Diabetes and infection: review of the epidemiology, mechanisms and principles of treatment.

An association between diabetes and infection has been recognised for many years, with infection being an important cause of death and morbidity in people with diabetes. The COVID-19 pandemic has re-kindled an interest in the complex relationship between diabetes and infection. Some infections occur almost exclusively in people with diabetes, often with high mortality rates without early diagnosis and treatment. However, more commonly, diabetes is a complicating factor in many infections. A reciprocal relationship occurs whereby certain infections and their treatments may also increase the risk of diabetes. People with diabetes have a 1.5- to 4-fold increased risk of infection. The risks are the most pronounced for kidney infection, osteomyelitis and foot infection, but are also increased for pneumonia, influenza, tuberculosis, skin infection and general sepsis. Outcomes from infection are worse in people with diabetes, with the most notable example being a twofold higher rate of death from COVID-19. Hyperglycaemia has deleterious effects on the immune response. Vascular insufficiency and neuropathy, together with altered skin, mucosal and gut microbial colonisation, contribute to the increased risk of infection. Vaccination is important in people with diabetes although the efficacy of certain immunisations may be compromised, particularly in the presence of hyperglycaemia. The principles of treatment largely follow those of the general population with certain notable exceptions.

Evaluation of functional and malignant adrenal incidentalomas.

BACKGROUND: Adrenal incidentalomas are adrenal masses discovered inadvertently. We undertook this study to review the clinical characteristics of patients with adrenal incidentalomas who presented to a tertiary endocrine center in Hong Kong. METHODS: Retrospective review of all 139 cases of adrenal incidentalomas that were referred to the Endocrine Centre of the Prince of Wales Hospital between June 1, 2000, and May 31, 2007. We reviewed detailed patient history, physical examination findings, and symptoms and signs related to hormonal hypersecretion or malignant neoplasm and recorded clinical indications for performing diagnostic radiological imaging. RESULTS: Sixty-one patients (43.9%) had nonfunctional benign adrenal adenomas, 52 (37.4%) had functional lesions, 15 (10.8%) had malignant adrenal lesions, and the remaining 11 (7.9%) had varying adrenal disease. Among those with functional lesions, 27 (19.4%) had lesions that secreted excess cortisol; 12 (8.6%), lesions that secreted aldosterone; 12 (8.6%), lesions that secreted excess catecholamines; and 1 (0.7%), a lesion that demonstrated excess secretion of cortisol and aldosterone. Only 5 of the 27 patients with cortisol-secreting adrenal incidentalomas had symptoms or signs of excess cortisol levels at presentation. CONCLUSIONS: Adrenal incidentaloma is a commonly encountered clinical problem. Functional or primary malignant adrenal incidentalomas can be detected at an earlier stage during hormonal and radiological evaluations, which provides an opportunity for further management.

Glucose intolerance and cardiovascular risk factors in Hong Kong: data from two occupation-based cross-sectional surveys.

AIMS: To examine the distribution of plasma glucose and related cardiovascular risk factors in two occupation-based cross-sectional surveys in a Chinese ethnic population. METHODS: Two cross-sectional surveys in a Hong Kong working population. In 1990, 1496 participants aged 18-66 years underwent an OGTT, anthropometric, and other biochemical measures. Identical measures were collected from 534 participants aged 20-72 years in 2001-2003. Data were direct age-standardised to compare CVD risk factor prevalence. Linear regression modelling was used to examine the distribution of continuous CVD risk factors. RESULTS: Mean (SD) 2-h plasma glucose values were 5.6mmol/l (2.1) in 1990 and 6.5mmol/l (2.5) in 2001-2003, an apparent increase of 0.5mmol/l (95% CI 0.3 to 0.7, p<0.001) after age and sex adjustment. However, there was no significant difference in the age-standardised prevalence of glucose intolerance, overweight or obesity. There were significantly smaller proportions of women with hypertension and hyperlipidaemia and male smokers in the second compared to the first survey. CONCLUSIONS: We observed a relatively adverse glycaemia profile, which may have worsened over time, in two healthy populations of survey respondents, with comparatively low rates of most CVD risk factors. This has implications for the future burden of disease associated with hyperglycaemia in this population.

Acute encephalopathy associated with influenza A infection in adults.

We report acute encephalopathy associated with influenza A infection in 3 adults. We detected high cerebrospinal fluid (CSF) and plasma concentrations of CXCL8/IL-8 and CCL2/MCP-1 (CSF/plasma ratios > or =3), and interleukin-6, CXCL10/IP-10, but no evidence of viral neuroinvasion. Patients recovered without sequelae. Hyperactivated cytokine response may play a role in pathogenesis.

