intervention group.

Among the 108 subjects in the intervention group, 19.4% had at least one unintended discrepancy in medications, involving a total of 43 drug factors. The majority (90.7%) of these factors were omission of drugs, and 4.6% were due to inappropriate dosages. Of all the drug factors involved, 69.8% involved prescribed drugs from hospitals, 25.6% were from a private clinic, and 4.6% were over-the-counter drugs. Overall, 41 recommendations were made, of which 32 (78.0%) were accepted by physicians and implemented.

Contact was made with 50 of the 90 non-institutionalised subjects 1 month after discharge to assess satisfaction with the programme. Of those contacted, 98.0% were satisfied with the programme and only one (2.0%) patient expressed a neutral opinion.

There were no statistical differences in the length of hospital stay, in-patient mortality, or mortality at 1 month or 3 months after discharge. There was also no statistical difference in the number of attendances at the accident and emergency department 1 month or 3 months after discharge or in the unplanned hospital readmission rate at 3 months after discharge. The unplanned hospital readmission rate 1 month after discharge, however, was significantly lower in the intervention group than that in the control group (13.2% vs 29.1%; P=0.005) [Table 3].

To the best of our knowledge, this is the first local prospective controlled study to investigate the effectiveness of a pharmacist-led medication review programme on medication appropriateness and clinical outcomes among geriatric in-patients in Hong Kong. This study has demonstrated superior outcomes that favour a pharmacist-led intervention. There was a substantial reduction in the use of inappropriate medications and all-cause unscheduled readmissions 1 month after hospital discharge. Nonetheless, analysis of length of hospital stay, number of all-cause emergency department visits, and mortality rate favoured neither the intervention nor the usual pharmacist care.

This study showed that one in five geriatric in-patients had an unintended medication discrepancy on admission. This figure was slightly higher than that found in a group of 3317 hospitalised medical patients (13%) over 1 year in an acute hospital in Hong Kong by Kwok et al.15 Subjects in our study were all elderly patients, whereas those in Kwok et al’s study were adults of all ages. Elderly subjects tend to have polypharmacy and thus are more vulnerable to unintended medication discrepancy when they move in and out of hospital or are transferred to another health care unit for further care. Unjustifiable medication discrepancies account for more than half of the medication errors that occur during transition of care and up to one third have the potential to cause harm.16 17 This does not bode well for our elderly patients with multiple co-morbidities.

Up to 30% of the discrepancies in our study involved medications that had been prescribed by private practitioners or purchased over-the-counter. Unlike medications prescribed from the Hospital Authority, these medications might be overlooked unless the admitting doctor specifically asks for a detailed drug history from the patient. Knowing the medication history and hence resuming these medications are important if new health problems are to be prevented. Pharmacist-led medication reconciliation is therefore a critical process that can enhance patient medication safety by compiling a complete and accurate medication list for patients in hospital.

This study revealed that more than half of the subjects (55.2%) received inappropriate medications. The majority of reasons for inappropriateness related to effectiveness, dosage, practical directions, and expense as reflected by the MAI. The inappropriate dosage and the questionable effectiveness might lead to not only failed pharmacological effects, but also potentially an untoward adverse drug reaction, especially in elderly individuals with pre-existing organ dysfunction.18 When a medication is not used according to the practical directions, it may lead to patient non-compliance. Optimising outcomes while reducing costs are the keys for medication management in today’s health care environment.19 Often there are several choices of drugs available to treat a disease or health condition and some are more expensive than others. The involvement of a ward-based pharmacist to review medication can enhance the use of appropriate medications in hospitalised patients and potentially reduce medication costs.

Following the medication review (60/93) and medication reconciliation (32/41), there were 92 recommendations that were accepted by the physician. The overall acceptance rate by physicians and the implementation of pharmacist recommendations in our study was 68.7% (92/134). This figure ranged from 39% to 100% in a previous systematic review of 32 studies.4 Our study did not specifically record recommendations accepted by physicians but not implemented. Hence the acceptance rate in our study may be underestimated. Nevertheless, the clinical pharmacist is encouraged to discuss the medication-related problems in person with the physician as well as contacting the patient in order to enhance the implementation rate.4

Pharmacy departments within the public hospital system in Hong Kong have strived to implement the aforementioned patient safety strategies in different specialties. Nonetheless, this is not a standard practice simply because of insufficient pharmacist staffing resources. In some hospitals, a pharmacist service is provided in wards, but this does not apply in all cases and is not standardised. Experience of a pharmacist-led medication reconciliation service from an acute teaching hospital in Hong Kong showed promising results over a 1-year trial run with high acceptance and recognition by other health care professionals.16 It is hoped that the clinical role of clinical pharmacists in patient medication management in hospitals can be encouraged. Another local study has demonstrated a positive impact on medication safety in patients with diabetes by pharmacists’ intervention in collaboration with a multidisciplinary team.20 The feasibility of incorporating a pharmacist as part of a multidisciplinary team of health care professionals must be explored in geriatric wards in Hong Kong. With increasing life expectancy, the expanding elderly population will equate to an increase in morbidity and mortality owing to drug-related problems where the need for trained health care professionals to perform medication reviews will be in even greater demand. To enhance safe drug use with limited resources, a systematic approach must be adopted to cover all aspects that affect drug therapy.

In terms of the impact on health care services utilisation, a recent systematic review and meta-analysis of the effectiveness of a pharmacist-led medication reconciliation programme revealed a substantial reduction in the rate of all-cause readmissions (19%), all-cause emergency department visits (28%), and adverse drug event–related hospital visits (67%).21 Our study revealed a significant reduction in unplanned hospital admissions (all-cause admission) at 1 month but not at 3 months. This implication might be due to an inadequate sample size to show the difference at 3 months. Alternatively, it might also imply that pharmacist intervention needs to be continued after patient discharge in order to have a sustained effect. This is supported by a study by Schnipper et al22 in which pharmacist intervention after patient discharge was associated with a lower rate of preventable adverse drug events 30 days after hospital discharge.

During the pharmacist review, cost-effectiveness of drug use was assessed through MAI. Alternative options such as less-expensive formulations or drugs but of the same quality would be recommended to the doctor in-charge. This was a means of encouraging cost-effective use of drugs in a hospital. Furthermore, the reduction in unscheduled hospital readmissions in the intervention group implies a potential saving in hospital costs. Although a detailed analysis was not performed in this study, a rough estimation is that nearly HK$2 million may be saved annually as a result of lower drug costs and reduced hospital admissions, even after considering the cost of employing a pharmacist. The estimation was based on the following calculations. The estimated drug saving as a result of a switch to a more cost-effective alternative was HK$7500 among the 108 patients in the intervention group. This can be projected to a saving of about HK$69 500 in a unit that admits 1000 patients annually. In the current study, there were 16 fewer readmissions in the intervention group compared with the control group. Assuming a daily cost of an acute hospital bed is HK$4680 and the mean length of hospital stay is 3 days, this equates to a potential saving of about HK$2 080 000 per year in a unit that admits 1000 patients annually. If it is assumed that a pharmacist spends 30 minutes for each patient at an hourly salary of HK$433, the projected cost of an additional pharmacist to run the intervention would be HK$216 500 per year. The net annual saving of this programme to serve 1000 patients in this unit would thus still be close to HK$2 million.

