Topic Update

Antimicrobial Resistance – The Challenge Ahead

Volume 3, Issue 3, December 2008

IP, Margaret

Professor, Department of Microbiology, The Chinese University of Hong Kong

Introduction - Global Concerns and Challenges

Throughout the world, healthcare professionals are concerned at the growing problem of antimicrobial resistance and the global emergence of multi-drug-resistant organisms (MDROs) in the health care setting and in the community. The use of penicillin in early 1940s on a wider scale, and the subsequent newly-introduced antimicrobials, was soon followed by the emergence of resistantmicrobes. Some of the seresistant organisms in relation to the introduction of antimicrobial agents are listed in Table 1. The prevalence of MDROs has increased dramatically worldwide during the last decades [1]. Most alarmingly are in infections caused by MDROs whereby resistance has developed for virtually all currently available drugs and no effective therapies are available. This is compromised by the lack of new discovery of potent classes of antimicrobials in recent time, with shortfalls in funding for the development of new drugs which often relies on interests andsupport from pharmaceutical industries.

In a wider context, this threat to treatment and control of infectious diseases ranges beyond that of common bacterial pathogens. Drug resistance to infectious agents causing tuberculosis, malaria, pandemics of HIV, and in fluenza including H5N1, is also increasingly recognized, affecting treatment and hampering their containment. Antimicrobial resistance makes infections more difficult to treat; prolongs duration and increases severity of illness. This lengthens the period of infectivity, enhances spread and poses the added challenge to infection control. In effect, this translates to increases in direct and indirect health care costs and a higher morbidity and mortality.

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Immunogenetics: MHC and non-MHC

Volume 3, Issue 2, August 2008

KWOK, SY Janette

Associate Consultant, Division of Transplantation and Immunogenetics, Department of Pathology and Clinical Biochemistry, Queen Mary Hospital, Hong Kong


Immunogenetics is the study of the immune response in relation to genetic makeup. The immune system protects the vertebrates from all potential harmful infectious agents such as bacteria, virus, fungi and parasites. The growing understanding of the immune system has influenced diversified biomedical disciplines, and is playing a significant role in the study and treatment of many diseases such as cancer and autoimmune conditions.

The launch of immunogenetics could be traced back to the demonstration of Mendelian inheritance of the human ABO blood grouping in 1910. Major developments leading to the emergence of immunogenetics were accounted by the rediscovery of allograft reactions during the Second World War and the formulation of the immunological theory of a llograft reaction and the clonal selection hypothesis by Burnett in 1959.

The field of immunogenetics has exploded during the last 25 years, thus expanding the range of concepts with the potential to improve the field of medicine with regard to transplantation, immunotherapy and the study of immune polymorphisms. Immunogenetics has poised on the brink of a new era, driven by the development of new technologies and shaped by fundamental discoveries about the mech anisms that regulate interactions between the adaptive and innate immune systems. Technologies are developed to revolutionize genetic analysis and providing new strategies for elucidating the genetic mechanisms that influence immune responsiveness and autoimmunity.

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The Autopsy Interview

Volume 3, Issue 1, April 2008

BEH, SL Philip 

Associate Professor (Forensic Pathology), Department of Pathology, Li Ka Shing Faculty of Medicine The University of Hong Kong

The autopsyinterview is an anomaly which arose in Hong Kong at a time when the Coroner did not speak the local language and the police officer investigating the death had very little medical knowledge. The hospital anatomical pathologists and forensic pathologists were therefore delegated the task of obtaining medical information from the Cantonese speaking next-of-kin which may be related to the death and providing a written English summary for the Coroner. The legal authority on the decision to autopsy or to waive an autopsy had always rested with the Coroner. However, the practical decisions were effectively made by the pathologists based on the available me dical information or the lack of information. 

In the context of this background, the autopsy interview developed in Hong Kong. It was a relatively easy exercise for the pathologist. The next-of-kin of the deceased attended interviews with the pathologist in the presence of a police officer. The pathologist asked for medical history and details of the circumstances of the death. The next-of-kin in the 70’s and 80’s were told an autopsy was to be performed as it was a legal requirement. In the rare circum stances where a request was made to waive the autopsy, the pathologist had to be convinced of the existence of a probable cause of death. Where none was evident, the application for waiver was denied and the opportunity to make the written waiver application denied too. The autopsy was again duly ordered by the Coroner on the basis that if the pathologist was unable to provide a cause of death, the cause of death was unknown and had to be established.

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Impact of Molecular Methods in the Diagnosis of Lymphomas

Volume 2, Issue 2, July 2007


BSc(Hons), MBBS, FHKCPath, FRCPA, Associate Consultant, Department of Pathology, Queen Elizabeth Hospital 

Overview of conventional molecular techniques in lymphomas

The use of molecular techniques in hematolymphoid pathology started with cloning of the immunoglobulin and T cell receptor genes. [1] This is followed by the cloning of a number of translocation breakpoints in some common lymphoma types.[2-4] Assay of chromosomal breakpoints not only helps in confirming a clonal proliferation but also prov ides an indication of the type of lymphoma. The main application is to establish clonality or lineage of a lymphoid proliferation. 

