Vitamin B₁₂ deficiency is a common condition affecting the elderly and tends to increase with age. Acquirement of vitamin B₁₂ into our body for cell metabolism involves dietary intake of vitamin B₁₂–enriched foods and the absorption of vitamin B₁₂ into our body for utilisation. The main dietary sources of vitamin B₁₂ are animal products because animals obtain vitamin B₁₂ through microbial symbiosis. The subsequent release of vitamin B₁₂ from food for absorption into the body is complex and requires intact function of stomach, pancreas, and ileum. Pathophysiological changes, multiple co-morbidities, coupled with multiple drug intake, and increasing dependency associated with ageing can lead to malnutrition due to inadequate intake and malabsorption of vitamin B₁₂, resulting in deficiency. Vitamin B₁₂ is essential for the normal metabolism and functioning of all cells in the body. Vitamin B₁₂ deficiency can pose significant adverse effects to organ systems with high cell turnover and metabolism like the bone marrow, gastro-intestinal tract, and brain. Fortunately, vitamin B₁₂ deficiency can be readily treated by vitamin B₁₂ replacement. Nevertheless, prompt diagnosis and treatment are required to prevent extensive and irreversible damage to the body.

In general, vitamin B₁₂ level declines with age and therefore prevalence of vitamin B₁₂ deficiency increases with age.1 Studies have shown that prevalence of vitamin B₁₂ deficiency among elderly can range between 5% and 40% depending on the definition of vitamin B₁₂ deficiency used.1 2 3 4 5 6 7 Many studies have used serum vitamin B₁₂ level with or without additional tests for its metabolites like homocysteine and methylmalonic acid (MMA) to estimate the prevalence of vitamin B₁₂ in the population. The most frequent serum vitamin B₁₂ cut-off to diagnose vitamin B₁₂ deficiency is 150 pmol/L (203 pg/mL). Using this serum vitamin B₁₂ cut-off alone, the prevalence of vitamin B₁₂ deficiency is estimated to be in the range of 5% to 15%.3 4 5 6 However, when higher serum vitamin B₁₂ cut-off at 258 pmol/L (350 pg/mL) or using elevated serum homocysteine or MMA level in addition to a low or low-to-normal serum vitamin B₁₂ level to diagnose vitamin B₁₂ deficiency, the prevalence of deficiency increases to 40.5%.1 3 Also, the prevalence of vitamin B₁₂ deficiency appears to increase with age among the elderly population.4 5 Furthermore, reports have indicated that institutionalised elderly with multiple co-morbidities and with increasing dependency are more prone to vitamin B₁₂ deficiency than non-institutionalised (free-living) elderly. In such individuals, the prevalence of vitamin B₁₂ deficiency has been reported to reach 30% to 40%.8 9 In our unpublished study on 2096 institutionalised elderly residents aged >65 years, the prevalence of serum vitamin B₁₂ level of <150 pmol/L was 34.9%, whilst in another local study conducted on non-institutionalised (free-living) elderly residents aged over 70 years, the prevalence of vitamin B₁₂ level of <140 pmol/L was only 6.6%.7

There is no precise or ‘gold standard’ test to diagnose vitamin B₁₂ deficiency. The diagnosis is usually based on identifying a low level of serum vitamin B₁₂ with clinical evidence of deficiency, which responds to vitamin B₁₂ replacement therapy. When there is a clinical suspicion of vitamin B₁₂ deficiency, the initial laboratory assessment includes serum vitamin B₁₂ levels, complete blood count, and blood film examination.10 11 12 Although the blood picture and classical finding of vitamin B₁₂ is megaloblastic anaemia, often times this is not seen especially in mild cases of vitamin B₁₂ deficiency. The investigations for vitamin B₁₂ deficiency are traditionally recommended for patients with macrocytosis, but macrocytosis with or without anaemia is neither specific nor sensitive to confirm the diagnosis.10 11 12 The reason for this is that macrocytosis can also be found in other conditions like folate deficiency and myelodysplastic disorders, and up to 84% of cases would be missed if macrocytosis is used as the only parameter to screen for vitamin B₁₂ deficiency.13

Tests to measure and quantify serum vitamin B₁₂ levels in the body are readily available and inexpensive. However, the screening test has some limitations and drawbacks. The main drawback is that there is no universally accepted serum vitamin B₁₂ cut-off to define deficiency although the value of <150 pmol/L (200 pg/mL) is often used, and at this serum vitamin B₁₂ level or below, metabolites like serum homocysteine, serum and urine MMA, become elevated. The World Health Organization has suggested to use this cut-off to define vitamin B₁₂ deficiency since the year 2008.14 However, some have argued that the cut-off value of 150 pmol/L is too low and inevitably does not reflect a sufficient level of vitamin B₁₂ in the body, and more so the clinical symptoms of vitamin B₁₂ deficiency like neurological symptoms can occur even if serum vitamin B₁₂ is above 150 pmol/L. Thus, a higher cut-off value of 220 to 258 pmol/L (298-350 pg/mL) based on more sensitive indicators of vitamin B₁₂ status like elevated serum homocysteine and MMA levels has been suggested.3 15 It should be noted that not all the vitamin B₁₂ circulating in the blood is in metabolically active form and a low serum vitamin B₁₂ level is not necessarily equivalent to tissue deficiency. The falsely low vitamin B₁₂ level can be related to the disturbance in vitamin B₁₂ metabolism but may not be associated with any tissue vitamin B₁₂ deficiency. Such situations can occur in people with folate deficiency, multiple myeloma, and transcobalamin I deficiency.10 11 12 On the other hand, falsely normal serum vitamin B₁₂ level may occur in the presence of liver disease, myeloproliferative disorder, congenital transcobalamin II deficiency, and intestinal bacterial overgrowth.10 11 12