This study had several limitations. First, a substantial proportion (35%) of all the admitted patients were not screened by a pharmacist on admission. This was due to a temporary pause in subject recruitment when patients were admitted on public holidays, when the pharmacist was on holiday or when she had to relieve another pharmacist in the hospital. Moreover, a substantial proportion (44%) of eligible subjects were not included owing to no consent or refusal. These factors might have resulted in selection or self-selection bias. Second, subject recruitment was not randomised, but done according to the day of admission. This might be a source of bias. Nevertheless, this would have minimal influence on the outcomes, as the baseline characteristics of the intervention and control groups were comparable. Third, the pharmacist who carried out the review and data extraction was not blinded to the study hypothesis and the group status of the subjects. This could potentially lead to information bias, although this might be partially offset by the fact that the majority of the information or data on the outcome measures were taken with reference to a well-established and validated tool. Fourth, this study was performed in a single unit, so generalisation to other settings is not possible. Fifth, MAI is an implicit tool that is subjective. A single pharmacist as the rater might limit the reliability of the assessment results. Nevertheless, the more explicit tools of STOPP/START criteria23 had also been referred to in addition to the MAI during the review process. Sixth, this study only addressed appropriateness of drug use, whereas underuse of drugs was not investigated. Finally, this study could not conclude a causal relationship between the reduction in inappropriate medications and the reduction in unscheduled hospital readmissions because there were several components in the intervention that included a medication review, medication reconciliation, and discharge counselling. It is difficult to be certain which of these components alone or in combination gave rise to the positive outcome of this study.

On the other hand, there were several strengths in this study. This was the first prospective controlled study of the effect of a pharmacist-led medication review programme on medication use and health services utilisation involving over 200 Chinese elderly patients in Hong Kong. Second, a well-validated tool was used to assess medication appropriateness. The use of the MAI tool focused on the patient and the entire medication regimen. Third, there was a comprehensive review of outcomes including quality of prescribing, health services utilisation, mortality, length of hospital stay, and patient satisfaction.

This study supported the role of a hospital-based clinical pharmacist to enhance appropriate medication use among elderly Chinese in-patients. A systematic medication review programme in a geriatric unit resulted in a reduced number of drug omissions and fewer inappropriate medications. The service provided by the clinical pharmacist and supported by geriatricians was welcomed by patients and their carers. Together with the potential to reduce hospital readmissions and their associated cost, it is hoped that an in-hospital pharmacist-led medication review programme can be recognised as one of the important strategies to enhance the safety and quality of prescription among elderly patients in hospitals. It is strongly recommended that these programmes be standardised and implemented in all medical and geriatric wards in Hong Kong. Future studies should recruit a larger sample size in a randomised controlled design in other geriatric hospital settings to reiterate our findings. Furthermore, these studies might consider including adverse drug event–related hospital visits as one of the outcome measures.

All authors have disclosed no conflicts of interest.

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9. Medication reconciliation. Patient Safety Network. Agency for Healthcare Research and Quality. US Department of Health & Human Services. Available from: http://psnet.ahrq.gov/primer.aspx?primerID=1. Accessed 11 Jun 2017.

10. Gurwitz J, Monane M, Monane S, Avorn J. Polypharmacy. In: Morris JN, Lipsitz LA, Murphy K, Bellville-Taylor P, editors. Quality care in the nursing home. St. Louis, MO: Mosby-Year Book; 1997: 13-25.

11. Wong CY, Lee TO, Lam MP. Pharmacist discharge intervention programme to reduce unplanned hospital use in patients with polypharmacy. Hong Kong Pharm J 2017;24(Suppl 1):S18.

12. Chan HH. To reduce avoidable readmission of patients who are categorized as high risk by 30-day hospital readmission model at medical ward of United Christian Hospital through medication reconciliation and discharge counseling. Hong Kong Pharm J 2017;24(Suppl 1):S21.

13. Hanlon JT, Schmader KE, Samsa GP, et al. A method for assessing drug therapy appropriateness. J Clin Epidemiol 1992;45:1045-51. Crossref

14. Spinewine A, Swine C, Dhillon S, et al. Effect of a collaborative approach on the quality of prescribing for geriatric inpatients: a randomized, controlled trial. J Am Geriatr Soc 2007;55:658-65. Crossref

15. Kwok CC, Mak WM, Chui CM. Implementational experience of medical reconciliation in Queen Mary Hospital. Hong Kong Pharm J 2009;16:50-2.

16. Rozich JD, Howard RJ, Justeson JM, Macken PD, Lindsay ME, Resar RK. Standardization as a mechanism to improve safety in health care. Jt Comm J Qual Saf 2004;30:5-14. Crossref

17. Cornish PL, Knowles SR, Marchesano R, et al. Unintended medication discrepancies at the time of hospital admission. Arch Intern Med 2005;165:424-9. Crossref

18. Cameron KA. Caregivers’ guide to medications and aging. National Center on Caregiving, Family Caregiver Alliance 2004. Available from: https://www.caregiver.org/caregiver%CA%BCs-guide-medications-and-aging. Accessed 11 Jun 2017.

19. Splawski J, Minger H. Value of the pharmacist in the medication reconciliation process. P T 2016;41:176-8.

20. Chung AY, Anand S, Wong IC, et al. Improving medication safety and diabetes management in Hong Kong: a multidisciplinary approach. Hong Kong Med J 2017;23:158-67. Crossref

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Periprosthetic joint infection (PJI) is an uncommon but serious complication after total knee arthroplasty (TKA). Treatment is often challenging and has a major impact on the patient. Multiple operations are often required and patients may suffer from a long period of disability. Moreover, PJI incurs considerable health care costs.1 2 3 Therefore, multiple strategies including antibiotic prophylaxis, body exhaust systems, and laminar airflow systems have been developed to reduce the incidence of PJI. Studies have also identified modifiable risk factors for PJI after elective total joint replacement,4 5 6 7 8 9 10 11 12 13 14 with the aim of further reducing the incidence of PJI. However, local data on the risk factors and bacteriological features associated with PJI are still lacking.

This study had several aims. First, it aimed to provide the most up-to-date local data on incidence of and risk factors for PJI, including age, sex, presence of diabetes, presence of rheumatoid arthritis, and one-stage bilateral TKA. Second, this study aimed to provide an update on the bacteriology of PJI after elective primary TKA and to examine the association between potential risk factors and bacteriology. Third, we attempted to determine which risk factors, including bacteriology, were more likely to be associated with early-onset infection after elective primary TKA.

It is hoped that risk factors can be optimised or modified to prevent infection after TKA. Furthermore, an improved understanding of local bacteriological patterns and their relationship with various risk factors can help guide antimicrobial therapy.

We reviewed 2543 elective primary TKAs performed at the Queen Mary Hospital, Hong Kong, from 1993 to 2013. Data were collected by an infection control nurse of the Department of Microbiology who was blinded to the study objectives. The cohort data were collected from the Hong Kong Hospital Authority’s Clinical Data Analysis and Reporting System, the Infection Control Team, and the hospital’s joint replacement division registry. The keywords used in the data search were ‘periprosthetic joint infection’, ‘total knee arthroplasty’, and ‘surgical site infection’. Revision arthroplasties and knee arthroplasties for malignant conditions were excluded from the study. In patients with a history of native joint infection, elective primary TKA was performed only after eradication of the infection. Patients with active bacteraemia were also precluded from elective primary TKA until they were infection-free. There were no cases of severe immunosuppression. In relation to infection control, the majority of perioperative protocols for primary TKA were the same throughout the study period. Preoperatively, intravenous antibiotic prophylaxis (1 g of cefazolin) was given within 1 h before skin incision. In patients with penicillin allergy, other antibiotics were prescribed as appropriate. Intra-operatively, laminar airflow and body exhaust systems were used. There was no routine use of antibiotic-loaded cement or postoperative antibiotics. Postoperative wound management was the same throughout the study period.

