Topic Update

Newborn Screening: Past, Present and the Future

Newborn Screening: Past, Present and the Future

Volume 11, Issue 2 August 2016  (download full article in pdf)


Editorial note:

In this topical update, Dr Chloe Mak reviews the history and development of newborn screening, in particular for Hong Kong. Both benefits and limitations of expanded newborn screening were discussed. The latest pilot screening programme, as stipulated in the Policy Address by Chief Executive, was also illustrated. We welcome any feedback or suggestions. Please direct them to Dr. Sammy Chen (e-mail: of Education Committee, the Hong Kong College of Pathologists. Opinions expressed are those of the authors or named individuals, and are not necessarily those of the Hong Kong College of Pathologists. 


Dr MAK Miu Chloe 

Department of Pathology, Princess Margaret Hospital 



Newborn screening (NBS) is one of the most successful public health programs in the 20th century. In fact, the idea of mass screening was totally new to the society before 1960’s. When Dr Ivar Asbjørn Følling discovered the disease phenylketonuria (PKU) leading to mental retardation in many children [1] and Dr Robert Guthrie invented a simple and reliable screening test using bacterial inhibition test for blood phenylalanine [2] together with the understanding of disease pathogenesis and effective treatment to prevent mental retardation initiated during early asymptomatic phase [3], the proposal of NBS was  

born. However, criticisms were vigorously received over the uncertainties of disease nature, assay validity and long-term treatment effectiveness. To begin with, NBS for PKU was tested as a pilot service in Massachusetts in 1962 [4]. World Health Organization (WHO) issued two landmark reports about population screening: “The Principles and Practice of Screening for Disease” [5] and “The WHO Scientific Group on Screening for Inborn Errors of Metabolism (IEM), Geneva” [6]. The latter report elaborates more on screening for IEM.

After the success of PKU screening in preventing mental retardation, the legislation for mandatory screening was made in 1975 in USA. More disorders were added to the panel, such as congenital hypothyroidism (incidence 1 in 2,200) in 1976, congenital toxoplasmosis (1 in 27,800) in 1986, hemoglobinopathies (1 in 2,900) and congenital adrenal hyperplasia (1 in 19,200) in 1990, biotinidase deficiency (1 in 42,000) in 1992, medium-chain acyl-CoA dehydrogenase deficiency (1 in 21,000) and cystic fibrosis (1 in 2,900) in 1999 in the New England Newborn Screening Program of the University of Massachusetts Medical School [7]. The Centers for Disease Control (CDC) launched the Quality Assurance Program for NBS laboratories since 1978 and now with more than 200 laboratories worldwide participated.

The first wave of NBS started in other countries soon, such as Canada in 1963, Singapore in 1965, Japan in 1967, Australia in 1967, Portugal in 1979, while in other Asian areas NBS was mostly initiated after 1980s: Mainland China, Hong Kong, India, Malaysia and Taiwan in 1980s; Bangladesh, Indonesia, South Korea, Philippines and Thailand in 1990s; Mongolia, Myanmar, Palau, Pakistan, Sri Lanka and Vietnam in 2000s [8-10]. The approach adopted was one-test-one-disease and the panel was limited to a few conditions usually including PKU, congenital hypothyroidism, maple syrup urine disease, homocystinuria, galactosemia, cystic fibrosis and/or congenital adrenal hyperplasia.


Expanded Newborn Screening for Inborn Errors of Metabolism

IEM is a huge group of clinically and genetically heterogeneous metabolic disorders (Table 1). There are more than 1,000 diseases mainly affecting children. The cumulative incidence was reported up to 1 in 800 [11, 12]. Some IEM are amenable to timely treatment with good prognosis. Traditionally, the diagnosis replies on one or more tests for one disease. However, the advent of tandem mass spectrometry (TMS) applications in amino acids and acylcarnitines detection enables the one-test-many-diseases breakthrough in NBS for IEM [13-15]. TMS accurately identifies analytes by their fingerprint molecular mass-to- charge ratios with commendable specificity and sensitivity. It only requires 0.3 mL whole blood to test for more than 30 diseases in a single dried blood spot. The analytical time takes about two minutes for one sample allowing a high-volume throughput with rapid turnaround time in a NBS setting. Table 2 shows the advantages and disadvantages of TMS applications in NBS. 


Table 1. Classifications of IEM

1. Disorders of amino acid and peptide metabolism
2. Disorders of carbohydrate metabolism
3. Disorders of fatty acid and ketone body metabolism
4. Disorders of energy metabolism
5. Disorders in the metabolism of purines, pyrimidines and nucleotides
6. Disorders of the metabolism of sterols
7. Disorders of porphyrin and haem metabolism
8. Disorders of lipid and lipoprotein metabolism
9. Congenital disorders of glycosylation and other disorders of protein modification
10. Lysosomal disorders
11. Peroxisomal disorders
12. Disorders of neurotransmitter metabolism
13. Disorders in the metabolism of vitamins and (non-protein) cofactors
14. Disorders in the metabolism of trace elements and metals
15. Disorders and variants in the metabolism of xenobiotics (article link) 


Table 2 Advantages and Disadvantages of TMS Applications in NBS

1. Detection of multiple analytes in the same analytical run
2. Small blood volume required (0.3 mL whole blood)
3. Fast analytical time about two minutes per sample
4. High throughput capacity
5. Accurate identification of molecular compounds by their fingerprint mass-to-charge ratios
6. Highly sensitive and specific with low false positive rate
7. Availability of commercial kits for acylcarnitines and amino acids

1. High capital cost
2. Skillful expertise
3. Lack of full automation


In 1998, the New South Wales Newborn Screening Program was the first center to implement expanded NBS based on electrospray ionization TMS [16]. In the next year, the New England Newborn Screening Program introduced an optional metabolic panel for 19 IEM [7]. Twenty IEM patients were identified after 2.5 years screening of 200,000 newborns [17]. The prospective study showed that screened patients had shorter hospitalization and required less extra parental care. There was no significant difference in parental stress among NBS screened true positive, false positive results and normal control groups. In the same year, Germany started its extended screening with an unrestricted approach and since 2005 streamlined into 10 conditions [18]. Japan piloted TMS-based NBS from 1997 to 2007 with screening of 606,380 babies [19] and 65 IEM patients were identified with overall incidence of 1 in 9,330. Mainland China piloted TMS based NBS in Shanghai from 2003 to 2007 with 116,000 newborns screened [20]. Twenty patients were positive for six IEM with mainly PKU, maple syrup urine disease, methylmalonic acidemia and propionic acidemia. The overall incidence of IEM was 1 in 5,800. There were significant differences in the disease spectrum between northern and southern Chinese [21]. For example, classical PKU with phenylalanine hydroxylase deficiency accounts for the majority of PKU in northern Chinese, whereas, 6-pyruvovyl-tetrahydropterin synthase deficiency was much more common among southern Chinese. There were around 1,300 new cases of PKU screened in China each year. Glucose-6-phosphate dehydrogenase (G6PD) deficiency was very prevalent in Guangzhou with incidence of 1 in 28 but not in Northern Chinese [22]. In addition to expanded NBS in some advanced provinces covering more than 30 IEM, congenital hypothyroidism and PKU are mandatorily screened throughout the whole mainland stipulated in the law of maternal and infant health (launched in 1994) and its action program (launched in 2000) [22].