Role of 'atypical pathogens' among adult hospitalized patients with community-acquired pneumonia.

BACKGROUND AND OBJECTIVE: Agents such as Mycoplasma pneumoniae, Chlamydophila pneumoniae and Legionella pneumophila are recognized as important causes of community-acquired pneumonia (CAP) worldwide. This study examined the role of these 'atypical pathogens' (AP) among adult hospitalized patients with CAP. METHODS: A prospective, observational study of consecutive adult CAP (clinico-radiological diagnosis) patients hospitalized during 2004-2005 was conducted. Causal organisms were determined using cultures, antigen testing and paired serology. Clinical/laboratory/radiological variables and outcomes were compared between different aetiologies, and a clinical prediction rule for AP was constructed. RESULTS: There were 1193 patients studied (mean age 70.8 +/- 18.0 years, men 59.3%). Causal organisms were identified in 468 (39.2%) patients: 'bacterial' (48.7%), 'viral' (26.9%), 'AP' (28.6%). The AP infections comprised Mycoplasma or Chlamydophila pneumoniae (97.8%) and co-infection with bacteria/virus (30.6%). The majority of AP infections involved elderly patients (63.4%) with comorbidities (41.8%), and more than one-third of patients were classified as 'intermediate' or 'high' risk CAP on presentation (pneumonia severity index IV-V (35.1%); CURB-65 2-5 (42.5%)). Patients with AP infections had disease severities and outcomes similar to patients with CAP due to other organisms (oxygen therapy 29.1% vs 29.8%; non-invasive ventilation 3.7% vs 3.3%; admission to the intensive care unit 4.5% vs 2.7%; length of hospitalization 6 day vs 7 day; 30-day mortality: 2.2% vs 6.0%; overall P > 0.05). Age <65 years, female gender, fever > or =38.0 degrees C, respiratory rate <25/min, pulse rate <100/min, serum sodium >130 mmol/L, leucocyte count <11 x 10(9)/L and Hb < 11 g/dL were features associated with AP infection, but the derived prediction rule failed to reliably discriminate CAP caused by AP from bacterial CAP (area under the curve 0.75). CONCLUSIONS: M. pneumoniae and C. pneumoniae as single/co-pathogens are important causes of severe pneumonia among older adults. No reliable clinical indicators exist, so empirical antibiotic coverage for hospitalized CAP patients may need to be considered.

Viral loads and duration of viral shedding in adult patients hospitalized with influenza.

BACKGROUND: The goal of this study was to characterize viral loads and factors affecting viral clearance in persons with severe influenza. METHODS: This was a 1-year prospective, observational study involving consecutive adults hospitalized with influenza. Nasal and throat swabs were collected at presentation, then daily until 1 week after symptom onset. Real-time reverse-transcriptase polymerase chain reaction to determine viral RNA concentration and virus isolation were performed. Viral RNA concentration was analyzed using multiple linear or logistic regressions or mixed-effect models. RESULTS: One hundred forty-seven inpatients with influenza A (H3N2) infection were studied (mean age+/-standard deviation, 72+/-16 years). Viral RNA concentration at presentation positively correlated with symptom scores and was significantly higher than that among time-matched outpatients (control subjects). Patients with major comorbidities had high viral RNA concentration even when presenting>2 days after symptom onset (mean+/-standard deviation, 5.06+/-1.85 vs 3.62+/-2.13 log10 copies/mL; P=.005; beta, +0.86 [95% confidence interval, +0.03 to +1.68]). Viral RNA concentration demonstrated a nonlinear decrease with time; 26% of oseltamivir-treated and 57% of untreated patients had RNA detected at 1 week after symptom onset. Oseltamivir started on or before symptom day 4 was independently associated with an accelerated decrease in viral RNA concentration (mean beta [standard error], -1.19 [0.43] and -0.68 [0.33] log10 copies/mL for patients treated on day 1 and days 2-3, respectively; P<.05) and viral RNA clearance at 1 week (odds ratio, 0.10 [95% confidence interval, 0.03-0.35] and 0.30 [0.10-0.90] for patients treated on day 1-2 and day 3-4, respectively). Conversely, major comorbidities and systemic corticosteroid use for asthma or chronic obstructive pulmonary disease exacerbations were associated with slower viral clearance. Viral RNA clearance was associated with a shorter hospital stay (7.0 vs 13.5 days; P=.001). CONCLUSION: Patients hospitalized with severe influenza have more active and prolonged viral replication. Weakened host defenses slow viral clearance, whereas antivirals started within the first 4 days of illness enhance viral clearance.