When serum vitamin B₁₂ results are normal but still the clinical suspicion of deficiency exists, additional ‘confirmatory testing’ may help to identify vitamin B₁₂ deficiency. There is compensatory elevation of homocysteine and MMA levels preceding the drop in serum vitamin B₁₂ level and these are regarded as more sensitive indicators of vitamin B₁₂ deficiency than just low serum vitamin B₁₂ level.11 12 16 17 Elevated serum homocysteine and MMA level (>3 standard deviations above the mean in normal subjects) has a sensitivity of 95.9% and 98.4%, respectively to diagnose vitamin B₁₂ deficiency.16 However, the reference intervals for serum MMA and homocysteine are variable among different laboratories. Serum MMA of 100 to 750 nmol/L, urine MMA of 1 to 4 nmol/L, and serum homocysteine of 6 to 29 µmol/L are the reference ranges for most methods.10 If the normalisation of elevated serum homocysteine and MMA levels in response to vitamin B₁₂ replacement therapy is used as a diagnosis of deficiency, up to 50% of patients may be missed when the diagnosis is based on low vitamin B₁₂ level (150 pmol/L) alone.18 19 Rise in homocysteine level before increase in MMA is an early indicator of vitamin B₁₂ deficiency. However, this is less specific than elevated MMA level for vitamin B₁₂ deficiency, since such elevated homocysteine levels can occur even in vitamin B₆ and folate deficiency states. Both homocysteine and MMA levels can be elevated in renal insufficiency, hypovolaemia, and inherited metabolic defects.12 Although elevated homocysteine and MMA levels can aid in the diagnosis of vitamin B₁₂ deficiency in people with ‘normal’ serum vitamin B₁₂ levels, there are concerns about these metabolite assays. Some have reported that serum MMA and homocysteine levels increase with age and the prevalence of elevated MMA and homocysteine levels is higher than the prevalence of low vitamin B₁₂ or clinically evident vitamin B₁₂ deficiency in the elderly.19 20 21 22 In this regard, using the assay for metabolites alone may result in overdiagnosis and overtreatment. The rationale for these findings is uncertain and some have suggested that it may be related to the increased prevalence of subclinical vitamin B₁₂ deficiency in the elderly. Moreover, these add to the controversies about whether to use metabolite estimation as the initial test to diagnose vitamin B₁₂ deficiency. Besides, other important considerations are that they are more expensive, not readily available, and reference intervals are not standardised. Currently, the initial test for vitamin B₁₂ deficiency is to assess serum vitamin B₁₂ levels, and only when there is low normal vitamin B₁₂ level, metabolite assay is most often suggested.11 12 However, the consensus for vitamin B₁₂ threshold levels for ordering the additional tests has not yet been reached.

In addition to elevation in homocysteine and MMA levels, a decrease in serum holotranscobalamin level is also considered an early marker for vitamin B₁₂ deficiency. Holotranscobalamin is composed of vitamin B₁₂ attached to a transport protein, transcobalamin II. It is a biologically active fraction of vitamin B₁₂ that can be readily taken up by all cells and represents only 6% to 20% of total serum vitamin B₁₂.23 In vitamin B₁₂ deficiency, serum level of holotranscobalamin decreases even before elevation in homocysteine and MMA levels occurs.24 It has been shown that holotranscobalamin is the most sensitive marker for vitamin B₁₂ deficiency, followed by MMA.23 25 Like homocysteine and MMA, holotranscobalamin cannot be tested in renal patients as its level increases in renal impairment.23 Furthermore, higher cost and lesser availability than homocysteine and MMA testing make it difficult to acquire wide clinical acceptance.

As we know elderly people are particularly at risk of vitamin B₁₂ deficiency. The main aetiologies can be divided under two main categories: inadequate dietary intake and impaired absorption of vitamin B₁₂ (Table 1).

It is believed that in developed countries, the most common cause for vitamin B₁₂ deficiency in the elderly is inadequate dietary intake.1 15 However, studies have shown that this is far from real. A French study showed that among 172 elderly patients with vitamin B₁₂ deficiency, only 2% accounted for inadequate intake,26 while in a hospital-based Chinese study on 52 patients, only 3.8% (median age, 73.5 years) with megaloblastic anaemia (98% had vitamin B₁₂ deficiency) had inadequate dietary intake.27 However, this can be a problem in strict vegans because animal products are the only dietary source of vitamin B₁₂. Usually, 2 to 3 mg of vitamin B₁₂ reserves are stored in the body primarily in the liver, and our daily requirement of vitamin B₁₂ is only about 2 to 3 µg. Thus, even with vegan diets, deficiency generally takes several years to develop. According to a local study on 119 older Chinese vegetarian women, the prevalence of deficiency was 42%.28 Besides, factors like poor health conditions, especially in those living in institutions, lead to inadequate nutritional intake and vitamin B₁₂ deficiency.

Often, vitamin B₁₂ deficiency can be seen even among the elderly consuming meat and animal proteins and this is because of malabsorption. Vitamin B₁₂ in animal food is bound to a protein, and after ingestion, it is broken down in the stomach by pepsin and hydrochloric acid to release free vitamin B₁₂ (Fig 129). The free vitamin B₁₂ is then bound to R-protein (transcobalamin I) found in saliva and gastric juice. The vitamin B₁₂-R-protein complex is also secreted in bile from the enterohepatic circulation. These complexes are then degraded by pancreatic enzyme to release free vitamin B₁₂ in the duodenum. The free vitamin B₁₂ is then bound to intrinsic factor secreted by the gastric parietal cells, and then they travel undisturbed until the distal 80 cm of ileum where they bind to mucosal cell receptors. Subsequently, vitamin B₁₂ is carried by transport protein, transcobalamin, via the portal system to all cells in the body for utilisation. About 60% of vitamin B₁₂ from food is absorbed through this pathway, and any pathophysiological changes in stomach, pancreas, and intestine result in disturbance of vitamin B₁₂ absorption. Food-cobalamin (vitamin B₁₂) malabsorption, first described by Carmel in 1995,30 is the most common cause of vitamin B₁₂ deficiency in the elderly and accounts for about 40% to 70% of cases.26 29 31 It is characterised by the inability to release vitamin B₁₂ from food or from its binding protein and thus, preventing vitamin B₁₂ from being taken up by intrinsic factor for absorption. It is defined by vitamin B₁₂ deficiency in the presence of sufficient dietary vitamin B₁₂ intake, negative Schilling test, and lack of anti-intrinsic factor antibodies.30 Clinically, it is diagnosed by exclusion of other disorders or factors causing vitamin B₁₂ deficiency. It can be corrected simply with oral vitamin B₁₂ supplement since free vitamin B₁₂ absorption is not affected.31 Any process that interferes with the release of free vitamin B₁₂, such as decreased production of gastric acid and pepsin for releasing vitamin B₁₂ from food, and impaired secretion of pancreatic enzyme for releasing vitamin B₁₂ from vitamin B₁₂-R-protein complex, can lead to malabsorption. Atrophic gastritis is the main cause of food-cobalamin malabsorption in the elderly. In the stomach, hypochlorhydria associated with atrophic gastritis interferes with vitamin B₁₂ release from the food and causes intestinal bacterial overgrowth to compete for vitamin B₁₂ uptake, resulting in a decline in vitamin B₁₂ in the body. The prevalence of atrophic gastritis in the elderly ranges from 20% to 50% and generally increases with age.26 32 According to Framingham Heart Study, the prevalence in age-group of 60 to 69 years was 24% and increased to 37% in people aged >80 years.33 Chronic Helicobacter pylori infection is strongly associated with atrophic gastritis,34 35 and a study reported that H pylori was found in 56% of people with vitamin B₁₂ deficiency.35 Other causes of food-cobalamin malabsorption include long-term consumption of proton pump inhibitors,36 histamine H₂ blockers,36 chronic alcohol consumption, gastric bypass surgery, and pancreatic insufficiency in patients with alcohol abuse and cystic fibrosis. Food-cobalamin malabsorption often produces a slow, progressive depletion of vitamin B₁₂. Clinical manifestations tend to be subtle and mild,2 although progression to more severe form, like pernicious anaemia (PA), can still occur in a minority of patients.26