Cohort characteristics, occurrence of PJI, and bacteriological data were retrieved. Bacterial type was defined as infection with skin flora or non-skin flora. Skin flora included methicillin-susceptible Staphylococcus aureus (MSSA), methicillin-resistant S aureus (MRSA), methicillin-susceptible coagulase-negative staphylococci (MSCNS), and methicillin-resistant coagulase-negative staphylococci (MRCNS). Other organisms were considered non-skin flora.

The following potential risk factors for PJI were analysed: age, sex, presence of diabetes, presence of rheumatoid arthritis, and one-stage bilateral TKA. They were examined by univariable analyses and then multivariable logistic regression to identify potential predictors of PJI, while controlling for confounders. We also studied the association of those potential risk factors with bacteriology and with the timing of infection onset; culture-negative PJI was excluded from these analyses. According to a working party convened by the Musculoskeletal Infection Society in 2014,15 PJI that occurs within 90 days of the index operation is considered early-onset infection, whereas PJI that occurs later is considered late-onset infection.

Both univariable and multivariable logistic regression in this study used the simultaneous entry method, with covariates of age (as a continuous variable) and sex, diabetes, rheumatoid arthritis, and one-stage bilateral TKA (as dichotomous variables). Outcomes are presented as odds ratios (ORs) with 95% confidence intervals (CIs). The regression model and data fitting were assessed using the Hosmer–Lemeshow goodness-of-fit test, and diabetes and one-stage bilateral TKA were excluded from the final model because of poor goodness-of-fit. For associations between potential risk factors and bacteriology and between potential risk factors and early onset of infection, only univariable analyses were used owing to small numbers of events. Categorical variables were compared with the chi-square test, whereas age was compared with the independent t test (two-tailed). Significance was assumed if P<0.05. All statistical analyses were conducted using SPSS version 22.0 (IBM Corporation, Armonk [NY], United States). The study was conducted in accordance with the principles outlined in the Declaration of Helsinki.

The incidence of PJI in our series was 1.34% (n=34). The incidence of early-onset infection was 0.39% (n=10) and that of late-onset infection was 0.94% (n=24). Among the cases PJI, 29.4% were early-onset infection. Early-onset infection occurred within a median of 17 days after arthroplasty (interquartile range, 9-32 days). Late-onset infection occurred within a median of 1 year and 8 months after arthroplasty (interquartile range, 7 months to 2 years and 11 months). Fifty-nine percent of infections occurred in the first year of surgery, whereas 74% occurred in the first 2 years.

The mean (standard deviation) age was 69 (9) years, with a range from 21 to 91 years; age followed a normal distribution. Overall, PJI developed in 10 males (1.9%) and 24 females (1.2%). In the one-stage bilateral TKA group, PJI occurred in 13 knees (1.2%). For the single-side TKA group, 21 knees (1.4%) developed PJI. Nine patients with diabetes (1.9%) and 25 patients without diabetes (1.2%) developed PJI. The highest rate of PJI, at 3.1%, was found in patients with rheumatoid arthritis, compared with 1.2% in patients without rheumatoid arthritis. The descriptive data are summarised in Table 1.

The most frequent causative organism was MSSA (26.5%, n=9), followed by MRSA (17.6%, n=6), Streptococcus spp (8.8%, n=3), MSCNS (5.9%, n=2), Escherichia coli (5.9%, n=2), Salmonella (5.9%, n=2), MRCNS (2.9%, n=1) and Mycobacterium tuberculosis (2.9%, n=1), The three cases of streptococcal infection comprised two Streptococcus dysgalactiae infections and one Streptococcus agalactiae infection. Culture-negative PJI comprised 23.5% of cases (n=8). Methicillin-resistant strains constituted 39% of all staphylococcal organisms. There was no significant association between the potential risk factors and skin flora infection (Table 2).

Rheumatoid arthritis was a significant risk factor of PJI in the univariable analysis, with an OR of 2.67 (95% CI, 1.15-6.20; P=0.02), as well as in the multivariable analysis, with an OR of 3.12 (CI, 1.29-7.56; P=0.01) [Table 3]. Being male (OR=1.9; P=0.11 in the multivariable analysis) and having diabetes (OR=1.54; P=0.27 in the univariable analysis) were not significantly associated with PJI.

Age (P=0.655), sex (P=0.961), diabetes (P=0.462), and rheumatoid arthritis (P=0.315) were not associated with early-onset infection (Table 4). Infection caused by skin flora was associated with early-onset infection (P=0.099), but the association was not statistically significant.

In this study, the incidence of PJI after primary TKA was 1.34% and the incidence of early-onset infection was 0.39%. The majority of PJIs (70%) were late-onset infections. The reported incidence of PJI after primary TKA ranges from 1.1% to 2.18%.16 17 18 Pulido et al16 reported the incidence of PJI after TKA to be 1.1%, of which 27% were diagnosed during the first 30 days after arthroplasty, and a majority of 65% were diagnosed in the first year after surgery. In our study, the average time to diagnosis was 431 days after the index surgery (range, 11-1699 days).

Rheumatoid arthritis was a significant risk factor for PJI after primary TKA. This finding is in keeping with the current literature.6 8 11 Although various authors have found male sex to be a risk factor for PJI,4 19 20 the association was not significant in this study. The OR of 1.9 may be of clinical importance but not significant as a result of the small number of PJIs and inadequate statistical power. The correlation between age and PJI has been a matter of controversy, with some reports mentioning young age as a risk factor for PJI4 21 and some otherwise.22 In our study, age was not associated with PJI occurrence. For one-stage bilateral TKA, age has been a controversial risk factor for PJI. Some studies16 23 have suggested that one-stage bilateral TKA is associated with an increased risk of superficial and deep infection. Hussain et al24 nonetheless reported a similar infection rate between one- and two-stage bilateral TKA. Our study did not find an association between one-stage bilateral TKA and PJI occurrence.

The local bacteriological pattern for PJI was comparable to that reported in the literature.4 16 In our study, skin flora and gram-positive bacteria were the most commonly isolated organisms, followed by gram-negative bacteria such as Escherichia coli and Salmonella. Coagulase-negative staphylococci were the most common causative organism in one study.4 In contrast, in our series, S aureus was the most common causative organism, particularly methicillin-sensitive strains. Methicillin-resistant strains were less common in our series, constituting 39% of all staphylococcal organisms.

Other authors have reported that male sex is a risk factor for PJI, which may be related to a sex difference in immune response to pathogenic bacteria. Studies6 have shown that males (compared with females) have a significantly higher likelihood of being a persistent S aureus carrier. However, our study did not support male sex as a risk factor for infection with skin flora. With regard to onset of infection, PJI caused by skin flora was positively associated with early-onset infection, although the association did not reach statistical significance (P=0.099). Direct inoculation and spread from contiguous foci of infection are more common in early-onset infection caused by wound complications and local soft-tissue conditions. In contrast, distant foci of infection, such as in bacteraemia, play a more important role in late-onset infection. Therefore, in early-onset periprosthetic joint infection with negative cultures, an empirical antibiotic regimen may provide adequate coverage against skin flora organisms.