The International Atomic Energy Agency had devoted a total of $6.7 million USD to assist developing countries developing the infrastructure for NBS, in particular for congenital hypothyroidism [23]. In 2008, the Working Group of the Asia Pacific Society for Human Genetics on Consolidating Newborn Screening Efforts in the Asia Pacific Region was formed with representatives from 11 countries, viz. Bangladesh, China, India, Indonesia, Laos, Mongolia, Pakistan, Palau, Philippines, Sri Lanka and Vietnam. [24].

In 2006, the American College of Medical Genetics (ACMG) announced a consensus statement to standardize the NBS panel and decision matrix with recommendations of a core panel of 29 disorders and 25 additional secondary targets disorders [25]. It also provides the act sheets and confirmatory algorithms on each condition (

Wilson-Jungner criteria have been recently revisited in the context of genomic and modern medicine. The emphasis has been shifted towards more on the benefits to the affected baby and the family from early diagnosis and the availability of a satisfactory medical system for subsequent patient management [26]. Whether curative treatment is available or not, this is not a mandatory pre-requisite for NBS implementation.


Newborn Screening in Hong Kong

In Hong Kong, two metabolic conditions have been screened on a population basis namely congenital hypothyroidism and G6PD deficiency since March 1984 under the Neonatal Screening Unit of Clinical Genetic Service, Department of Health. The local incidence of CH is about 1 in 2,500, while that of G6PD deficiency is 4.5% in male and 0.3% in female newborn [27]. The program significantly lowered the mortality and morbidity. Apart from antenatal education through the Maternity and Child Health Centers, the Department of Health also provides follow-up and counseling to affected families.

The third was neonatal hearing screening. Language development is significantly improved if the hearing loss is treated before the age of 6 months. A local feasibility study was performed in 1999 screening 1,064 infants with an incidence of permanent deafness 1 in 355 [28]. A two-stage program was implemented in all Hospital Authority hospitals with maternity service since 2007 [29].

In 2008, a Coroner inquest was called into the acute death of a 14-year-old boy with a postmortem genetic diagnosis of glutaric acidemia type II (multiple acyl-CoA dehydrogenase deficiency) [30]. The Coroner’s report recommended that “the Department of Health, the Hospital Authority, the Faculty of Medicine of various universities and others concerned should carry out a feasibility study to see whether universal check may be carried out on all newborn babies for congenital metabolism defect” ( ner_report_july08.pdf).

In 2012, the University of Hong Kong conducted the first territory-wide pilot study funded by the SK Yee Medical Fund Foundation ( The study tested the feasibility of expanded NBS in public hospitals with an OPathPed model [31]. In 2013, a private NBS for IEM service commenced in the Chinese University of Hong Kong, sponsored by Joshua Hellmann Foundation for Orphan Disease ( medicine-services/jhf-newborn-metabolic- screening-program/).

In 2015, the Policy Address by the Chief Executive announced that a working group was established between the Department of Health and Hospital Authority to study the feasibility and logistics of expanded NBS for IEM in the public healthcare system ( 1/14/P201501140477.htm).

The feasibility study in the form of a pilot study was officially initiated on 1 October 2015 and lasts for 18 months, testing in two public hospitals with the collaboration between the Department of Health and the Hospital Authority. The aim of this pilot study is to demonstrate the feasibility of implementing NBS for IEM while developing and optimising education on IEM to public and healthcare professional, the screening tests, laboratory algorithms, clinical management and follow-up algorithms and programme evaluation. Twenty four conditions are included (Table 3). Educational materials were distributed to public and healthcare professionals (figure 1). A video was broadcasted in antenatal clinics and postnatal wards (CantoneseMandarin and English version). 


Table 3 Screening Panel of Government-initiated Pilot Study

Disorders of Amino Acids
Classical phenylketonuria 6-pyruvoyl-tetrahydropterin synthase deficiency Argininosuccinic acidemia

Maple syrup urine disease Citrullinemia type I Citrullinemia type II Tyrosinemia Type I Homocystinuria

Disorders of Organic Acids

Multiple carboxylase deficiency Glutaric acidemia type I Methylmalonic acidemia Propionic acidemia

Isovaleric acidemia 3-hydroxy-3-methylglutaryl-CoA lyase deficiency Beta-ketothiolase deficiency

Disorders of Fatty Acid Oxidation

Carnitine uptake deficiency
Carnitine-acylcarnitine translocase deficiency Carnitine palmitoyltransferase II deficiency Medium-chain acyl-CoA dehydrogenase deficiency Very long-chain acyl-CoA dehydrogenase deficiency Glutaric acidemia type II


Congenital adrenal hyperplasia Biotinidase deficiency
Classic galactosemia 


Pros and Cons of Expanded Newborn Screening

NBS for IEM enables early diagnosis and treatment, prevents morbidity and mortality, avoids unnecessary investigations, alleviates family’s anxiety, predicts prognosis and provides valuable information for family planning and genetic counseling. In addition, some maternal diseases with treatment implications can also be detected during NBS, such as primary carnitine deficiency, PKU and vitamin B12 deficiency. The storage of DBS on a population scale can be a valuable asset in quality assurance, biomedical researches and forensic investigations.

NBS is shown to be cost- effective. Although randomized clinical trial on clinical utility and cost-effectiveness is difficult due to the rarity of individual IEM, cost- effectiveness in PKU [32-34], congenital hypothyroidism [35-37] and MCADD [34, 38, 39] were well documented. Table 4 shows some examples of studies on the outcome comparison between screened and unscreened patients.