Pernicious anaemia, a result of autoimmune atrophic gastritis (type A atrophic gastritis), is most often diagnosed in the elderly. Earlier studies suggested that PA was restricted to Northern Europeans, but subsequent studies indicate that PA affects virtually all ethnic groups.37 Pernicious anaemia was considered a classical cause of vitamin B₁₂ deficiency before food-cobalamin malabsorption was described, and accounted for 15% to 25% of vitamin B₁₂ deficiency in the elderly in studies.9 In a local study on 296 Chinese patients, definite PA was diagnosed in 61% of patients having megaloblastic anaemia with vitamin B₁₂ or folate deficiency.38 Pernicious anaemia is characterised by destruction of gastric mucosa, especially fundal mucosa, primarily by a cell-mediated mechanism.39 There is progressive destruction and eventual loss of intrinsic factor producing gastric parietal cells. Moreover, auto-antibodies in gastric juices bind and block the vitamin B₁₂–binding site of intrinsic factor and prevents the uptake of vitamin B₁₂. The end result is gastric atrophy and depletion of intrinsic factor leading to poor absorption of food-bound, free, and biliary vitamin B₁₂.2 Malabsorption is more complete and severe in PA compared to food-cobalamin malabsorption which is more partial in nature,2 and so the manifestations are more overt and severe in PA. Two antibodies, anti-parietal cell antibody and anti-intrinsic factor antibody, have been described in PA. Anti-parietal cell antibody is more sensitive (90%) but less specific (50%) for diagnosis of PA as it can also be found in other autoimmune diseases.29 39 On the other hand, anti-intrinsic factor antibody is less sensitive (50%) but more specific (98%), and its presence is almost diagnostic of PA.29 39 Schilling test, traditionally used to diagnose intrinsic factor–related malabsorption, is now rarely performed. Although PA is associated with excess risk of gastric carcinoma and gastric carcinoid tumour,40 the benefit of endoscopic surveillance has still not been established. Once the patient is diagnosed with PA, single endoscopic screening for gastric cancer or carcinoid tumours is recommended, but subsequent routine endoscopic surveillance recommendation is inconclusive.41

In the elderly, long-term use of medications for co-morbidities can interfere or reduce vitamin B₁₂ absorption. These include proton pump inhibitors and histamine H₂ blockers, which suppress gastric acid secretion and prevent release of vitamin B₁₂ from food.42 Other drugs like metformin reduces intestinal availability of free calcium ions for vitamin B₁₂–intrinsic factor complex uptake by ileal cell membrane receptors,43 and cholestyramine interferes with vitamin B₁₂ absorption from intestine.44

Vitamin B₁₂ is essential for metabolism of all cells in our body. In humans, two enzymatic reactions are dependent on vitamin B₁₂—methylmalonyl coenzyme A mutase (MUT) reaction and 5-methyltetrahydrofolate-homocysteine methyltransferase (MTR) reaction (Fig 2). The MUT reaction is an important step in the extraction of energy from protein and fat in the mitochondrial citric acid cycle. In the MTR reaction, vitamin B₁₂ and folic acid are required for the conversion of homocysteine to methionine that is important for maintaining the integrity of nervous system. Tetrahydrofolate is also regenerated via the MTR reaction for DNA synthesis. Hence, in vitamin B₁₂ deficiency, multi-organ systems can be affected and hence associated with wide spectrum of clinical manifestations. However, clinically overt vitamin B₁₂ deficiency with classical feature of macrocytic anaemia and neuropathy is infrequently seen in the elderly.2 Very often they have mild, subclinical deficiency, which are usually asymptomatic.2

Clinical manifestations of vitamin B₁₂ deficiency are usually non-specific and are highly variable according to severity or organ systems involved.9 There is no one clinical feature unique to all patients with vitamin B₁₂ deficiency. Non-specific symptoms and signs are loss of appetite, diarrhoea, fatigue and weakness, shortness of breath, low blood pressure, confusion, and change in mental states.9 29 Classical manifestations include Hunter’s glossitis, megaloblastic anaemia, and subacute combined degeneration of spinal cord (Table 29).

Hyperhomocysteinaemia, as an independent risk factor for cardiovascular disease, has been receiving increased attention. Elevated homocysteine level is associated with an increased risk for atherosclerotic and thrombotic events.45 Meta-analysis of 30 studies involving 5073 ischaemic heart disease (IHD) events suggested that elevated homocysteine level was at most a modest independent predictor of IHD and stroke risk in healthy populations, and a 25% reduction in homocysteine levels was associated with 11% and 19% reduction in IHD and stroke, respectively.46 Another meta-analysis also provided a strong evidence of the causal association between homocysteine and cardiovascular disease, and showed that lowering homocysteine level by 3 µmol/L could reduce the risk of IHD by 16% and stroke by 24%.47

Vitamin B₁₂, folic acid, and vitamin B₆ are required for homocysteine metabolism, and often nutritional deficiency of these vitamins can cause hyperhomocysteinaemia. In contrast to severe hyperhomocysteinaemia associated with genetic disorders, hyperhomocysteinaemia resulted from nutritional deficiency is mild but is still associated with increased risk of atherothrombosis. The proposed mechanism for hyperhomocysteinaemia on inducing endothelial dysfunction and thus atherosclerosis includes homocysteine-induced endoplasmic reticulum stress, oxidative stress, and proinflammatory response.48 Animal models of hyperhomocysteinaemia have confirmed the causal relationship between hyperhomocysteinaemia and the development of endothelial dysfunction and accelerated atherosclerosis.48