Fan et al20 reported 479 TKAs and rates of 1.9% for superficial wound infection, 0.2% for early deep infection (n=1), and 0.6% for late deep infection (n=2). Methicillin-sensitive S aureus and coagulase-negative staphylococci were causative organisms. Lee et al25 reviewed 1133 primary TKAs and found a 0.71% incidence of PJI. The most common causative organisms in descending order were methicillin-sensitive S aureus, coagulase-negative staphylococci, methicillin-resistant S aureus, and Pseudomonas aeruginosa. This finding is in keeping with our data. Among risk factors identified by Lee et al25 were young age, diabetes, anaemia, thyroid disease, heart disease, lung disease, and long operating time. However, the researchers identified limitations of having only a small number of patients with infection (n=8) and insufficient power for analysis. In addition, multivariable analysis should have been performed to account for the effect of confounders among the multiple risk factors. They also reported the limitation that the mean follow-up duration was only 2 years. A short follow-up period may underestimate the occurrence of late-onset infection.

Our study has several limitations. The number of PJI-positive cases was small and thus subgroup analysis was limited. This study included subjects treated at a single centre in Hong Kong; multicentre studies may improve the representativeness of local data. In addition, perioperative management for elective TKA has evolved over the past 20 years, including the introduction of an MRSA-screening programme in 2011. In the screening programme, a nasal swab is taken from all elective joint-replacement patients. Patients with a positive result are prescribed 5 days of decolonisation therapy including a daily chlorhexidine bath. Furthermore, intravenous vancomycin is now administered for prophylaxis instead of cefazolin.26

There are many potential risk factors for PJI documented in the literature. Nonetheless, only a limited number were included in this study, most of which are not be modifiable. Thus, it may not provide the necessary guidance for preoperative optimisation. Furthermore, the exclusion of some potential risk factors may have led to inadequate control for potential confounding factors. Inclusion of more risk factors with better characterisation is needed to provide a more comprehensive understanding and to better account for the confounding effect of other variables.

The incidence of PJI after elective primary TKA in our institution over two decades from 1993 to 2013 was 1.34%. Rheumatoid arthritis was a significant risk factor for PJI in this series. In the early-onset infection group, PJI was caused by skin flora, but this was not statistically significant. It is hoped that this study has updated the local data for PJI after primary TKA and serves as a model for future related studies.

We thank colleagues from the Department of Orthopaedics and Traumatology and the Infection Control Team at the Queen Mary Hospital for their assistance in data collection, and those who advised on this project to make its publication possible.

The authors have no conflicts of interest to disclose.

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25. Lee QJ, Mak WP, Wong YC. Risk factors for periprosthetic joint infection in total knee arthroplasty. J Orthop Surg (Hong Kong) 2015;23:282-6. Crossref

26. Cheng VC, Tai JW, Wong ZS, et al. Transmission of methicillin-resistant Staphylococcus aureus in the long term care facilities in Hong Kong. BMC Infect Dis 2013;13:205. Crossref

There is no doubt that smoking is a serious hazard to health.1 2 3 One in two smokers will be killed by smoking; if one can help two smokers to quit, at least one life will be saved.4 Individual counselling by trained therapists can assist smokers to quit.5 6 7 The counselling usually involves review of the participant’s smoking history and motivation to quit, provision of problem-solving strategies to deal with high-risk situations, and encouragement. Smokers who receive individual counselling are 39% more likely to cease smoking in the long term than smokers who receive minimal behavioural intervention.5 Another method to increase the smoking cessation rate is nicotine replacement therapy (NRT). Such therapy (eg, gum, transdermal patch, and lozenges) is cost-effective in smoking cessation and increases the rate of quitting by 50% to 70%.8 9 10 11 Combining counselling and pharmacotherapy has been shown to further increase smoking cessation success rates by more than 80% when compared with minimal intervention or usual care.12 If a smoker quits smoking in the absence of external assistance, there is only a 3% to 5% chance of sustained abstinence at 6 to 12 months.13

In Hong Kong, the Smoking Counselling and Cessation Programme (SCCP) consists of individual counselling and provision of NRT and is available from the Hospital Authority; similar services are also provided by the Department of Health and the Tung Wah Group of Hospitals.14 The Hospital Authority operates 58 smoking cessation and counselling centres. Despite this available support, only about 19% of current smokers in Hong Kong have tried a smoking cessation service.15 In contrast, the prevalence of assisted quit attempts was 59.4% in Australia in 2008-2009 and 53.6% in the United Kingdom in 2010.16

The SCCP in Hong Kong is offered as part of chronic care, and general out-patient clinics (GOPCs) provide a good opportunity for health care professionals to refer smokers to an SCCP. Frontline GOPC health care professionals in Hong Kong may encounter high refusal rates of SCCP service when smokers know they must pay a service charge. Currently, smoking cessation and counselling centres SCCC charge HK$50 [~US$6.40] (HK$45 [~US$5.80] at the time of this study) for an initial face-to-face consultation, unless the client is exempt (eg, those receiving the Comprehensive Social Security Allowance or civil servants). There is no extra charge for NRT.

A review article in the Cochrane Library by Reda et al17 proposed that if all costs to smokers are covered, the proportion of smokers who attempt to quit, use smoking cessation treatments, and succeed in quitting will significantly increase compared with provision of no financial support. Reda et al17 also suggested that even though the absolute differences in quitting were small when an intervention group was compared with a control group (total events: 134 of 1409 vs 75 of 1351, respectively), the costs per person successfully quitting were low or moderate (US$119 to US$6450). However, all the studies included in that review were conducted in western countries, where the health care financing systems may differ from that of Hong Kong. In this study, we aimed to determine whether the booking and attendance rates at a smoking cessation service (SCCP) in a primary care setting could be increased if the patient received a financial incentive, as payment-in-kind, to offset the service fee.

This was a multicentre non-randomised cluster-controlled trial involving six GOPCs of the Hong Kong Hospital Authority’s Kowloon West Cluster and conducted from November 2015 to April 2016. The study protocol was approved by the Hospital Authority Kowloon West Cluster Research Ethics Committee (Ref No. KW/EX-15-169(91-08)). Non-random cluster sampling was used to choose participating clinics and assign them to study group, in order to avoid contamination of participants between the intervention and control groups. Three clinics (Ha Kwai Chung GOPC, West Kowloon GOPC, and Tsing Yi Cheung Hong GOPC) were assigned to the intervention group and three (Cheung Sha Wan GOPC, Li Po Chun GOPC, and South Kwai Chung GOPC) to the control group. A standard regular SCCP was available at all six clinics. The SCCP counsellors were trained nurses or pharmacists and all underwent the same smoking cessation counselling training provided by the Hospital Authority Head Office. The GOPC staff and SCCP counsellors were not involved in clinic selection or assignment.

The study centres were six of the 73 government-funded primary care GOPCs, and the majority of their patients were from a lower socio-economic class or older patients with chronic illnesses. The patient profiles from the six GOPCs shared a similar socio-demographic background and disease profile. There was no pre-study SCCP booking rate available, but the total number of smokers recruited from the three control clinics into the SCCP during the study period was similar to the number of SCCP referrals made by the three clinics during an equivalent period in the previous year (November 2014 to April 2015). The attendance rate for booked SCCP appointments was logged by the clinic computer system and was 50% to 60% among all six clinics.