Southern blot analysis was the standard technique in molecular studies. The advent of the polymerase chain reaction (PCR) provides an alternative technical approach to Southern blot analysis, allowing molecular studies to be performed in many diagnostic laboratories. PCR technique is technically simpler, has a much faster turnaround time, requires a much smaller quantity of clinical materials, and can be performed on archival, formalin-fixed, paraffin-embedded samples (Figure 1).[5] Advances in PCR techniques allow accurate quantitation of the template (real time PCR) and make it possible to use RNA as the starting material (revers transcriptase PCR).[6] Fluorescence in situ hybridization (FISH) utilizes oligonucleotide probes to localize specific chromosomal segment so that translocation can be visualized under the fluorescence microscope.[7] This “interphase cytogenetics” technique obvi ates the need of fresh specimen and cell culture and revolutionizes the traditional cytogenetics.[8] Although FISH may not be as sensitive as PCR-based methods, it is superior in detecting complex karyotypic abnormalities involving multiple fusion partners and has lower false negative rates in detection of chromosomal translocations in some lymphoma types.

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Recent perspectives in glucose-6-phosphate dehydrogenase (G6PD) deficiency

Volume 2, Issue 1, March 2007

Dr Edmond S K Ma

MD (HK), FRCPath, FHKAM (Pathology)

Department of Pathology, Hong Kong Sanatorium & Hospital


G6PD catalyzes the conversion of glucose-6-phosphate (G6P) to 6-phosphogluconate concurrent with reduction of NADP to NADPH, which in turn acts through glutathione and catalase pathways to detoxify hydrogen peroxide, thus counteracting oxidative stress to the cell. In the body, red cells are most susceptible to oxidative damage because oxygen radicals are generated continuously as haemoglobin cycles from deoxygenated to oxygenated forms, as well as being readily exposed to exogenous oxidizing agents present in the blood. Hence G6PD deficiency is a prototype cause of haemolytic anaemia due to intrinsic red cell enzyme abnormality.

Deficiency of G6PD enzyme, an X-linked recessive disorder and the commonest inheritedenzymopathy in humans, is prevalent in Southern China. In Hong Kong, the prevalence of G6PD deficiency is 4.47% for males and 0.27% for females based on data generated from neonatal screening. Clinical manifestations of G6PD deficiency range from neonatal jaundice and episodic haem olysis precipitated by drugs, fava beans and infection, to the more severe cases of chronic non-spherocytic haemolytic anemia (CNSHA) associated with Class I G6PD variants. Occasionally, neonatal jaundice if severe enough may cause death or permanent neurological damage. Furthermore, patients with CNSHA may require intermittent blood transfusions. While more than 400 G6PD variants have been characterized using biochemical parameters, only around 129 variants have been deciphered at the molecular level [1]. Similar to inherited globin disorders, the spectrum of G6PD mutations is different between ethnic groups. The common G6PD variants previously reported in the Chinese, such as G6PD Canton (nt 1376 G→T), Kaiping (nt 1388 G→A) and Gaohe (nt 95 A→G) are associated with mild to moderate clinical severity, and are categorized as Class II – III variants.

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Diagnosing Wilson disease in the post-genomic era

Volume 1, Issue 3, November 2006

Dr Ching-Wan LAM, MBChB(CUHK), PhD(CUHK), FRCPA, FHKAM(Pathology)

Associate Professor, Department of Chemical Pathology, The Chinese University of Hong Kong, Prince of Wales Hospital


Resident Specialist, Division of Clinical Biochemistry, Department of Pathology, Queen Mary Hospital

Wilson disease (WD) (MIM # 277900) is an autosomal recessive disorder of copper transport. Clinical manifestations of WD vary widely. The age of onset ranges from three to more than 50 years of age. The initial onset of symptoms can be hepatic, neurological, psychiatric or as an acute haemolytic crisis. The prevalence of WD has been estimated to be approximately 1 in 30,000 in the Caucasian population. Although the prevalence of WD in the Hong Kong Chinese has not been investigated, based on our local experiences, WD is common and is the most common inherited liver disease in Hong Kong. In addition, investigators in Japan have suggested that the prevalence of WD in Asians might be higher than that reported in the U.S. and Europe.