Although meta-analyses have shown reduction of cardiovascular risk with reduction of homocysteine levels,46 47 vitamin supplementation (with vitamin B₆, vitamin B₁₂, and folic acid) to lower homocysteine in the body may not be transformed into clinically beneficial vascular outcomes. In a double-blind, randomised controlled trial of 3680 adults with non-disabling cerebral infarction, subjects who received a combination of vitamin B₆, vitamin B₁₂, and folic acid showed moderate reduction in total homocysteine levels, but there was no effect on vascular outcomes (recurrent ischaemic stroke and coronary heart disease) during 2 years of follow-up.49 Probably a longer duration of treatment may be necessary or there may be other factors governing the clinical response. Therefore, we need more controlled trials to explore the vascular benefits of vitamin supplementation.

Neuropsychiatric manifestations in the absence of haematological abnormalities are commonly seen in the elderly.2 50 These include paraesthesia, weakness, gait abnormalities, and cognitive or behavioural changes. Although the exact mechanism of how vitamin B₁₂ deficiency causes neuropsychiatric disorder is unclear, the disruption of both MUT and MTR vitamin B₁₂–dependent reactions seem to play a role. Vitamin B₁₂ deficiency disrupts MUT reaction with accumulation of MMA; MMA is a myelin destabiliser and can affect normal myelin formation. Besides, disruption of MTR reaction leads to insufficient supply of methionine and S-adenosylmethionine (SAM), which is essential for the myelination of myelin sheath, phospholipids and neurotransmitter synthesis, for maintaining brain and nervous system function.51 Furthermore, high levels of homocysteine due to vitamin B₁₂ deficiency are associated with an increased risk of atherosclerotic vascular disease, and this in turn may increase the risk of cognitive impairment or dementia. It has been shown that low serum vitamin B₁₂ is associated with a 2- to 4-fold higher risk of cognitive impairment.50 The prevalence of low serum vitamin B₁₂ has been reported to be significantly higher in the people with Alzheimer’s disease (AD).52 However, the causal relationship between vitamin B₁₂ deficiency and the development of AD remains controversial. Amyloid deposition and hyperphosphorylation of tau protein are believed to be involved in the mechanism of AD. The SAM-dependent methylation is involved in the regulation of mechanism of presenilin I expression, γ-secretase activity, and thus amyloid levels; SAM is also involved in the regulation of tau phosphorylation.51 Moreover, hyperhomocysteinaemia has been shown to be associated with a significant increase in amyloid level and amyloid deposition on cortex and hippocampus in mouse models of AD.53 Overall, vitamin B₁₂ deficiency may have implications in the neuropathological process of AD.

Depression is a common psychiatric manifestation of vitamin B₁₂ deficiency. Involved in the synthesis of neurotransmitters, SAM may be implicated in mood disorders. In a population-based study of 3884 elderly people, deficiency of vitamin B₁₂ was associated with almost 70% more likelihood of having a depressive disorder.54 In another cross-sectional study of 700 community-dwelling, physically disabled women aged ≥65 years, vitamin B₁₂–deficient women were twice more likely to have severe depressive symptoms.55 Although controlled studies to show response to vitamin B₁₂ replacement therapy in depression are lacking, it is recommended that all patients with vitamin B₁₂ deficiency should be managed as part of depression treatment. Psychosis, including delusion and hallucination, has also been reported in vitamin B₁₂–deficient patients. Although the exact mechanism is unknown, vitamin B₁₂ replacement even after a prolonged period (at least up to 2 years) has shown good outcomes in patients with psychosis.56

In general, vitamin B₁₂ replacement therapy helps to reverse the haematological abnormalities and psychiatric disorders. However, even after correcting serum vitamin B₁₂ and its metabolite levels, or haematological abnormalities, the ability to reverse cognitive impairment (dementia) and neurological disorders is not promising.50 51 52 The longer the time the neurological disorder or cognitive impairment presents before treatment, the less likely it can be reversed. It is suggested that prompt correction of deficiency should be done within 6 to 12 months of cognitive impairment in order to obtain maximum response.57 Nevertheless, continuous replacement therapy may still help to prevent symptoms from deteriorating. Treatment for subtle or subclinical deficiency is still debatable although prompt diagnosis and treatment might prevent the progress to clinically overt deficiency.

Classical treatment for vitamin B₁₂ deficiency is parenteral administration, usually intramuscular injection, to correct the deficiency and build up tissue storage. There are two forms of vitamin B₁₂ for parenteral administration: cyanocobalamin and hydroxocobalamin. It is believed that hydroxocobalamin is converted to active enzyme more easily and retained in the body for a longer period of time than cyanocobalamin, and therefore be administered in intervals of 3 months. The regimen for vitamin B₁₂ therapy varies across countries and between individual practices. Generally, the schedule for vitamin B₁₂ replacement is 1 mg daily for a week or 1 mg 3 times a week for 2 weeks, followed by 1 mg per week for 1 month, and then 1 mg per month as maintenance dose.9

Around 1% to 5% of free vitamin B₁₂ can be absorbed along the entire intestine by passive diffusion. Oral vitamin B₁₂ replacement is theoretically as effective as parenteral administration even in patients with PA or ileal disease, provided that the dosage is high. However, the unpredictable absorption by passive diffusion makes recommendation of a standard dose difficult. A Cochrane review supports the use of high-dose vitamin B₁₂ (1 mg and 2 mg daily) in elevating serum vitamin B₁₂ level and achieving haematological and neurological responses, even in patients with PA or with ileal resection.58 The recommendation for oral replacement is 1 mg daily for a month, and then 125 to 250 µg daily as maintenance dose for patients with dietary insufficiency and food-cobalamin malabsorption, while for PA the maintenance dose is 1 mg daily.29

Vitamin B₁₂ does not have side-effects even when prescribed in large doses.59 However, hypokalaemia, resulting from uptake of circulating potassium by newly growing and dividing haematopoietic cells, can be severe or sometimes life-threatening. Transient potassium replacement at the initial stage of vitamin B₁₂ replacement, especially in those with low-normal serum potassium, can prevent subsequent hypokalaemia.