Convenience sampling was used to recruit current smokers at the time of recruitment,15 who were identified during a doctor’s consultation or nurse’s assessment during the daytime. Information about this study and possible recruitment of patients for SCCP referral was given to doctors and nurses before the start of the study. After valid consent had been obtained, participants were invited to complete a questionnaire to provide background information, smoking status, and decision to join an SCCP. Assistance was given with the questionnaire if required. The questionnaires distributed to the control group (online supplementary Appendix 1) and the intervention group (online supplementary Appendix 2) stated the usual SCCP service charge of HK$45. The intervention group’s questionnaire additionally stated that a HK$50 supermarket coupon would be given to SCCP attendees. Those who agreed to participate in the SCCP were directed to make an appointment via the registration counter.

The SCCP counsellors in the intervention group were briefed by the authors about the process of issuing a supermarket coupon as payment in-kind to SCCP attendees. The SCCP session was carried out as usual, regardless of study group. In clinics in the intervention group, the supermarket coupon was given to SCCP participants after payment of the service charge.

Current smokers who were aged 18 years or older were eligible for the study. Participants were excluded if (1) the SCCP service charge was waived—for example, if they were a Comprehensive Social Security Allowance recipient or a civil servant; (2) they were as mentally incapacitated and unable to give consent; or (3) they were pregnant, as there was concern that NRT may increase the risk of congenital respiratory anomalies.18

A structured questionnaire in traditional Chinese script (online supplementary Appendices 1 and 2) was used to collect the following information:

(1) Age, sex, mean personal monthly income, and whether the participant thought the clinic was a convenient place to go;

(2) Smoking history: age when starting smoking, number of years of smoking, the mean number of cigarettes consumed per day (CPD), and time to the first cigarette of the day (TTFC) after waking. The nicotine dependence level was measured by CPD and TTFC, which have been shown to be independent predictors of quitting outcome.19 A categorical scoring method has been deemed adequate for many purposes19 and was adopted in this study (CPD categories of 0-10, 11-20, 21-30, and ≥31; TTFC categories of ≤5, 6-30, 31-60, and ≥61 minutes);

(3) Rating (range, 0-10) of perceived importance of, readiness for, and confidence in smoking cessation, which have been reported to be associated with smoking behavioural change20;

(4) If the smoker agrees to join the SCCP.

The questionnaire comprised 14 questions. The relevance and content validity of the questionnaire were reviewed by senior doctors. It was also pilot-tested in 10 smokers for face validity.

The rates of agreement between questionnaire response rate for intention to book an SCCP appointment, actual SCCP booking rate via the registration counter, and SCCP attendance rate were compared between the intervention and control groups. Defaulters or participants who rescheduled their SCCP sessions outside the study period were treated as non-attendees. Smokers who joined the SCCP were followed up by telephone by smoking-cessation counsellors on the seventh day after the first consultation to enquire whether they had quit smoking and were not smoking on the day of the call. This is a standard outcome measure of the SCCP used by the Hospital Authority.

The sample size was based on the annual quit rate of smokers in 2014 (of 9.6%) for all GOPCs under the Hospital Authority, according to an internal report. In a Cochrane review of health care financing systems to increase the uptake of tobacco-dependence treatment, full financial interventions (ie, covering all costs) directed at smokers could increase abstinence rate at 6 months or longer by 2.45 times that of smokers with no financial intervention (risk ratio=2.45, 95% confidence interval [CI]=1.17-5.12, I²=59%, 4 studies).17 In a study by Kaper et al,21 the adjusted odds ratio for abstinence after reimbursement was 2 to 4 times that after no reimbursement. It was thus estimated that offering reimbursement to attend an SCCP would triple the programme attendance rate. Using the formula established by Casagrande et al,22 65 participants were required in each group in order to obtain an alpha of 0.05 and 80% power. Assuming a 20% attrition rate, 80 participants were required in each group.

Data analysis was performed with SPSS (Windows version 20.0; IBM Corp, Armonk [NY], United States). The level of significance was set at 5%. Data of the intervention and the control groups were summarised by descriptive statistics. Categorical variables were expressed as percentages and compared between the two groups by Pearson’s chi-square test or Fisher’s exact test. Continuous variables were tested for normality with Shapiro-Wilk’s test. Normally distributed variables were expressed as means with standard deviations and compared with Student’s t test. Variables that were non-normally distributed were presented as medians with interquartile ranges and compared with the Mann-Whitney U test. The association between participants’ characteristics, reimbursement, and outcomes were studied by univariate logistic regression analysis and multivariable logistic regression analysis using backward elimination, yielding crude odds ratios (ORs) and 95% CIs. Intention-to-treat analysis was used, and missing data were handled by listwise deletion.

In the control group clinics, a total of 90 smokers were approached, of whom two refused to participate in the study (response rate, 98%). Seven were excluded, as their questionnaires were incomplete or their SCCP fee would have been waived. In the intervention group clinics, a total of 151 smokers were approached, of whom 28 refused to participate in the study (response rate, 81%). Thirty-one were excluded, as their questionnaires were incomplete or their SCCP fee would have been waived. There were 81 and 92 smokers (total, 173) recruited into the control group and intervention group, respectively.

There was no statistical difference between the two groups in terms of sex; age when starting smoking; mean cigarette consumption per day; TTFC; perceived importance of, readiness for, and confidence in smoking cessation; perceived convenience of clinic location; mean monthly income; and waiting time for SCCP (Table 1). More than 90% of participants were male, had a mean monthly income of <HK$30 000, and believed that the SCCP clinic was conveniently located. The median age at starting smoking was 18 years. Nearly half of the smokers were medium smokers, consuming 11 to 20 CPD. The TTFC was less than 31 minutes for more than 67% of smokers. The rating (from 0 to 10) of perceived importance of, readiness for, and confidence in quitting was 5, 3, and 4, respectively. The waiting time for an SCCP appointment was longer than 1 month for over 65% of participants.

The age and the duration of smoking of the participants were statistically different between the two groups. The mean age of the control group was 4 years older than that of the intervention group (61.6 vs 57.6 years; P=0.048). The mean duration of smoking in the control group was 4 years longer than that in the intervention group (41.4 vs 36.9 years; P=0.047).

The Figure summarises the SCCP booking and attendance rates. In the intervention group, 47 smokers (51%) indicated on the questionnaire their agreement to join an SCCP, whereas only 23 smokers (28%) did so in the control group. Of those who agreed in principle, 39 (83%) in the intervention group made a booking compared with only 19 (83%) in the control group. For those who had booked an SCCP place, 19 (49%) and 11 (58%) attended the sessions in the intervention and control group, respectively. Three smokers (16%) in the intervention group were lost to follow-up and were counted as non-quitters. Four smokers (21%) in the intervention group and two (18%) in the control group quit successfully by the seventh day.

Univariate logistic regression analysis (Table 2) revealed that the financial intervention was associated with a higher rate of agreeing to join an SCCP (OR=2.634, 95% CI=1.399-4.959; P=0.003) and booking of an SCCP appointment (OR=2.401, 95% CI=1.242-4.644; P=0.009), but not with attending an SCCP. Factors that were associated with a higher rate of agreeing to join, booking, and attending an SCCP session were consuming 11 to 20 CPD and higher ratings of perceived readiness for and confidence in smoking cessation. Other factors that were associated with a higher rate of agreeing to join and booking an SCCP session were ≤5 minutes for TTFC and higher rating of perceived importance of smoking cessation.