There are also limitations in expanded NBS. First, because of the short history of expanded NBS developed only in the last two decades, long-term evaluation is still lacking. Recently, the Southeastern Newborn Screening Genetics Collaborative and the Public Health Informatics Institute collaborated to address the long-term issue through international effort. Second, patients with early symptom onset before release of NBS result would not benefit. False negative can happen to patients with mild or atypical presentation or use of non-standardized cutoff values and testing strategies. Third, since TMS allows one-test-multiple-diseases, some diseases which are not required by the program would also be unraveled. Conditions which are benign or with doubtful pathological significance may be identified, for examples, 3-methylcrotonyl-CoA carboxylase deficiency and short-chain acyl-CoA dehydrogenase deficiency. Detection and disclosure of carrier status such as in sickle cell disease and cystic fibrosis may create confusion to the parents [40, 41]. Fourth, although screening is available and even mandatory in some countries, treatment is not and not all screened positive children received proper treatment. Some treatments require special drugs and milk formulae. The clinical follow-up system may not be as well established as the screening program. Fifth, NBS results can be false positive or inconclusive. The overall sensitivity and

specificity of TMS-based NBS is already commendable more than 99% with false positive rate from 0.07% to 0.33%, positive predictive values from 8% to 18% [20, 42-46]. False positive may lead to unnecessary hospitalizations and parental anxiety [47]. Measures such as better education and communication, algorithmic interpretation rules and two-tier testing system, can be implemented to reduce false positive rates andpotentialadverseeffects.



NBS represents the highest volume of genetic testing. It is more than a test and it requires a comprehensive healthcare system from pre- analytical, analytical to post-analytical phase involving expertise from public health, healthcare management, clinical, pathology and information technology. The field of NBS and IEM is still expanding. More disorders are under evaluation and covered such as severe combined immunodeficiency [48, 49] and X-linked adrenoleucodystrophy [50]. Various different or new technologies are applied to enhance the diagnostic performance, increase throughput, allow more automation and decrease costs [51-54]. Although a genomic approach for NBS is technically feasible, it entails a lot of difficult technical, clinical, social and ethical issues with hazards more than good [55]. On the other hand, using SNP array approach to detect a large panel of well-known pathogenic mutations on a wide spectrum of disorders would be more pragmatic. Expanded NBS is shown to be economically valid with significant reduction in critical care and chronic medical care expenditures. Last but not the least, NBS saves lives. 


Table 4 Outcome comparison between screened and unscreened IEM patients

Reference Study Results
Wilcken et al. [56] Screening more than two million babies The handicap rate 1 in 74,074 in the clinical group versus 1 in 232,558 in NBS group
Boneh et al. [57] Six babies with glutaric acidemia type I detected by NBS These patients benefited from mild protein restriction and carnitine supplement. All patients except one had normal cognitive and gross motor development, versus in unscreened patients with glutaric acidemia type I leads to acute encephalopathy and debilitating dyskinetic dystonia.
Klose et al. [58] 57 patients clinically diagnosed with organic acidemias and fatty acid oxidation defects Sixty-three percent of these patients presented within the first year of life and 54% suffered from acute metabolic crises with eight deaths.
Majority of these metabolic crises (93.5%) and death (87.5%) could have been prevented by expanded NBS and early treatment.
Schulze et al. [44] 250,000 neonates for 23 metabolic diseases and 106 patients with positive screening results followed for 42 months Seventy patients received proper treatment and remained asymptomatic. Six patients developed symptoms and three died. Nine patients presented earlier than the availability of screening results. Overall, 1 in 4,100 babies benefited from the early screening and subsequent treatment.
Cipriano et al. [59] Decision-analytic model analyzing 21 diseases taking into account of the disease severity, analytical sensitivity and specificity, need of confirmatory tests, specialist management, start-up and operating costs, hospital-related costs and potential deflation of future costs and benefits. Bundling PKU together with 14 diseases was the most cost-effective strategy with $70,000 Canadian dollars per life-year gain.
Seymour et al. [60] Systemic reviews published by the Health Technology Assessment in United Kingdom Recommended screening for PKU, biotinidase deficiency, congenital adrenal hyperplasia, MCADD and glutaric acidemia type I
Pollitt et al [61] Systemic reviews published by the Health Technology Assessment in United Kingdom Considered screening as many conditions as possible with the emphasis on the benefits of early diagnosis to the patients and the family. The availability of effective treatment was not a compulsory pre- requisite.
Filiano et al. [62] Cost-benefit study The lifetime costs for one cerebral palsy patient from infancy to 65 years old were $167,000 to $1 million USD as at 1998. The costs included medical charges, developmental services, special education and lost wages. Projected yearly savings of $36,600,000 (USD as at 1998) could be achieved through expanded NBS. The saving was twice of the incremental cost for NBS.
Couce et al. [63] 10-year clinical follow-up of 137 IEM patients picked up by expanded NBS The incidence was 1 in 2,060 newborns. With the long-term management, death rate was only 2.92% and majority of the survivors (95.5%) were asymptomatic after a mean observation of 54 months.
Linder et al. [64] 373 IEM patients detected from a cohort of 1,084,195 newborns studying the efficacy and outcome of 10-year experience in expanded NBS Presymptomatic diagnosis and treatment of other IEM achieved the same clinical benefits as in PKU.





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The sick returned traveller

The sick returned traveller

Volume 11, Issue 1 January 2016  (download full article in pdf)


Editorial note:

With increasing international travel, awareness and knowledge on the microbiology aspects of the returning traveller is essential, in order for timely diagnosis of infectious diseases acquired abroad and for administration of effective clinical management and public health control measures. In this issue of the Topical Update, Dr. Samson Wong presents a synopsis of the conditions associated with the returned traveller, which will be of practical application to any medical professional. We welcome any feedback or suggestion. Please direct them to Dr. Janice Lo (e-mail:, Education Committee, The Hong Kong College of Pathologists. Opinions expressed are those of the authors or named individuals, and are not necessarily those of the Hong Kong College of Pathologists.


Dr. Samson SY WONG
Assistant Professor, Department of Microbiology, The University of Hong Kong, Queen Mary Hospital, Hong Kong


The number of international travellers has been increasing over the past 20 years. In 1995, there were 530 million international arrivals; this figure increased to 1,138 million in 2014 [1]. This rising trend has only been punctuated in 2003 and 2009, coinciding with two infectious disease epidemics, SARS and pandemic influenza, respectively. With the unprecedented volume, speed, and reach of international travel comes an increasing number of patients who developed travel-related health issues. About 15–64% international travellers may develop health problems during their travel [2–5]. The risk depends on the duration of travel, destination, behaviour of the travellers, and the use of prophylactic measures. In most studies, gastrointestinal (usually in the form of travellers’ diarrhoea) and respiratory illnesses are the commonest complaints, followed by skin problems, fever, and other conditions such as altitude sickness, envenoming, accidents and injuries. In this article, we shall focus on the concerns and precautions in the laboratory diagnosis of some important infections in the returned travellers.