Correction of risk factors associated with vitamin B₁₂ deficiency, like antibiotics for H pylori infection and intestinal bacterial overgrowth, stopping or replacing offending medications are also important in the management and prevention of vitamin B₁₂ deficiency. Some institutions have even recommended universal vitamin B₁₂ supplement for people aged ≥60 years in view of the high prevalence of vitamin B₁₂ deficiency among this popualation.15

Vitamin B₁₂ deficiency is prevalent among the elderly. Elderly people are particularly at risk of deficiency because of the increasing prevalence with increasing age of atrophic gastritis–associated food-cobalamin malabsorption, PA, and due to drug intake for co-morbidities. Symptoms and signs of vitamin B₁₂ deficiency are usually vague and unrecognised. Treatment may always be useful to correct clinical abnormalities like vitamin B₁₂–related haematological abnormalities, psychiatric and depressive symptoms. For neurological disease and dementia, prompt vitamin replacement is necessary before it becomes irreversible or permanent. Both oral and parenteral administration of vitamin B₁₂ are effective and without untoward side-effects. Overall, we are in support of screening for vitamin B₁₂ deficiency in the elderly. However, accurate diagnosis of vitamin B₁₂ deficiency remains controversial. To diagnose vitamin B₁₂ deficiency, laboratory tests have their limitations, and this makes it difficult to choose a reliable and easily available tool for screening. Although there is no formal recommendation for screening for vitamin B₁₂ deficiency in asymptomatic elderly people, the high prevalence, higher risk of deficiency in the elderly, easy and safe treatment availability warrant more liberal testing and vitamin supplementation in the elderly.

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38. Chan CW, Liu SY, Kho CS, et al. Pernicious anemia in Chinese: a study of 181 patients in a Hong Kong hospital. Medicine (Baltimore) 2006;85:129-38. Crossref

39. Toh BH, van Driel IR, Gleeson PA. Pernicious anemia. N Engl J Med 1997;337:1441-8. Crossref

40. Hsing AW, Hansson LE, McLaughlin JK, et al. Pernicious anemia and subsequent cancer. A population-based cohort study. Cancer 1993;71:745-50. Crossref

41. Hirota WK, Zuckerman MJ, Adler DG, et al. ASGE guideline: the role of endoscopy in the surveillance of premalignant conditions of upper GI tract. Gastrointest Endosc 2006;63:570-80. Crossref

42. Schuümann K. Interactions between drugs and vitamins at advanced age. Int J Vitam Nutr Res 1999;69:173-8. Crossref

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There is a global epidemic of allergic diseases in the developed world and Hong Kong has not been spared. This review provides an overview of the epidemiology of allergic diseases in Hong Kong and matches it to the provision of local health care services as well as training in allergy.

The International Study of Asthma and Allergies in Childhood (ISAAC)1 2 3 4 5 6 and other local studies7 8 9 10 11 provide data on the prevalence and changing trends for some allergic diseases in Hong Kong. The ISAAC was a multi-country cross-sectional survey that provided a global epidemiological map of eczema, asthma, and rhinoconjunctivitis in 1995, 2000, and 2003. Children aged 6 to 7 years and 13 to 14 years were studied. The ISAAC Phase Three was a repetition of the ISAAC Phase One that aimed to evaluate the possible trend of disease prevalence after a period of 5 to 10 years.

In 2001, the prevalence of those who had ever been diagnosed with asthma in 6- to 7-year-olds was 7.9%. This reflected an increase of about 0.04% compared with 1995. In 2002 the prevalence of having asthma ever in 13- to 14-year-olds was 10.1%, representing a decrease in prevalence of 0.15% per year since 1995.

In 2001, the prevalence of lifetime eczema in 6- to 7-year-olds was 30.7% and current eczema was 4.6%. This reflected an increase in the current eczema prevalence of 0.12% per year since 1995. In 13- to 14-year-olds, the prevalence of lifetime eczema was 13.4% and that of current eczema was 3.3%. This reflected an increase of 0.08% per year since 1995.

In 2002, the rhinoconjunctivitis prevalence in 13- to 14-year-olds was 22.6% and showed a decrease of 0.2% per year since 1995. Similar figure for 6- to 7-year-olds was 17.7% in 2001 and this represented an increase of 0.7% per year since 1995.

The Asthma Insights and Reality in Asia-Pacific Study was conducted twice in Asian countries, including mainland China, Hong Kong, Korea, Malaysia, The Philippines, Taiwan, and Vietnam, to gain insight into asthma management.12 In the first survey of more than 3000 adults and children, more than 40% of asthmatic patients had at least one hospitalisation or visit to the emergency department for acute exacerbation. Inhaled corticosteroid use was reported by only 13.6% of the respondents. Another study performed 10 years after the first survey showed that less than 5% of patients achieved a level of complete asthma control, while more than one third were in the uncontrolled asthma category. Patients tended to overestimate their level of control and tolerated a high degree of impairment of their daily activities.12 13 14 Most participants younger than 16 years had inadequately controlled asthma (53.4% ‘uncontrolled’ and 44.0% ‘partly controlled’). The demands for urgent health care services (51.7%) and use of short-acting β-agonists (55.2%) were high.15

There are little epidemiological data on asthma and allergy in Hong Kong adults. In a review of data from local public hospitals in 2005, asthma ranked fourth and fifth highest as a cause of respiratory hospitalisations (5.7%) and respiratory inpatient bed-days (2.6%), respectively.16 The overall crude hospitalisation rate for asthma in 2005 was 76/100 000, and was high at both extremes of age. The age-standardised mortality rate of asthma increased between 1997 (1.33/100 000) and 1998 (1.82/100 000), but decreased thereafter to 1.4/100 000 in 2005. The overall annual change in asthma mortality was not significantly different between 1997 and 2005. The prevalence of current wheeze increased from 7.5% in 1991/1992 to 12.1% in 2003/2004 among people older than 70 years; the corresponding figures for asthma were 5.1% and 5.8%.17

A number of studies have examined the prevalence of food allergies and adverse food reactions in a wide age range of Hong Kong children.9 10 11 18 In 2009, parent-reported adverse reactions in 2- to 7-year-olds was 8.1%. A study involving children aged 7 to 10 years reported in 2010 that ‘probable’ food allergy in Hong Kong was 2.8%.10 In 2012, the prevalence of food allergy in children from birth to 14 years was 4.8%, of which shellfish was by far the commonest food causing allergic symptoms, alongside egg, milk, peanuts, and fruits.10

Children with food allergies have 2 to 4 times higher rates of co-morbid conditions, including asthma, rhinoconjunctivitis, and eczema. Strikingly 700/100 000 of the population (15.6% of children with food allergies) aged 14 years or younger are estimated to be at risk for anaphylaxis, which is high relative to other countries. Almost 50% of cases are estimated to be caused by foods, with drug allergy also being a cause.11

Regarding other allergic diseases, Leung et al19 reported glove-related symptoms in nearly one third of 1472 employees in a teaching hospital in Hong Kong. Most of these allergies could be classified as glove dermatitis, whereas only 3.3% had symptoms suggestive of latex allergy. About 7% of 133 participants had positive skin prick testing to one or more of the five latex extracts.