Multivariable logistic regression analysis (Table 3) revealed that the financial intervention was associated with a higher rate of agreeing to join an SCCP (OR=4.963, 95% CI=2.173-11.334; P<0.001) and of booking an SCCP appointment (OR=4.244, 95% CI=1.838-9.799; P<0.001), but not with actual attendance. Higher ratings of smokers’ perceived readiness for smoking cessation was associated with a higher rate of agreeing to join, booking, and attending an SCCP session. Other factors that were associated with a higher rate of agreeing to join an SCCP and making a booking were ≤5 minutes and 6-30 minutes of TTFC and a mean monthly income of HK$10 000-29 999. Mean cigarette consumption of 11 to 20 CPD was associated with a higher rate of attendance at an SCCP.

In Hong Kong, there are so far no published data on the effect of reimbursement on booking and attendance rates for smoking cessation programmes. Overseas studies have evaluated the effect of reimbursement on quitting attempts and abstinence rates, but not attendance at smoking cessation services. This study provides some insights into this area.

The participants in the control and intervention group were comparable except for mean age (62 vs 58 years) and duration of smoking (41 vs 37 years). Simply offsetting the HK$45 SCCP fee with a HK$50 supermarket coupon significantly increased smokers’ willingness to join or actually book an SCCP session (OR=4.963 and 4.244, respectively) [Table 3]. This finding suggests that a financial intervention may make more smokers consider joining an SCCP. With further counselling and NRT in the SCCP, the road to successful smoking cessation may be shortened.

The lack of an association between attendance rate and reimbursement might be explained by the waiting time for SCCP (Table 4). Owing to human resource constraints, more than 65% of SCCP appointments had to be scheduled for over a month after participant recruitment. The mean waiting time was 37 days for the intervention group and 33 days for the control group. The attendance rate dropped from 69% to 37% when the appointment date was over a month away. This finding was in keeping with an overseas study that reported long waiting times as one of the reasons for non-attendance at a quitting programme.23 Future local studies might involve exploring the reasons for programme non-attendance and would help service providers to improve the SCCP and help more smokers quit.

In a local evaluative study of the integrated smoking cessation services of the Tung Wah Group of Hospitals in 2011, the majority of clients (52.6%) consumed 11-20 CPD.24 More than half (54.4%) of those who attended smoking cessation clinics of the Tung Wah Group of Hospitals had a high dependency on nicotine.24 In agreement, our study found that smokers consuming 11-20 CPD were significantly more likely to attend an SCCP than lighter smokers (OR=4.443). We also found that smokers with shorter TTFC were significantly more likely to agree to join or book an SCCP session (TTFC ≤5 minutes: OR=9.788 and 9.871, respectively; TTFC 6-30 minutes: OR=3.954, and OR=4.916, respectively).

Individuals in the quitting preparation stage display the highest motivation-ruler ratings.20 In our study, smokers with a higher rating of readiness were more likely to have a higher rate of deciding to join, book, or attend an SCCP (Table 3). This finding indicates that smokers who were recruited to join an SCCP were prepared to quit. Concerns that offering a financial incentive might invite smokers who had no genuine intention to quit are unfounded. Offering help to smokers for quitting was one of the MPOWER (Monitor, Protect, Offer, Warn, Enforce, and Raise) measures described by the World Health Organization to combat the global tobacco epidemic.25 Hong Kong is fortunate to have a well-established smoking cessation programme, so the service deserves to be fully used.

The smokers recruited into this study were a convenience sample of attendees at GOPCs, so their characteristics would differ from those of the general smoking population in Hong Kong15 in terms of a larger proportion of males (90.8% vs 83.9%), higher daily cigarette consumption (48.6% consuming 11-20 CPD vs 56.0% consuming 1-10 CPD), and larger proportion of economically inactive smokers (38.7% vs 21.0%). The results thus may not be generalised to the whole population of Hong Kong smokers. Furthermore, retirement and economic inactivity may influence smoking habits26 and act as confounders, but these were not controlled in the multivariable analyses.

The control and intervention groups were not very comparable: the control group was slightly older and had smoked for slightly longer. Estimation of the sample size was suboptimal, as the total numbers of eligible smokers during the recruitment period and the estimated increase in attendance rate by financial incentives were not available before the study. Sample-size estimation was based on abstinence rates from previous studies instead of attendance rates. The number of participants who actually attended (19+11=30) may be too small to show any statistical difference between SCCP attendance rates because the difference was less than the three-fold increase for the sample-size calculation.

In addition, the SCCP service in some clinics was restricted to certain days or times of the week owing to availability of counsellors. Some smokers, especially those who were working, may not have been able to find a session at a convenient time. This situation could have affected the booking and attendance rate between different clinics. In one of the returned questionnaires in which the participant ticked the box “agree to join SCCP” but did not make a booking, there was a written remark in Chinese: “Time does not fit”.

This study was non-randomised and the doctors and nurses were not blinded to the financial intervention, because of the difficulty of running a complex workflow with limited resources. We assumed all doctors and nurses tried their best to assist smokers to quit. The possibility that those in the intervention group were more passionate in persuading patients to quit smoking cannot be excluded. The assignment of participants to the intervention or control group was not random and may explain the differences in the baseline characteristics of participants in the two groups. Moreover, it is unknown whether there would be a difference in behaviour if free SCCP was offered from the beginning, instead of providing a fixed-amount HK$50 supermarket coupon that offered an extra HK$5. Only the 7-day quit rate was used as the final programme outcome, as it was a standard outcome in the study centres. Future research with a robust randomisation process may be considered, as well as the use of longer abstinence periods such as 1 month, 3 months, and 12 months.

This study revealed that provision of a financial incentive that would indirectly cover the SCCP service fee might increase the proportion of smokers who agree to attend and make a booking to attend an SCCP. To reduce the barriers to accessing an SCCP service, budget holders should consider providing free and timely SCCP to motivated smokers. It is essential to catch smokers’ moment of hesitation and to increase their access to the service.

Online supplementary information (Appendices 1 and 2) is available for this article at www.hkmj.org.

We thank the Hong Kong College of Family Physicians (HKCFP) for granting the HKCFP Trainee Research Fund 2015 for this study. We also thank the doctors and nurses in Cheung Sha Wan GOPC, Ha Kwai Chung GOPC, Li Po Chun GOPC, West Kowloon GOPC, South Kwai Chung GOPC, and Tsing Yi Cheung Hong GOPC for participant recruitment; Drs LS Chu, T Fong, KM Ho, and SY Tse for advice during research design; and Ms Ellen Yu and Mr Edward Choi for their support during the statistical analyses.

The authors have no conflicts of interest to disclose.

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Haemoglobin Bart’s hydrops fetalis syndrome (BHFS), also known as homozygous α⁰-thalassaemia major or homozygous α-thalassaemia 1, was first described in 1960.1 2 It was considered fatal in the 1960s to 1970s,3 and fetuses often died in utero, were stillborn or died during the early neonatal period.4 When prenatal screening and diagnosis for thalassaemia first started in Hong Kong in 1983, BHFS was advocated as an indication for termination of pregnancy.5 Nonetheless, the availability of intrauterine transfusions (IUTs)6 7 and intrauterine exchange transfusions (IUETs) enabled affected fetuses to survive the perinatal period.