Spectrum of infections and approach to the sick returned traveller

The spectrum of travel-related infections is diverse. A large body of information is available from individual centres and from GeoSentinel which consists of 63 travel clinics in 29 countries on 6 continents ( page/geosentinel. Accessed on 2 December 2015). However, similar data are lacking in Hong Kong, and one should note that the prevalence of different infections in the literature may not be applicable locally because of differences in the adoption of prophylactic measures and habits of travel. Data from the more recent GeoSentinel surveillance are consistent with earlier studies in that the commonest illnesses in returned travellers affected the gastrointestinal tract, respiratory system, skin, or presented as fever or systemic illnesses (Table 1) [6–9]. Fever is a common manifestation in such patients, which may occur as an undifferentiated febrile illness or be associated with specific symptoms such as rash, arthritis/arthralgia, or other localizing symptoms. The presence of localizing signs and symptoms helps to narrow the differential diagnoses. Most studies in the literature described malaria as one of the commonest causes of fever, followed by dengue in the more recent series (Table 2). Although malaria is certainly a diagnosis not to be missed, it is not the commonest aetiology of fever in returned travellers in Hong Kong. For example, in 2014, 23 cases of malaria and 112 cases of dengue were notified to the Department of Health [10]. Given that both diseases are primarily imported from endemic countries, dengue would be commoner as a cause of fever in the travellers in Hong Kong.

The clinical approach should always begin with a thorough history including a detailed itinerary (with stopovers), potential exposure history, and prophylactic measures. Despite the long list of differential diagnoses to each clinical syndrome, the most likely causes can often be suggested by the geographical areas visited, the likely incubation period of the disease, and the relevant exposure history. Some important infections associated with specific exposures are listed in Table 3. Subsequent choice of organ imaging and laboratory investigations is guided by the most likely diagnosis. It is important that after the initial assessment, one must not miss conditions that are clinically severe and potentially treatable, as well as those that have a high risk of hospital or community transmission. Severe infections must be investigated and treated urgently, such as sepsis, severe malaria, haemorrhagic fevers, and central nervous system infections. Examples of diseases that require prompt infection control precautions include viral haemorrhagic fevers, Middle East respiratory syndrome (MERS), avian influenza and infections caused by other novel influenza viruses.


Important clinical syndromes and laboratory investigations


Malaria must always be considered as a potential cause of fever occurring in anyone who develops fever seven days after travelling to an endemic area [11]. Missing a case of malaria, especially falciparum malaria, can lead to serious and often fatal outcomes which in turn, may lead to medicolegal litigations. There are no pathognomonic clinical signs and symptoms of malaria. Patients are sometimes erroneously diagnosed to have influenza or gastroenteritis initially because of the non-specific clinical symptoms [12–15]. The textbook description of periodic fever is only present in 8–23% of malaria patients [12, 13]. Appropriate laboratory testing must be performed in any patient with a compatible travel history.

The diagnosis of malaria is conventionally made by examination of the thin and thick blood films. The four species of human Plasmodium, P. vivax, P. ovale, P. malariae, and P. falciparum are distinguished morphologically. In the past decade, the simian malaria P. knowlesi has emerged as an important cause of human malaria in some Southeast Asian foci, especially in Malaysian Borneo. P. knowlesi infection of travellers has been well reported. The difficulty with P. knowlesi is that its morphology closely resembles other human plasmodia, especially P. malariae. Definitive speciation can generally be made using molecular techniques [16]. Quantification of the level of parasitaemia is essential for falciparum malaria both upon initial diagnosis and serial examination of the blood smear because the level of parasitaemia carries prognostic significance and failure to reduce the level of parasitaemia after antimalarial treatment could signify drug resistance.

Any positive blood smear results must be conveyed to the attending clinician immediately. This is especially critical for P. falciparum which is a medical emergency in the non-immune travellers. It is important to remember that one single negative blood smear cannot exclude malaria. It is generally recommended that in patients with a negative blood smear but with a high clinical suspicion for malaria, at least three blood smears must be repeated over 48 hours to exclude the diagnosis [17–19]. Alternatives to microscopic diagnosis of malaria include antigen detection and nucleic acid amplification tests (NAAT) from peripheral blood. Immunochromatographic antigen detection kits are widely accepted as a form of rapid diagnostic test [20]. These are particularly useful as a form of point-of-care testing and in situations where experienced microscopists are not available. The major drawbacks include the limited sensitivity in patients with low level parasitaemia and their inability to differentiate all four species of human plasmodia. Speciation is clinically essential because P. vivax and P. ovale infections require radical cure with primaquine. NAAT is currently the most sensitive method for detection of bloodborne parasites and mixed infections, and also allows definitive speciation in problematic cases, including P. knowlesi infection [21]. Availability is, however, currently limited to a few centres and the turnaround time is often too long for routine diagnostic purposes.


The arthropod-borne viruses are fast becoming some of the most important causes of emerging and re-emerging infectious disease outbreaks in tropical and subtropical countries. This is contributed by the global climate and environmental changes, as well as the geographic spread of the vectors, especially mosquitoes. There is a long list of arboviruses, many of which belong to the families of Togaviridae (mosquito-borne; e.g. Chikungunya, Ross River, Eastern, Western, and Venezuelan equine encephalitis viruses), Flaviviridae (e.g. mosquito-borne dengue, yellow fever, Japanese encephalitis, Zika, Murray Valley encephalitis viruses; tick-borne encephalitis virus), and Bunyaviridae (e.g. mosquito-borne Rift Valley fever virus; tick-borne Crimean-Congo haemorrhagic fever virus; sandfly-borne Toscana and sandfly fever viruses) [22].

The global incidence and geographical extent of dengue have been growing over the past five decades with regular outbreaks in different parts of the world [23]. The most recent outbreak is the ongoing epidemic (at the time of writing) in Taiwan, with 39,350 indigenous cases in 2015 (as of 1 December 2015) [24]. This is also the commonest notifiable arbovirus infection in Hong Kong with occasional local transmissions. Dengue is a relatively common cause of fever in returned travellers, causing 2–16.5% of the cases [25]. The disease is traditionally classified into uncomplicated dengue fever, dengue haemorrhagic fever, and dengue shock syndrome. The last two entities are usually associated with secondary infections due to serotypes of the virus that are different from the one causing the first episode of infection. Since 2009, the World Health Organization re-classified the disease into dengue fever and severe dengue, the latter being characterized by severe plasma leakage, bleeding, and organ impairment [23].

Chikungunya is another arbovirus infection that has gained much attention in the past decade since an outbreak started in Kenya in 2004, with subsequent spread to the Indian Ocean islands till 2006, and infected over one third of the population in La Réunion [26]. Outbreaks of this togavirus have been repeatedly reported in recent years, affecting countries in Asia, Africa, the Pacific islands, Central and South Americas. Likewise, infections due to Zika virus received little attention until it caused large outbreaks in the Yap State of Federated States of Micronesia in 2007 and the French Polynesia in 2013 [27]. Zika virus is endemic in various countries in Africa, Asia, Oceania, the Pacific islands, and since 2014, in Latin and South America (especially Brazil, but also Chile, Colombia, Suriname, Jamaica, and Dominican Republic) [27, 28].