There are only four immunology and allergy specialists (Medical Council Specialist Registration S34) in Hong Kong. Two of these clinicians, both of whom were trained abroad, are in private practice and the other two are not involved in allergy practice. There are no registered allergy specialists in adult medicine in public hospitals.

There are six specialists in Paediatric Immunology and Infectious Diseases (PIID; Medical Council Specialist Registration S56) of whom two work full time and four work part time, mainly in an allergy/immunology practice in the Hospital Authority (HA) hospitals/university sector. There is another PIID specialist working in private practice. Most of these clinicians only work part time on allergy.

Many patients with allergic diseases in Hong Kong are treated by non-allergy specialists, such as general practitioners, or specialists in dermatology, respiratory medicine, ear nose and throat medicine, and paediatrics. While these excellent clinicians undoubtedly have experience in looking after patients with allergies, it is unclear how many have received formal training in managing complex multi-system allergies or whether their continuous professional development (CPD) activities include allergy.

If one assumes that PIID specialists spend on average 40% of their working week (5.5 days) on allergy, irrespective of whether they are full or part time (a generous estimate), then Hong Kong has 2 full-time equivalent (FTE) adult allergists and 2.8 FTE PIID specialists consulting for allergy. The overall ratio is therefore estimated to be around one allergist to 1.46 million population in Hong Kong, which is near the bottom of the world league table published by the World Allergy Organization (Table20).

There is a stark contrast in Hong Kong between the level of service provision for children and that for adults. The ratio of paediatric and adult allergists per head of population is around 1:460 000 (assuming there are about 1.3 million children in Hong Kong who are younger than 18 years) and 1:2.8 million (assuming there are about 5.7 million adults), respectively. There are no allergists for adult patients in public hospitals. The very low numbers of allergists (4.8 FTE) compares unfavourably with other specialties in Hong Kong, for example, there are 226 cardiologists, 164 gastroenterologists, 162 respiratory physicians, 190 otorhinolaryngologists, and 92 dermatologists. These data, combined with the average waiting times at public hospitals of 6 to 9 months for a new allergy appointment, clearly indicate that the demands for allergy services are unmet. The disease burden cannot be absorbed by the private sector as there are also very few private allergists.

Laboratory support is essential for the good practice of allergy and immunology. There are two Hong Kong Medical Council–registered immunologists (S44) who have also received some allergy training. One of them directs a public laboratory service in immunology and allergy as well as providing a limited service for drug allergy, while the other is not involved with allergy. Their budget does not allow a comprehensive menu of relevant tests to support the specialty.

In countries where there are more allergists per head of population than in Hong Kong, patients still consult non-allergy specialists instead of an allergist, even for a condition that often has an allergic cause such as rhinitis (Fig 120).This suggests that there is a relative global lack of understanding of what allergists can offer in health care. Clearly much needs to be done in public and professional education.

In the absence of allergists, patients may suffer because they may find it hard to get state-of-the-art medicine and diagnostics. Pharmaceutical companies are less likely to register their products in a country where the drugs will be prescribed only rarely. Furthermore, there is a high probability that unproven diagnostic procedures and therapies could be introduced if mainstream medicine is unavailable, or conventional tests are used inappropriately.21 Finally, with a lack of allergy specialists, it becomes difficult to train future generation of clinicians, researchers, and teachers in allergy.

There are 12 acute paediatric units admitting children and adolescents for various acute exacerbations of diseases, including systemic allergic reactions and acute asthmatic attacks. The level of acute care is comprehensive and includes intensive care unit support when indicated. Data from the HA suggest that one in 10 patients with anaphylaxis attending acute emergency departments has been admitted to a paediatric intensive care unit.22

Ambulatory and out-patient follow-ups, however, are sometimes fragmented, especially for the prevention of anaphylaxis and investigation to identify allergens. Adrenaline auto-injector (eg EpiPen [Dey LP, Napa, California, US]) availability is very limited, although much improved recently, probably as the result of an audit report identifying the unmet need.22

Only four hospitals have designated allergy clinics to investigate food and drug allergy (Queen Mary Hospital [QMH], Prince of Wales Hospital [PWH], Princess Margaret Hospital [PMH], and Queen Elizabeth Hospital [QEH]). Some paediatricians with gastro-intestinal training look after patients with non-immunoglobulin E (IgE)–mediated food allergy with predominant gastro-intestinal symptoms.

Most of the paediatric units in Hong Kong have asthma clinics that are run by paediatricians with respiratory training. Care of patients with allergic rhinoconjunctivitis is largely provided by general paediatricians in conjunction with other organ specialists such as ear, nose and throat surgeons and ophthalmologists; there are long waiting times, ranging from 6 to 12 months.

Five hospitals have dermatology clinics (QMH, PWH, United Christian Hospital, Caritas Medical Centre, and Pamela Youde Nethersole Eastern Hospital) run by paediatricians with dermatology training, but also treating some patients with allergies.

Currently, there is one single immunology/allergy public laboratory service in QMH that provides limited numbers of specific IgE, human leukocyte antigen, and tryptase tests. Clinical investigational laboratories for in-vivo allergen skin tests and challenge protocols are run by specialists in PIID or paediatrics. Food and drug challenges are provided at QMH and PWH on a regular basis, but may be occasionally provided by other hospitals such as QEH, PMH, and Kwong Wah Hospital. The waiting time is generally about 6 months. There are no commonly accepted local challenge protocols, so those used by internationally recognised paediatric allergy centres are followed.

Currently, the four PIID centres have two FTE staff plus four part-time staff who work mainly on food and drug allergies. The trained dietician and nurses work only on a part-time basis. There is also one private PIID specialist.