Since the world’s first reported case of survival in 1985 in Canada,8 increasing numbers of BHFS survivors have been reported worldwide, including in Hong Kong.9 The traditional view of its fatality has been challenged,10 11 and in the 1990s there was lively debate about the ethical concerns surrounding active resuscitation and treatment of BHFS babies. Regular transfusions and iron chelation allow BHFS patients to survive even beyond adulthood, and haematopoietic stem cell transplantation12 13 14 offers a cure for this disease, albeit at the expense of possible significant morbidities and compromised quality of life. Long-term morbidities for this cohort of patients thus become an important issue to address. Information gathered by this territory-wide retrospective study will assist physicians in contemplating perinatal management and counselling of parents.

The setting for this study was all eight public hospital paediatric haematology units in Hong Kong that care for patients with transfusion-dependent thalassaemia. Records of patients diagnosed with BHFS (either antenatally or postnatally) who survived beyond the neonatal period and who were subsequently managed long-term at those units from 1 January 1996 to 31 December 2015 were retrieved from the Hong Kong Hospital Authority’s Clinical Data Analysis and Reporting System using the International Classification of Diseases diagnostic code 282.7, searching only for Haemoglobin-Bart’s disease. Data cross-checking was performed with the help of the Hong Kong Paediatric Haematology and Oncology Study Group and paediatric haematologists from the eight hospitals.

Information about patient and parent characteristics, availability of antenatal care and diagnosis, antenatal ultrasonographic findings, reasons for continuation of pregnancy, use of intrauterine transfusions, perinatal course, presence of congenital malformations, subsequent neonatal and long-term neurodevelopmental outcome, and availability of stem-cell transplantation and subsequent outcomes were collected and studied. Patients with BHFS who were not born in Hong Kong were excluded from this study. No missing cases were identified during the 20-year study period, as confirmed from personal communications with both paediatric and adult haematologists from all public hospitals in Hong Kong. As BHFS pregnancies are considered high risk owing to possible maternal-fetal complications, it was presumed that no cases would have been managed by private doctors without support from a neonatal intensive care unit.

This study was primarily descriptive in nature. Statistical analyses were performed with the Statistical Package for the Social Sciences (SPSS) version 22.0 (IBM Corp., Armonk [NY], United States). Continuous variables are expressed as median and range.

This study complied with the Declaration of Helsinki and approval was obtained from the Institutional Review Board of The University of Hong Kong / Hong Kong Hospital Authority West Cluster and all other clusters of participating hospitals. Verbal (parental) consent was obtained but formal written consent was not required by the institutional review board, as this retrospective study did not involve direct patient care (Ref No. HKUCTR-2148).

Surviving patients with BHFS were identified in five of the eight local paediatric haematology units. A total of nine infants were found, of whom five were female and four male. All patients were Chinese, and all were confirmed to be homozygous for the Southeast Asian α-thalassaemia deletion. Six pairs of parents were heterozygous for the Southeast Asian deletion, and three pairs refused genetic testing, one of which was suspected to be a case of non-paternity (case 7). For case 6, the mother was heterozygous for the Southeast Asian deletion (α-thalassaemia 1), whereas the father had an α3.7 single deletion (α-thalassaemia 2). The child demonstrated maternal uniparental disomy and isodisomy (Tables 1 and 2).6 13 14 15 16 17 18 19 20

Among the nine mothers, one received no antenatal care, two received antenatal care in a local private centre, and one received antenatal care in mainland China. All were considered normal and received no IUT. For the remaining five mothers who received antenatal care in a public hospital, all had BHFS diagnosed antenatally in their neonates (two by cordocentesis, one by chorionic villus sampling, one by amniocentesis, and one by both cordocentesis and chorionic villus sampling). All five couples decided to continue the pregnancy after counselling: two for religious reasons and three out of personal preference. All five patients had IUT/IUET performed two to four times. Antenatal ultrasonography of seven fetuses revealed cardiomegaly in four and hydropic changes in two, one of which subsequently resolved after IUT. Placentomegaly was detected in three mothers and polyhydramnios in one. Pre-eclampsia was reported in two mothers and was controlled with antihypertensive drugs (Tables 2 and 3).6 13 14 15 16 17 18 19 20

Preterm delivery occurred in seven of the nine cases, with a median gestational age at delivery of 33 weeks. All infants had respiratory depression at birth and required resuscitation, neonatal intensive care unit admission, and intubation. Surfactant for respiratory distress syndrome was required by five infants, and five demonstrated persistent pulmonary hypertension of the newborn, which required high-frequency oscillation ventilation and inhaled nitric oxide administration. Inotropic support with or without hydrocortisone was required by four infants with haemodynamic instability (poor cardiac contractility, heart failure, and/or hypotension). In case 6, the infant required cardiopulmonary resuscitation for more than 20 minutes after cardiac arrest. Postnatally, exchange transfusion was performed in five babies: two received a double-volume transfusion and three received a single-volume transfusion. Three infants received a transfusion within the first 24 hours of life. The median pre- and post-transfusion haemoglobin level was 90 and 170 g/L, respectively. All infants showed improved haemodynamic stability after transfusion. Congenital malformations were noted in all cases in this cohort (Tables 3 and 4).6 13 14 15 16 17 18 19

All four male babies had hypospadias that required urethroplasty, and two had concomitant undescended testes that required orchidopexy. Dental (case 1) and skeletal (case 3) anomalies were noted in two patients. Regarding the cardiovascular system, patent ductus arteriosus was noted in five cases and a secundum atrial septal defect in three. Regarding the digestive system, one infant (case 3) had type 3 jejunal atresia, for which end-to-end anastomosis was performed on day 4 of life. Two patients had neonatal hepatitis: one case resolved with time and the other still requires regular follow-up for elevated transaminase levels. No cases of cerebrovascular malformations were identified in this local cohort.

Both survivors who have reached adulthood are of short stature and have failed to achieve their final adult height, that is, to reach their predicted mid-parental height. Nonetheless, both had a normal puberty. Among the nine survivors, two have long-term neurological deficits, both manifested as mild spastic diplegia, although not affecting mobility. Five infants had delayed development, one of whom continues to have borderline low intellect (IQ, 80-89) after reaching adulthood (case 1). Two have normal intellect (cases 2 and 4) despite the need for multidisciplinary training during infancy, and the remaining two (cases 6 and 7) are attending mainsteam schools that provide extra training and support. The two cases diagnosed most recently (cases 8 and 9) have had normal development to date (Tables 3 and 4).6 13 14 15 16 17 18 19

Two patients received a stem-cell transplant: one an human leukocyte antigen DR 1 antigen–mismatch sibling-donor cord-blood transplant, and the other a 10/10 peripheral-blood stem-cell transplant from a matched unrelated donor. Both patients underwent transplantation at 20 to 21 months of age. Both achieved 100% donor chimerism 1 month after transplantation and remain transfusion-independent. Of the remaining seven patients who require regular transfusion every 3 to 6 weeks, only one shows moderate hepatic iron overload (case 2), and none have demonstrated infective complications. All five survivors older than 2 years received iron chelation therapy: three with deferasirox and two with deferiprone (one of whom has changed to deferoxamine owing to neutropenia). The median serum ferritin level was 1961 pmol/L (range, 411-5312 pmol/L). Endocrinopathies were noted in three patients: one had primary gonadal failure but did not require hormonal replacement therapy (case 1), one had hypogonadism requiring testosterone (case 5), and one (case 2) had partial adrenal insufficiency requiring stress-dose steroid but not regular hydrocortisone replacement (Tables 4 and 5).6 13 14 15 16 17 18 19

In Southeast Asia, BHFS is the most common cause of fetal hydrops.5 21 Because it is an autosomal recessive disorder, when both parents have two α-globin gene deletions in cis on chromosome 16 (each parent, --/αα), any offspring will have a 25% chance of having BHFS. In BHFS, haemoglobin tetramers of only gamma chains (γ₄) is ineffective in erythropoiesis and oxygen delivery to tissues. The ensuing anaemia and tissue hypoxia interfere with organogenesis and development and also lead to fetal heart failure, extramedullary erythropoiesis, and maternal complications. In contrast to --^FIL and --^THAI gene deletions reported in the Philippines and Thailand, respectively, the --^SEA or Southeast Asian deletion (the most common mutation in Hong Kong and demonstrated in all nine BHFS cases in this study) affects only the α-globin gene while sparing the embryonic ζ-globin gene, thus permitting production of Portland 1 (ζ₂γ₂) and Portland 2 (ζ₂β₂) haemoglobins. Hence, the affected fetus can survive through the antenatal and early neonatal period.