Given the large number of arboviruses, the choice of diagnostic tests should be guided by the geographical area(s) of travel and clinical syndrome. Arbovirus infections commonly manifest as systemic febrile illnesses with or without rash, arthralgia or arthritis, encephalitis or meningoencephalitis, or viral haemorrhagic fever (Table 4) [22, 29]. Many of the viruses are geographically restricted. Requests for investigations against specific viruses should be guided by the travel history and clinical manifestations. Viral culture can be performed for some viruses, but this is generally not the test of choice in most circumstances. Viral serology, preferably with paired sera for antibody testing, is one of the options of investigation, though the availability of serological tests for rarer infections is limited. Antibody testing is readily available for arboviruses such as dengue, Japanese encephalitis, and chikungunya. It should be remembered that antibody testing may be negative in the very early stage of disease, and a second serum should always be obtained. The paired antibody profile in dengue patients can also help to differentiate primary from secondary infections. Another drawback in viral antibody testing is the potential cross reactivity between different viruses, which is common among flaviviruses for example. In terms of dengue diagnostics, detection of the viral NS1 antigen in serum is superior to IgM antibody detection in the first two to three days after disease onset, a window period where IgM is often negative [30]. A combined NS1 antigenaemia and IgM antibody testing is currently a common approach to initial diagnosis of dengue. The use of NS1 lateral flow assay kits may even allow point-of-care testing for dengue, and if the roles of urine and saliva NS1 are substantiated by further studies, this will facilitate the diagnosis of dengue in resource-limited settings [31, 32]. NAAT is another option for early diagnosis of dengue which also permits detection of co-infection by different serotypes (and with other arboviruses) and genotyping of the infecting viral strains [33–35]. Antibody detection (IgM and IgG) and NAAT can also be used for the diagnosis of chikungunya and Japanese encephalitis. Consultation with clinical virologists should be made in order to choose the most appropriate tests, especially when unusual viral agents are suspected.

Enteric syndromes

Important enteric infections encountered in returned travellers include travellers’ diarrhoea, enteric fever, and amoebiasis. Travellers’ diarrhoea is the commonest travel-related infection, affecting 10–40% of individuals travelling from developed to developing countries [36]. It is most often a bacterial infection caused by various diarrhoeagenic Escherichia coli (especially enterotoxigenic strains) and other enteorpathogens such as Campylobacter, Salmonella, and Shigella. Other pathogens include viruses (especially Norovirus, classically associated with passenger ships) and parasites (such as Cryptosporidium, Giardia, Cyclospora) as well as mixed infections. Most cases of travellers’ diarrhoea are self-limiting. Specific microbiological investigations may not be necessary in milder cases, but should be considered in those with more severe manifestations (such as fever, dysentery, bloody diarrhoea, cholera-like symptoms), persistent symptoms, or in immunocompromised individuals [36]. Specific requests for viral agents (antigen detection or NAAT for Rotavirus, NAAT for Norovirus) or special concentration and staining for protozoa (e.g. modified acid-fast staining for Cryptosporidium, Cyclospora, and Cystoisospora) are necessary if routine bacterial cultures are unremarkable.

Enteric fever in Hong Kong can be indigenous or imported. This is most commonly due to typhoid and paratyphoid fevers, caused by Salmonella enterica Typhi and Paratyphi (A, B, C) respectively. Laboratory diagnosis of typhoid and paratyphoid fevers remains problematic. A positive culture from blood or other specimens (stool, urine, bone marrow) provides the definitive diagnosis, though this is not always possible due to the kinetics of bacterial shedding and circulation at different sites or prior antibiotic usage, and that bone marrow culture (the most sensitive type of specimen) is not routinely performed in this setting. Serological testing has been an important adjunct to diagnosis. Unfortunately, the widely available Widal’s test is neither sensitive nor specific for this purpose, especially when only a single serum is tested. Newer serological assays such TUBEX TFTM (IDL Biotech, Sweden) and TyphidotTM (Reszon Diagnostics, Malaysia) have improvements over the Widal’s test, but their performance in the field has not been encouraging [37, 38]. Perhaps more promising in the future is the detection of Salmonella Typhi and Paratyphi in peripheral blood by NAAT [39]. This approach has the additional benefit of detecting other circulating pathogens as a panel (e.g. using multiplex PCR) for systemic febrile illnesses in travellers, such as Plasmodium, Babesia, Rickettsia, Orientia, and other pathogenic bacteria and viruses [40].

Entamoeba histolytica infection most often manifests as amoebic colitis; extraintestinal amoebiasis is less frequently seen and the usual presentation is amoebic liver abscess. Intestinal infection is mainly diagnosed by faecal microscopy. As in the case of other enteric parasites, multiple stool samples (usually at least three) should be examined. E. histolytica is morphologically identical to at least three other species of Entamoeba, viz. E. dispar, E. moshkovskii, and E. bangladeshi. Definitive identification is best achieved by molecular methods. Antigen detection assays are viable alternatives for the detection E. histolytica in stool [41]. Some of these kits can concurrently detect other enteric protozoa such as Giardia intestinalis and Cryptosporidium. Not all of the antigen detection assays, however, are able to differentiate E. histolytica and E. dispar. Microscopy is less useful in amoebic liver abscesses; amoebae are seen in only 20% or less of liver aspirates [42]. Stool samples of patients with amoebic liver abscesses have positive microscopy for E. histolytica in only 8–44% of the cases [42]. Antibody testing is helpful in the diagnosis of amoebic liver abscess; a positive serology is present in over 95% of the patients [41–43]. The major drawback of serology is that it cannot differentiate active from past infections with E. histolytica, and hence it is less useful for populations in endemic areas.

Other issues

Space does not permit further discussion on other travel-related infections. Two more recent issues may require attention from clinical and laboratory colleagues. Firstly, the transmission of epidemic-prone infectious diseases through travel, and in particular, air travel, has caused much concern in the past few years. Examples include avian influenza and other novel influenza viruses, MERS-CoV (and the SARS-CoV in 2003), Ebola virus and other agents of viral haemorrhagic fevers. Although these are relatively uncommon causes of infection in returned travellers (with the exception of pandemic influenza in 2009), transnational spread of these infections remains a constant threat to non-endemic countries and contingency plans for surveillance, screening, clinical management, infection control, and laboratory diagnostics must be formulated in anticipation [44].

Secondly, the importation of antibiotic-resistant bacteria from travellers has emerged as another menace [45–47]. The main microbes of concern include extended-spectrum beta-lactamase and carbapenemase-producing Enterobacteriaceae, multidrug-resistant Acinetobacter baumannii and Pseudomonas aeruginosa, methicillin-resistant Staphylococcus aureus, and vancomycin-resistant enterococci. These may be causing active infections or merely colonizing the travellers. Areas with the highest risks are the Indian subcontinent, Southeast Asia, and Africa [48–51]. Encounters with hospitals or medical facilities abroad could be due to medical problems that appeared during travel or being part of an increasingly popular medical tourism. Admission screening for multidrug-resistant organisms should be considered for patients with recent hospitalization in overseas facilities.