Local anaphylaxis guidelines have been drafted and are pending approval and implementation. The Hong Kong College of Paediatricians has issued guidelines to improve care for atopic dermatitis. Different hospitals may have different in-house guidelines for asthma or they may be adopted from international guidelines.

Allergen immunotherapy is very limited in public service. The reasons are multifactorial and include affordability, availability, and accessibility.

Lack of central funding may seem to be a hindrance to provision of allergy services, but the real problem is the shortage of skilled staff. Many trained nurses experienced in skin testing and allergy education have left their jobs or have been redeployed to other areas. To cater for the current service demands and to achieve reasonable waiting times, more staff need to be trained urgently, for instance, a resident trainee, advanced practice nurses, and even clerical support.

There is currently no formal allergy clinical service provided in the public sector for adults. Clinicians, including a few dermatologists, respiratory physicians and otolaryngologists, who have an interest in allergy provide an ad-hoc service to patients with various allergic disorders. Limited skin prick tests are provided. There are, however, no specialty nurses or technicians specially trained in this area.

In 2013, the Division of Rheumatology and Clinical Immunology, together with the Division of Clinical Immunology (Pathology) set up a Drug Allergy Clinic at QMH to provide consultations for Hong Kong West Cluster patients. Because of resource restrictions, these consultations are limited to the diagnosis and confirmation of general anaesthetic and antibiotic allergies.

Hong Kong has produced only one locally trained immunologist who is an HIV (human immunodeficiency virus) specialist currently working in the Department of Health. There have been no trainees in allergy and immunology since 1998.

Data retrieved on 30 June 2013 from an analysis of HA data (personal communication) indicate that almost 400 000 patients have drug allergy, with 44 018 having three or more drug allergies. Almost 5000 patients (mainly adults) have three or more antibiotic allergies. This is a huge potential clinical workload that impacts on many other specialties, and is a growing area of allergic disease that needs to be addressed urgently.

Only one laboratory service for allergy/immunology in Hong Kong is directed by accredited immunologists in the public sector (at QMH). The service cannot offer a complete portfolio of tests because of budgetary constraints.

The first Fellowships of the subspecialty of PIID were conferred in 2012 (Medical Council Registration S56). Among the first 12 Fellows, five work principally in the field of immunology and allergy. Paediatric units of four regional hospitals (QMH/The University of Hong Kong [HKU], PWH/The Chinese University of Hong Kong [CUHK], PMH, and QEH) are accredited to be the training centres and they have formed a training network. Allergy is an integral part of the PIID programme.

Allergy and hypersensitivity is one of the five areas of knowledge requirement for the training in allergy and immunology under the Hong Kong College of Physicians (HKCP). The other four areas include autoimmune and immune complex diseases, primary and secondary immunodeficiency, transplantation, and lymphoproliferative diseases. Training in adult allergy is hampered by the lack of trainers and the lack of an allergy clinical service in the public sector.

Training of immunology is under the Hong Kong College of Pathologists (HKCPath). The goal of training is to produce specialist immunologists who are able to direct a laboratory service in clinical immunology and tissue typing, to advise clinicians on the management of immunological disorders, including allergy, autoimmunity, immunodeficiency, and malignancy of the immune system. At present such training is only available at QMH where there are two immunologists.

With the introduction of potent targeted biologics, greater understanding of the genetics and epigenetics determining allergic disease expression, improved strategies and vaccines for allergen-specific desensitisation, novel approaches to allergy prevention, and the advent of an era of stratified medicine, the need for more allergists, allergy services, research, and trainees in the specialty have never been more urgently required. In an otherwise high-quality health care landscape in Hong Kong, allergy services and training are a seriously unmet need. The deficiencies should be remedied without delay for the benefit of the patient community.

The recommendations described below are adapted from a recent authoritative report about allergy23 and should also be seen in the context of the declaration of the World Allergy Organization in 2013.24

(1) We recommend that urgent advice is sought from the major stakeholders on how one might remedy the unmet need for allergy services and training in Hong Kong.

(2) We recommend that the best model for allergy service delivery is a ‘hub-and-spoke’ model (Fig 223). The ‘hub’ would act as a central point of expertise with outreach clinical services, education, and training provided to doctors, nurses, and allied health care professionals in primary and secondary care (the ‘spokes’). In this way, knowledge regarding the diagnosis and management of allergic conditions could be disseminated throughout the region. The hub and spokes in its entirety forms the ‘allergy centre’. The hub should lead and coordinate the activities of the entire centre.

(3) Each hub should have an allergy service both for adults and for children to share in knowledge transfer and resources. In addition to hubs, a network of satellite allergy services could be established at different hospitals (for instance by changing the emphasis of one or two existing clinics a week designated for respiratory medicine, otorhinolaryngology, and/or dermatology to become allergy clinics), which can then link to one of the allergy hubs for academic, clinical, and educational support. This solution might not incur substantially more resources, as the complex multi-system allergy cases could be transferred from the other clinics and managed in a new dedicated allergy service.

(4) We recommend that paediatric and adult services in an allergy centre should each be led by an allergy specialist and each should be supported by at least one other clinical colleague (another allergy specialist or an organ specialist with a special interest in allergy), at least one trainee, specialist dietician and nursing support, and a technician for routine allergy testing, counselling, and education.

(5) The hub forming the allergy centre will be collaborating, not competing, with single organ specialists or with general paediatricians, internists, and general practitioners. It is envisaged that the tertiary allergy centres would work together with other colleagues to provide joint, integrated, and holistic care for the most complex allergy cases, which are often characterised by multi-system involvement. To facilitate this interaction, it is recommended that clear criteria are defined for the types of patients that could be referred to tertiary specialist allergy centres.

(1) We recommend that two pilot allergy centres are created by recruiting allergy specialists (from overseas if necessary) to start the services and to oversee a training programme.

(2) We recommend that each of the new appointees is a joint appointment between the HA and a university. Each appointee should be supported by three trainees, a specialist nurse, and a dietician.