In Hong Kong, prenatal screening using a cut-off for maternal mean corpuscular volume of ≤80 fL and prenatal diagnosis using chorionic villus sampling, amniocentesis, and cordocentesis have been practised since 1983,22 23 24 25 thereby contributing to a decline in BHFS incidence for two decades. Despite public health endeavours in prenatal screening, however, BHFS babies continue to be born without prior prenatal diagnosis or parental counselling, resulting in adverse maternal and fetal outcomes.26 Causes of this phenomenon are principally two-fold: lack of proper antenatal screening and diagnosis, as well as improper implementation of screening or diagnostic procedures (Table 1). Better public education in both mainland China and Hong Kong would rectify the situation. Such education should stress the importance of early accurate prenatal diagnosis and the possible serious sequelae of late presentation or delayed diagnosis. Obstetricians should also note that normal paternal mean corpuscular volume does not exclude fetal BHFS because of the rare occurrence of maternal uniparental disomy (case 6)27 and non-paternity (possible in case 7).27 Routine mid-trimester scanning is imperative and diagnosis of BHFS should be considered if ultrasonography or clinical features are suggestive of BHFS (cardiomegaly, placentomegaly,18 28 and hydrops), regardless of the parents’ mean corpuscular volume.27 Placental thickness measurement allows early detection of BHFS in the first trimester, even before the appearance of hydropic features.18 28 If hydropic changes are detected, confirmation by cordocentesis and haemoglobin electrophoresis is warranted.

Suggested salient points of counselling for parents who opt for continuation of pregnancy are shown in the online supplementary Appendix. Once considered fatal, BHFS can now be detected and diagnosed antenatally, with survival being possible albeit not without complications. Detailed antenatal counselling for parents who are contemplating continuation of an affected pregnancy is crucial. Possible maternal-fetal complications, such as gestational hypertensive disorder and intrauterine growth restriction or death, should be addressed. On the basis of local experience, IUT is advised because there is a risk of miscarriage or intrauterine infection (case 9). Multiple IUTs may be indicated if fetal anaemia is suggested by serial Doppler ultrasonography (peak systolic velocity of the middle cerebral artery of >1.5 multiples of the median). Premature delivery and perinatal respiratory depression are often encountered. Neonatal intensive care unit admission and intubation are anticipated from local experience. Inotropic support may be required in the early neonatal period, as well as cardiopulmonary support, such as mechanical ventilation, surfactant treatment, high frequency oscillation ventilation, and nitric oxide inhalation for persistent pulmonary hypertension of the newborn. Exchange transfusion is often performed postnatally, in most cases within the first 24 hours of life.

Congenital malformations are often encountered, the most common being genitourinary and musculoskeletal defects, but are usually amenable to surgical correction. It is worth noting that all male babies in our local cohort displayed hypospadias. Two-thirds of our patient cohort showed growth retardation, global developmental delay, and/or long-term residual neurological deficits. These findings are comparable to those from an international case series29 and an overseas case report.11 Lifelong hypertransfusions every 4 to 6 weeks and iron chelation are expected for BHFS survivors. Haematopoietic stem-cell transplantation is a possible cure and has been successful in some local cases (Table 3). Nevertheless, transplant-related mortality and morbidity should not be overlooked. The proposal that parents produce a subsequent sibling to serve as a ‘saviour baby’ and potential donor is feasible but raises ethical concerns. Careful consideration and proper parental counselling are necessary.

Globally, 69 survivors are reported in the international BHFS registry29 with our local cohort (n = 9) contributing about one-seventh of cases. Approximately two-thirds of all cases used IUT29 (41/69; 59%), which is similar to the proportion of local cases (5/9; 56%). Globally29 and locally, most infants were delivered prematurely (respectively, 47/66; 71% and 7/9; 78%). Approximately one-fifth (14/69) of all BHFS survivors underwent stem-cell transplantation,29 again similar to our local situation (2/9). Congenital anomalies were present in all of the local patients, compared with two-thirds (37/55; 64%) worldwide,29 although urogenital and limb defects remained the most common. Nearly half (26/55; 47%) of global BHFS survivors demonstrated various degrees of transient or permanent neurodevelopmental impairment,29 in contrast to two-thirds of our cohort. Sohan et al (2002)30 described the first BHFS survivor in the United Kingdom: a 38-week-old baby girl of Hong Kong parents, who was referred at 21 weeks of gestation for hydrops fetalis, received serial IUT and had BHFS antenatally diagnosed. Two exchange transfusions were performed postnatally and the baby was discharged on day 6 of life followed by transfusions every 4 to 5 weeks. At the time of that publication, she was 18 months old and had normal growth and development apart from bilateral transverse palmar creases and a mild lobster-claw deformity of the right foot.30

This is the first territory-wide multicentre retrospective study to describe in depth the basic demographic characteristics and perinatal and long-term outcomes of BHFS survivors in Hong Kong over the past two decades or so. It also explores the reasons and cultural circumstances for which parents opted to continue the pregnancy despite public health endeavours to promote antenatal screening. Furthermore, it adds two more local cases to those submitted and recently published by the BHFS International Consortium.29 However, the small sample size precludes statistical analyses, and the data covers only the eight local public hospitals with haematology units and a period of 20 years (as the cut-off age in Hong Kong for paediatric care is 20 years and the Clinical Data Analysis and Reporting System began only in 1996). Survivors beyond 20 years of age and patients who defaulted follow-up to receive long-term medical care in the private sector or overseas were excluded from this study. In addition, the numbers of abortions and stillbirths, as well as BHFS babies with early neonatal death were not studied. Multidisciplinary collaboration between obstetricians, paediatric haematologists, and adult-care physicians at all local hospitals and concerted efforts in data collection and analysis are recommended. With the establishment of the Hong Kong Children’s Hospital in 2018, it is hoped that a standardised protocol of management and counselling can be compiled, data collection streamlined, and analysis facilitated for future research.

To conclude, survival of patients with BHFS is possible but not without short- and long-term complications. Local epidemiology of BHFS survivors is similar to that reported for an international registry. Detailed antenatal counselling of parents with a non-judgemental attitude and cautious optimism are imperative.

Online supplementary information (Appendix) is available for this article at www.hkmj.org.

We thank the Hong Kong Paediatric Haematology and Oncology Study Group and the paediatric haematologists from the eight participating hospitals for patient management, case contribution, and data cross-checking.

The authors have no conflicts of interest to disclose.

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