And not just for the microbiologists

Although the majority of tests for infective complications among the returned travellers are performed by the clinical microbiology laboratory, other specialties of clinical pathology may sometimes be involved in the investigation. The commonest scenario is the examination of peripheral blood films by haematology colleagues for malaria parasites. In addition to Plasmodium species, other pathogens that may be seen in the blood films include Babesia spp., Trypanosoma spp. (the African T. brucei gambiense and T. brucei rhodesiense, as well as the American T. cruzi), microfilariae, and the spirochaete bacterium Borrelia spp. The identification of Babesia spp. is sometimes mistaken for Plasmodium spp. because of the presence of intra-erythrocytic ring forms [52]. The travel history, especially when the destination is not a malaria-endemic region, should alert the microscopist to the possibility of babesiosis. Other morphological features that are suggestive of Babesia include the absence of stipplings and malarial pigments, presence of multiple pleomorphic rings within a single erythrocyte, and arrangement of the parasites in a Maltese cross appearance. Borrelia burgdorferi, the cause of Lyme disease, is possibly the best-known Borrelia species. However, B. burgdorferi is not normally seen in the peripheral blood smear. When spirochaetes are observed, the possibility of tick-borne or louse-borne relapsing fever should be considered. Tick-borne borrelioses are zoonoses caused by over 30 species of Borrelia and they have a global occurrence. Louse-borne relapsing fever, on the other hand, is restricted to countries in the Horn of Africa (Ethiopia, Eritrea, Somalia, and Sudan) nowadays. It is caused by Borrelia recurrentis which causes infection in humans only. The significance of louse-borne relapsing fever as a potential re-emerging infection is highlighted by the recent cases reported amongst asylum seekers who travelled to Europe from East Africa [53–56]. Definitive identification of Borrelia species requires molecular testing of the blood sample by sequencing of the 16S rRNA gene and other targets.

In addition to blood smear examination, the anatomical pathologist may encounter unexpected or unusual infections. Some of these infections may present as subacute or chronic lesions and may be seen in immigrants from foreign countries rather than recent travellers. Examples include colonic or liver biopsies with E. histolytica or Schistosoma; soft tissue or visceral lesions due to larval stages of nematodes (such as dirofilariasis or onchocerciasis) or cestodes (such as sparganosis, cysticercosis); skin biopsy in patients with cutaneous or mucocutaneous leishmaniasis; bone marrow, liver, spleen, or lymph node biopsies in patients with visceral leishmaniasis. Most of these are relatively rare in Hong Kong, but they may spice up our otherwise mundane everyday routines.


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Table 1. Illnesses in returned international travellers from GeoSentinel surveillance.


USA [6]

USA [7]

Canada [8]

Global centres [9]






Number of travellers studied





Systems involved





Gastrointestinal tract





Respiratory system










Fever or systemic illness





Neurological system





Genito-urinary tract and gynaecological system, sexually-transmitted infections






Table 2. Causes of fever in returned international travellers from GeoSentinel surveillance.


USA [6]

USA [7]

Canada [8]

Global centres [9]






Number of patients presenting with fever or systemic illness

























Enteric fever





Respiratory tract infections





Active tuberculosis





Urinary tract infection




















Hepatitis A and E





Acute HIV infection





Viral syndrome





Unspecified febrile illness





Epstein-Barr virus infection and infectious mononucleosis-like syndrome






Table 3. Exposure history that should raise suspicion to specific infections.


Potential infective complications

Sex, blood, body fluids, surgical operations, intravenous drug use

Hepatitis B and C, HIV infection, syphilis

Tattoos, body piercing, other body modification procedures

Hepatitis B and C, HIV infection, syphilis, non-tuberculous mycobacterial infections


Antibiotic-resistant bacteria (colonization or infection)

Ingestion of raw or undercooked food

Various foodborne infections including bacterial and viral gastroenteritis, protozoal and helminth infections, brucellosis, listeriosis, toxoplasmosis, hepatitis A and E


Histoplasmosis, coccidioidomycoses, other endemic mycoses,
cutaneous larva migrans, strongyloidiasis


Schistosomiasis (Katayama fever), leptospirosis

Arthropod bites

Various arthropod-borne infections, such as dengue, chikungunya, Zika virus infection, rickettsioses, relapsing fevers, malaria, babesiosis, leishmaniasis, trypanosomiasis, dirofilariasis

Dog, bat and other animal bites

Rabies, bat rabies, herpes B virus infection, bite wound infections

Animals and animal products

Hantaviruses, Lassa fever, Crimean-Congo haemorrhagic fevers, avian influenza, MERS, plague, rat-bite fevers, leptospirosis, Q fever, brucellosis, tularaemia, anthrax, psittacosis.

Note that the exact risk of specific infections depends not only on the exposure history, but the geographical location of exposures.


Table 4. Some common arboviruses and their typical clinical syndromes.

Common clinical syndromes

Common causative agents

Systemic febrile illness ± rash

Dengue virus, West Nile virus, Yellow fever virus, Zika virus, chikungunya virus

Arthralgia, arthritis ± rash

Chikungunya virus, Ross River virus, Barmah Forest virus, dengue virus, West Nile virus, O’nyong’nyong virus

Encephalitis or meningoencephalitis

Japanese encephalitis virus, Murray Valley encephalitis virus, St. Louis encephalitis virus, West Nile virus, tick-borne encephalitis virus, California encephalitis virus, La Crosse virus, Rift Valley fever virus, Toscana virus, Eastern equine encephalitis virus, Venezuelan equine encephalitis virus, Western equine encephalitis virus

Viral haemorrhagic fevers

Crimean-Congo haemorrhagic fever, Rift Valley fever virus, yellow fever virus, dengue virus, Kyasanur Forest disease virus, Omsk haemorrhagic fever, severe fever with thrombocytopenia syndrome virus

Note that the clinical syndromes and severity of disease caused by any single arbovirus can vary substantially. For example, many infections can either be subclinical or manifest as undifferentiated fever or produce a fulminant disease, such as viral haemorrhagic fever or meningoencephalitis. The likelihood of various potential pathogens depends on the exact geographical areas involved.