In 1993, the gene responsible for WD was identified, and the gene product was predicted to be a copper binding P-type adenosine triphosphatase. The ATP7B gene, which consists of 21 exons, spans a genomic region of about 80kb and encodes a protein of 1465 amino acids. ATP7B is expressed primarily in the liver and kidney. The protein plays a dual function in the hepatocytes. One role is biosynthetic, delivering copper to apocaeruloplasm in within the Golginetwork. The other role of ATP7B is to transportexcess copper out of the cell and into the bilecanaliculus for subsequent excretion from the body with bile. ATP7B is localized in the trans-Golgi network of hepatocytes under low copper conditions, redistributes to cytoplasmic vesicles when cells are exposed to elevated copper levels, and then recycles back to the trans-Golgi network when copper is removed. Therefore, an ATP7B mutant will result in a reduction in the rate of incorporation of copper in to apocaeruloplasmin or a reduction in biliary excretion of copper, or both. For example, a WD mutant protein, R778L, has recently been shown to be extensively mislocalized, presumably to the endoplasmicreticulum. Defective biliary excretion leads to accumulation of copper in the liver with progressive liver damage and subsequent copper overflow to the brain, causing loss of coordination and involuntary moments. Deposition in the cornea produces Kayser-Fleischer rings, and accumulation in the other sites causes renal tubular damage, cardiomyopathy, hypoparathyroidism osteoporosis, and arthropathy, etc.

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The Roles and Expectations of the Specialist in Clinical Microbiology and Infection

Volume 1, Issue 2, July 2006

Raymond WH Yung

Infection Control Branch, Centre for Health Protection, Department of Health & Infectious Disease Control Training Centre, Hospital Authority

In the past three years, we have witnessed the revived recognition of the importance of the specialty of Clinical Microbiology and Infection. The SARS outbreak reminded the medical profession that the line of defence which we had built against infection was still not robust enough to handle major outbreaks. Three reports were published after the outbreak. They outlined the deficiencies found and recommended what should be done for the future.1-3 Many of the recommendations are relevant and will impact on the future development of the specialty of Clinical Microbiology and Infection. Let me quote from the report of the Hospital Authority Review Panel, Paragraph 2.40: ‘… to control an outbreak of an unknown infectious disease … rapid implementation of measures to prevent spread and control the impact are vital, viz. 1) effective surveillance, data collection and sharing; 2) high level of awareness and implementation of effective infection control measures; 3) rapid and comprehensive contact tracing; and 4) timely declaration and enforcement of isolation and quarantine measures’.

Other than infection control is sues, the SARS outbreak further reinforced the role of the Clinical Microbiologist in several aspects. Firstly, the clinical microbiology service supports not only clinical care of individual infected patients, but also supports the protection of the health of the general population. Besides possessing strong command in the science of clinical microbiology, solid knowledge in epidemiology and crisis management to facilitate investigation and control of outbreaks is al so essential. In the context of provision of the daily service, the Clinical Microbiologist has a consultative role in managing patients with infectious diseases, from the arrival at a presumptive diagnosis based on clinical and ancillary laboratory/radiological findings, to advising on the appropriate diagnostic microbiological investigations, to interpreting results based on clinical and epidemiological information, and to recommendation of management options. Apart from attending to the individual patient, the Clinical Microbiologist, as the infection control specialist, undertakes to decisively direct and advise on the consequent infection control issues, both within the institution and in the community. Synthesis of epidemiological data with knowledge of the infectious agent, such as transmission route, incubation period, duration of infectiousness and susceptibility to disinfection, will enable the microbiologist to recommend specific measures to define at risk groups for contact tracing and to implement measures to prevent and control further spread of the infection to ensure public health.

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Laboratory diagnosis of human disease caused by H5N1 influenza virus

Volume 1, Issue 1, March 2006

JSM Peiris & Wilina Lim

Department of Microbiology, The University of Hong Kong & Virology Division, Public Health Laboratory Services Branch, Centre for Health Protection, Department of Health, Hong Kong SAR 

Avian influenza A subtype H5N1 is endemic in poultry across south-east Asia and continues to cause zoonotic disease in humans. So far, transmission of virus from avian to humans appears very inefficient and sustained transmission from human-to-human has not occurred. However, with the continued opportunity for human exposure over an ever increasing geographic range, it is possible (though not inevitable) that H5N1 virus may acquire the ability to transmit efficiently from human-to-human, leading to a pandemic.

Human disease caused by H5N1 influenza virus typically presents either as a rapidly progressing viral pneumonia, often with evidence of marked lymphopenia, leucopenia and mild to moderate liver dysfunction. Some patients also have evidence of diarrhea and other gastro-intestinal manifestations. The disease may progress to acute respiratory distress syndrome (ARDS), multiple organ dysfunction and death (1-5). However, in the individual patient, it is not possible to make a reliable diagnosis of avian influenza H5N1 purely on clinical grounds. Furthermore, some patients may manifest a milder course of the disease presenting merely as a self-limited influenza-like illness. Virological diagnosis is therefore essential.

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