(3) We recommend that the two pilot allergy centres should be located at QMH/HKU and PWH/CUHK (hubs), so that Hong Kong, Kowloon, and the New Territories are covered. Two pilot centres are required because of the heavy burden of allergic disease and the capacity of a solitary centre in Hong Kong would very soon become overextended. Both QMH and PWH have a long distinguished history of looking after children with allergic and immunological diseases, but both lack a dedicated allergist in adult medicine. Creation of an allergy centre that integrates existing strengths in paediatric clinical/academic/education in allergy with a new adult clinical/academic/education allergy service would be a major catalyst to bridging the obvious gaps in service and academic provision. Formal designation of both hospitals as pilot allergy centres could also provide formal encouragement to hospital and university management for some internal realignment of resources. Finally creating these innovative allergy centres could provide significant opportunities to attract private funding from benefactors to grow the discipline subsequently.

(4) We recommend that metrics for success of each pilot centre be predefined and progress in the first 5 years be assessed against those goals. If the pilot is successful, then the model should be continued and could even be extended to other suitable clinical/academic centres.

(5) We recommend that the HKCP training curriculum for immunology and allergy is updated as soon as possible. In addition, we suggest that the HKCP and HKCPath consider creating an intercollegiate training programme in immunology and allergy to produce clinical immunologists who will direct allergy/immunology laboratories and consult for allergic patients. This can be extended to other colleges and cross-college training is encouraged by the Hong Kong Academy of Medicine. In due course, a core curriculum in allergy could be shared by all interested colleges in addition to a college-specific curriculum. This model is already being explored for subspecialty training in genetics and genomics among some academy colleges.

(6) We recommend the training of allergy as a main subject to be included in the college training guidelines in allergy and immunology and four allergy and immunology trainees majoring in allergy are recruited every 4 years.

(1) It is envisaged to develop an immunology and allergy centre at the Hong Kong Children’s Hospital (HKCH) for management of complex allergy cases from 2018 onwards (a hub). A team of core medical and nursing staff will be based at HKCH, but will also run an outreach programme by linking up with other network hospitals.

(2) When the immunology and allergy centre at the HKCH is operational, there will need to be some reorganisation with parts of the top-tier paediatric allergy services in the ‘hub’ hospitals being moved to the HKCH (which will then become the new hub), leaving satellite services in the previous ‘hub’ hospitals (the spokes) in situ.

(3) To facilitate a smooth transition to the HKCH, we recommend at least four to five FTE PIID specialists majoring in allergy/immunology to be appointed to run the top-tier service at the HKCH, to provide training and conduct local relevant audit/research (hub). A further 12 PIID specialists will be required to provide step-down and secondary services in both the training (PMH, PWH, QEH, QMH) and non-training (other HA paediatric units) posts for the specialty and general paediatrics (spokes).

(4) We recommend that common protocols, guidelines, care pathway, and a referral network, especially for complex cases, should be agreed and formally created.

(5) We recommend that four PIID trainees are recruited every 3 years, of which at least two resident specialists majoring in allergy/immunology should be trained. This will maintain a sustainable public workforce for specialty development and cover for normal turnover. It should then be possible to produce 12 PIID specialists in three cycles (around 9 years), of whom 50% will have majored in allergy/immunology with the rest majoring in infectious diseases. Therefore, the estimated total required workforce for PIID in the public sector for the hub-and-spoke model could be 18 to 20 with eight in the hub (four to five in allergy and immunology and two to three in infectious diseases) and about 12 in the spokes working in both the specialty and general paediatrics.

(6) We recommend that allergy is added to the title of the PIID training programme so it will become a PIAID (paediatric immunology allergy and infectious diseases) programme and the paediatric discipline should also be so named.

Drug allergy is common and constitutes a major clinical problem, which needs to be managed by allergy specialists. We recommend resources to be made available to establish two separate supraregional drug allergy services at QMH and PWH (as they already have a limited service) to cover Hong Kong Island and Kowloon/New Territories. This could be part of the new pilot centres.

We recommend that two supraregional laboratories for Hong Kong should be created with a focus on drug and food allergy that are directed by accredited immunologists. The laboratories should be adequately funded so that they have sufficient manpower, equipment, and budget for reagents to widen the scope of routine laboratory services to include tests for specific IgE to a wide spectrum of whole allergen extracts and to allergen components, basophil activation tests, and lymphocyte function tests. This can be incorporated into existing laboratory support at QMH and PWH with only a relatively modest increase in resources. These laboratories could then support the new pilot centres.

We recommend that collaboration is established between the Hong Kong Institute of Allergy (as the professional platform) and Hong Kong Allergy Association (as the allergy charity) to create an agenda for professional CPD (such as regular workshops) as well as engaging and educating the public about allergy. These organisations are strongly encouraged to involve other professional societies and charities as appropriate when designing their strategies.

(1) We recommend that the appropriate Government department should audit the level of allergy training staff in schools receive, and consider taking urgent remedial action to improve this training where required.

(2) We recommend that the Government should review the desirability of schools holding one or two generic auto-injectors.

Solving the urban air pollution problem is a huge challenge. Bold, realistic, and moral leadership by national leaders is required to address this increasingly important public health issue. We recommend that it is essential to develop effective strategies to reduce pollution, to engage the public, and to monitor whether the strategies result in a significant improvement in the prevalence of pollution-related diseases in Hong Kong and mainland China.

Epidemiological data support a rising trend in many allergic diseases. The provision of services and training for specialists in allergy is mismatched with disease burden and there is a large unmet need that should be remedied without delay. Key recommendations are proposed that could help bridge the gaps, including the creation of two pilot allergy centres in a hub-and-spoke model in the public sector. This could require recruitment of specialists from overseas to start the process in the likely event that there are no accredited allergy specialists in Hong Kong who could fulfil this role in the short term.

Drs CKW Lai, CS Lau, YY Wu, and Prof TF Leung are consultants or serve on advisory boards and/or receive travel expenses and lecture fees to attend international meetings from various pharmaceutical companies including GlaxoSmithKline, AstraZeneca, Takeda, Mundipharma, Boehringer, ALK-Abello, AbbVie, Bristol-Myers Squibb, Celltrion, Janssen, Novartis, Pfizer, Roche, Sanofi, and Union Chimique Belge. Dr TH Lee is President of the Hong Kong Institute of Allergy and Honorary Clinical Professor, The University of Hong Kong. Dr Marco Ho is Chairman of the Hong Kong Allergy Association.

The Hong Kong Allergy Alliance is a group of individuals with an interest in allergy drawn from academia, HA hospitals, private practitioners, representatives from the HA, Hong Kong Institute of Allergy, Hong Kong Thoracic Society, Hong Kong Allergy Association, patients, and drug company representatives from ALK.

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