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Pathology of Non-Alcoholic Fatty Liver Disease

"Non-alcoholic fatty liver disease1" by Nephron - Own work. Licensed under CC BY-SA 3.0 via Wikimedia Commons -

Volume 10, Issue 1, January 2015

Dr. Anthony W.H. Chan

Associate Professor Department of Anatomical and Cellular Pathology, Prince of Wales Hospital, The Chinese University of Hong Kong


Non-alcoholic fatty liver disease (NAFLD) is a serious global health problem and associated with over-nutrition and its related metabolic risk factors including central obesity, glucose intolerance, dyslipidaemia and hypertension. It is the most common metabolic liver disease worldwide and its prevalence in most Asian countries is similar to that in the States, Europe and Australia. About 10-45% of Asian population have NAFLD. With “westernized” sedentary lifestyle, the prevalence of NAFLD in general urban population in the mainland China is about 15%. NAFLD is even more prevalent in Hong Kong. Our recent study demonstrated that NAFLD is found in 27.3% of Hong Kong Chinese adults by using proton-magnetic resonance spectroscopy. We further realized that 13.5% of Hong Kong Chinese adults newly develop NAFLD in 3-5 years. Both prevalence and incidence of NAFLD in Hong Kong are alarmingly high. Accurate diagnosis of NAFLD is crucial to allow prompt management of patients to reduce morbidity and mortality. NAFLD is composed of a full spectrum of conditions from steatosis to steatohepatitis (NASH) and cirrhosis. Various non-invasive tests, based on clinical, laboratory and radiological tests, have been developed to assess the degree of steatosis and fibrosis in NAFLD. However, liver biopsy remains the gold standard for characterizing liver histology in patients with NAFLD, and is recommended in patients with NAFLD at high-risk of steatohepati tis and advanced fibrosis (bridging fibrosis and cirrhosis), and concurrent chronic liver disease of other aetiology. This article reviews pathological features of NAFLD and highlights some practical points for our daily diagnostic work.

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Molecular Classification and Genetic Alterations of Diffuse Large B-cell Lymphoma

"Glass ochem" by Purpy Pupple - Own work. Licensed under CC BY-SA 3.0 via Wikimedia Commons -

Volume 9, Issue 2, July 2014

Dr CHOI Wai Lap

Department of Clinical Pathology Tuen Mun Hospital


Diffuse large B-cell lymphoma (DLBCL) is the commonest subtype of non-Hodgkin lymphoma, accounting for about 30% to 40% of newly diagnosed non-Hodgkin lymphoma worldwide and in Hong Kong. DLBCL is heterogeneous in clinical presentation, morphology, immunophenotype, cytogenetics and prognos is. In the WHO Classification of Tumours of the Haematopoietic and Lymphoid Tissues published in 2008, several specific clinicopathological entities of DLBCL have been recognized, while leaving the rest to DLBCL, not otherwise specified, which is by far the most prevalent entity among the large B-cell lymphomas. In the following discussion, the term DLBCL will be used interchangeably with DLBCL, not otherwise specified.

Gene expression profiling and molecular classification of DLBCL

Gene expression profiling (GEP) is the simultaneous measurement of the transcription levels of thousands of genes to their corresponding messenger RNAs (mRNAs). GEP can be achieved by various technologies including DNA microarray, serial analysis of gene expression (SAGE) and most recently next generation sequencing (RNA-Seq). Using DNA microarray technology on DLBCL, two distinct molecular subgroups were discovered based on the similarity of their gene expression pattern with a possible cell of origin (COO): the germinal centre B-cell-like (GCB-cell-like, or abbreviated as GCB) and the activated B-cell-like(ABC-like, or abbreviated as ABC). These molecular subgroups showed significantly different survival rates when treated with conventional cyclophosphamide, doxorubicin, vincristine and prednisolone (CHOP) chemotherapeutic regimen.

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Thyroid Dyshormonogenesis

Volume 9, Issue 1, January 2014

Dr YUEN Yuet Ping

Department of Chemical Pathology Prince of Wales Hospital


Congenital hypothyroidism (CH) is an important preventable cause of mental retardation. To prevent irreversible brain damages caused by hypothyroidism, sufficient doses of thyroxine should be started within a few weeks after birth.(1) Since neonates with CH have no obvious or minimal clinical manifestations, biochemical screening in the newborn period has become the best public health strategy for early detection of affected neonates. In Hong Kong, a territory-wide screening programme for CH was started in 1984.(2) Cord blood samples are collected immediately after birth for measurement of thyroid stimulating hormone (TSH) by a single laboratory dedicated for newborn screening. The incidence of CH in Hong Kong was reported to be 1 in 2,404, which is comparable to that in other populations.

Causes of congenital hypothyroidism

The aetiologies of CH are summarized in Table 1.(7) Approximately 80-85% of CH are caused by thyroid dysgenesis, which is a group of congenital disorders of thyroid gland development or migration. Affected patients may have complete thyroid gland aplasia, hypoplasia or ectopic glands. The large majority of thyroid dysgenesis cases are sporadic and only about 5% has a genetic basis.(8,9) Thyroid dyshormonogenesis describes a group of inherited disorders which affect the biochemical pathway of thyroid hormone synthesis. These disorders collectively account for 10-15% of CH cases. Approximately 1/4 of patients with CH in Hong Kong have some forms of thyroid dyshormonogenesis.(10) Some neonates detected by newborn screening program have transient instead of permanent CH. Although this subgroup of patients does not require life- long thyroid hormone replacement, early identification and treatment in early years of life is equally important.(11) The time course of recovery of the hypothalamic-pituitary-thyroid axis in patients with transient CH depends on the underlying cause. Although most of the transient CH are due to acquired conditions such as iodine deficiency or maternal transfer of autoantibodies, a few genetic causes have been described.

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Epidemiology of Cervical Human Papillomavirus Infection in Hong Kong: Implications on Preventative Strategy

Volume 8, Issue 2, July 2013

Prof. Paul KS Chan

Professor, Department of Microbiology, Prince of Wales Hospital The Chinese University of Hong Kong


The family Papillomaviridae is comprised of a large group of viruses found in many mammalian species. Infection with papillomaviruses can be asymptomatic or results in the development of benign or malignant neoplasia. Cervical cancer is the most important consequence, in terms of disease burden, of human papillomavirus (HPV) infection. To date, the genomic sequences of more than 150 HPV types have been characterized. Of these, more than 40 types can infect the female genital tract, and at least 15 types are epidemiologically linked to cervical cancer. Over the last few years, there has been a vast increase in using HPV DNA detection as an adjunctive or primary tool in cervica l cancer screening programmes. Primary prevention of cervical cancers associated with the two most common types (HPV16 and HPV18) can now be achieved by vaccination. A thorough understanding on the epidemiology of cervical HPV infection is essential to maximize the clinical benefits and cost-effectiveness of HPV-based diagnostic tests and vaccines. In this review, some key epidemiological features of HPV infection in Hong Kong are presented to assist the formulation of strategies applicable to Hong Kong.

Prevalence of infection

“How common is cervical HPV infection?” This is always the first question to ask before any advice on vaccination can be made. Local studies on “well-women” self-referred for cervical screening showed that the prevalence of cervical HPV infection (defined as having an HPV DNA-positive cervical scrape sample) was around 8% among adult women aged 26-45 years. 1,2 The figure “1 in 12” is recommended for public education. While the studies reported a significant association between number of life-time sexual partners and smoking exposure, the prevalence among those without any recognizable risk factors is high enough to recommend vaccination in general for everyone.

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Laboratory Testing For Anti-NMDAR In Autoimmune Encephalitis: The HSSA- Pathology Queensland Experience

Volume 8, Issue 1, January 2013

Bob Wilson MSc, FFS(RCPA), Kerri Prain, BSc, David Gillis, FRCPA FRACP FFS(RCPA) and Richard Wong GDM FRCPA FRACP FRCP.

Division of Immunology, Central Laboratory, HSSA-Pathology Queensland, Royal Brisbane and Women’s Hospitals, Herston, Brisbane, 4061, Australia.


The spectrum of antibodies against intracellular, cell surface and synaptic neuronal antigens has expanded rapidly in recent years. The antigenic targets include ion channels, receptors involved in neurotransmission across synapses and proteins associated with them. There are now more than twenty anti-neuronal antibodies detected in association with neurological diseases. These antibodies may be associated with underlying malignancies and are commonly referred to as paraneoplastic antibodies (PNAs). Many PNAs have been correlated with neurological manifestations and fall into two groups: those that are cytotoxic for example anti-purkinje cell antibody-1 (PCA-1/Yo) and anti-neuronal nuclear antibody-1 (ANNA-1/Hu); and others that have functional activity, such as anti-N-Methyl-D-Aspartate receptor (NMDAR) and anti-Voltage-gated potassium channel (VGKC). Recently there has been a marked interest in both anti-NMDAR and anti-VGKC antibodies as the presence of these antibodies identify patients with treatable neurological disease.

Anti-NMDAR was initially described as a paraneoplastic antibody associated with ovarian teratoma, with a characteristic clinical picture of encephalitis with psychiatric features, cognitive dysfunction and seizures. 1 2 Although subsequent case series have confirmed that ovarian teratoma is a frequent association, it has become apparent that many patients who are positive for anti-NMDAR do not have evidence of an associated malignancy.

There is also some evidence supporting the need for rapid identification of anti-NMDAR. Patients who are diagnosed and treated with immuno-suppressive/immunomodulatory therapy within 40 days of disease onset, have been reported to have a better clinical outcome than those treated after 40 days.

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Virtual Electron Microscopy – update after one year of routine use

Volume 7, Issue 2, July 2012

Dr. King Chung Lee

Consultant Pathologist, St. Paul’s Hospital

Honorary Consultant, Queen Elizabeth Hospital


Virtual microscopy using whole slide scanning has become increasingly popular in quality assurance program, teaching of pathologists and undergraduates and reproducibility studies 1-2. This concept was first extended to electron microscope (EM) about a year ago 3. This is made possible by two discoveries. Firstly, a free software component capable of stitching sequential pictures into a virtual slide that can be read by another free software. Secondly, an EM function capable of capturing up to 500 images covering a specified area automatically. Because of the simplicity acceptable degree of user intervention during the process and unsurpassed advantages over the conventional method, it was quickly adopted in routine renal biopsy diagnostic EM service and become the only routine service virtual microscopy system in Hong Kong. For those who are interested, you can download a sample from and view it by Aperio ImageScope software, which was available for free download from the Aperio website,

Summary of implementation

In the last year, over 400 renal biopsy cases were handled in our EM laboratory and over 1000 virtual ultrathin sections were generated (average 2.7 sections per case). The average EM time used in capturing is about 50 minutes per section. The average computing time is 40 minutes per section. The virtual ultrathin sections were either directly interpreted by Pathologists or screened and annotated by our EM tec hnologist before passing to Pathologists.

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Chronic lymphocytic leukaemia – the role of conventional and molecular cytogenetics

Volume 7, Issue 1, January 2012

Dr W. S. Wong

Associate Consultant, Department of Pathology, Queen Elizabeth Hospital

Dr. K.F. Wong Chief of Service, Department of Pathology, Queen Elizabeth Hospital


Chronic lymphocytic leukaemia (CLL) is the commonest chronic lymphoproliferative disorder of mature B-cells and affects mainly elderly. It is characterized by the presence of≥5x109/L monoclonal and often CD5+CD23+B-lymphocytes in peripheral blood. Haematogists usually have no problem in reaching the diagnosisas the majority of the cases have classical morphological and immunophenotypic features; however, it is an extremely heterogeneous disease clinically with highly variable clinical course.

Some patients are asymptomatic and do not require treatment while others progress early and require aggressive treatment. A number of clinical and biological parameters as well as molecular biomarkers have been demonstrated to predict the clinical outcome of the disease [1]. Molecular diagnostics has greatly improved the understanding of pathogenesis of CLL by pointing to candidate genes, for example 17p13 deletion, a common genetic aberration seen in CLL, corresponds to a tumour suppressor gene TP53. Moreover, different genetic subgroups have been shown to be associated with different prognosis: poor survival in 17p or 11q deletions and better survival in trisomy 12, normal karyotype or 13q deletion with the best survival found in isolated 13q deletion [2]. Cytogenetic studies may also help in the diagnosis of problem cases with atypical morphology or immunophenotypic profiles.

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Laboratory Role in Toxicology: From Diagnostic to Theranostic

Volume 6, Issue 1, July 2011

Dr W. T. Poon

Associate Consultant, Department of Pathology, Princess Margaret Hospital


Toxicology analysis involves detection, identification and measurement of foreign compounds and their metabolites in biological and other specimens. It plays a useful role in them a nagement of poisoned patients when the diagnosis is in doubt, the administration of antidotes or protective agents is contemplated, or the use of active elimination therapy is being considered. As the scope and complexity of clinical toxicology continues to increase, continuing effort is required for the laboratory to expand its diagnostic capability and coverage. Apart from patient care, identification of a lethal or emerging toxin also serves to provide useful information for toxico-vigilance of potential public health threats and helps to prevent further poisonings. Some common and important herbal poisonings that have occurred in Hong Kong would be discussed as examples.

Apart from poisoning diagnosis, laboratory test can be used to predict the risk of adverse event to drugs in individual patients. It is now feasible to identify the genetic basis for certain toxic side effects and drugs will then be prescribed only to those who are not genetically at risk. Theranostic is the term used to describe the process of diagnostic therapy for individual patients - to test them for possible reaction to taking a new medication and to tailor a treatment for them based on the test results. In Hong Kong, genotyping for human lymphocyte HLA-B*1502 is recommended prior to administering carbamazepine for patients in order to avoid the development of Stevens-Johnson syndrome. An increasing number of pharmacogenetic tests are now available for clinical application. The criteria required of a pharmacogenetic test to make it useful for local application would be discussed.

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