Cytokine responses in a severe case of glandular fever treated successfully with foscarnet combined with prednisolone and intravenous immunoglobulin.

Viral loads and cytokine responses Epstein-Barr virus (EBV) were measured in an 18-year-old boy with severe glandular fever complicated by a mild anaemia, severe thrombocytopaenia and neutropaenia. Hepatosplenomegaly was detected by abdominal ultrasound in the presence of significant hepatitis. Cytokine testing demonstrated elevated cell-mediated Th1 (IFN-gamma, IL-12, sTNFR1, CXCL10, CXCL9 and CCL3) and humoral Th2 (IL-4) immune responses. Serum antibodies to EBV virus capsid antigen (VCA) IgM and IgG antibodies were detected, together with a raised EBV DNA level (up to about 70,000 DNA copies/mL) in the acute phase of the illness. This EBV DNA load decreased rapidly in response to treatment with a combination of foscarnet, intravenous immunoglobulin and prednisolone, and the boy's symptoms settled eventually after approximately 50 days of illness, following this combined antiviral and immune-modulating therapy. Detailed immunological, virological, haematological and biochemical laboratory parameters are presented to document this patient's severe EBV disease and eventual recovery.

Use of anti-diabetic drugs and glycaemic control in type 2 diabetes-tThe Hong Kong Diabetes Registry.

In this report, we examined the usage of anti-diabetic treatments including oral anti-diabetic drug (OAD) and/or insulin and their combination from baseline data of a consecutive cohort of 7549 Chinese type 2 diabetic subjects in the Hong Kong Diabetes Registry. Pattern of usage of anti-diabetic treatment and corresponding glycemic control was analyzed. OAD failure was defined as the need to add insulin to maintain glycemic target (glycated hemoglobin, HbA(1c) level<7%) with or without continuation of OAD. There were 4109 [54.4%] women and 3440 [45.6%] men (age: median 57.0 years; range 13-92 years). The mean HbA(1c) level was 7.7+/-1.8% with 39.7% attaining glycemic target. Long disease duration was associated with more complex regimens and the respective rates of OAD failure requiring insulin use were 23.7%, 39.3%, 57.1% and 75.9% in those with disease duration <5 years, 5-9.9 years, 10-19.9 years and > or =20 years (p<0.001). In conclusion, in a clinic-based type 2 diabetic population, 39.7% attained glycemic target with HbA(1c)<7%. Long disease duration and complexity of treatment regimens were associated with suboptimal glycemic control. Early intensification of therapy and system improvement are needed to enhance the effectiveness of these drugs in clinical practice.

Failure to confirm HIV infection in two end-stage HIV/AIDS patients using a popular commercial line immunoassay.

Immunoassays using either viral lysate (Western blot) or recombinant/synthetic antigen (immunoblot) for anti-HIV capture are still the preferred method to confirm HIV infection. Two cases of HIV-1-infected patients presented with acquired immunodeficiency syndrome (AIDS)-defining illnesses. Laboratory tests were performed using multiple commercial HIV test kits on multiple sera from both patients over several weeks. Both patients were strongly positive on the anti-HIV/p24 antigen combined screening assay. Yet, HIV-1 infection could not be confirmed using a popular commercial immunoassay. Eventually, HIV infection was confirmed using an alternative commercial Western blot assay as well as an HIV quantitative PCR test. In laboratories without nucleic acid testing (NAT) for HIV, indeterminate results may delay confirmation of HIV infection, if commercial line immunoassays alone are available. Some end-stage HIV/AIDS patients may not produce antibodies to specific HIV antigens and may therefore give indeterminant or negative results on some immunoassays, depending on the type of antigen used. This report highlights the utility of having NAT available when diagnosing difficult cases of HIV infection, especially in light of the recent Centers for Disease Control and Prevention move towards more universal, routine, HIV testing.

Risk factors associated with life-threatening rickettsial infections.

We retrospectively analyzed 92 cases of severe rickettsial infections in patients (median age = 49 years, 57% male, 37.0% with scrub typhus) in Hong Kong. Immunofluorescence assay was used for diagnostic confirmation. Identification of > or = 1 diagnostic sign (exposure history, rash, or eschar) was possible in 94.6% of the cases. Multivariate analysis suggested that pulmonary infiltrates (odds ratio [OR] = 25.2, 95% confidence interval [CI] = 3.9-160.9, P = 0.001) and leukocytosis (OR = 1.3, 95% CI = 1.0-1.5 per unit increase, P = 0.033) were independent predictors of admission to an intensive care unit (14.1%). Delayed administration of doxycycline was independently associated with major organ dysfunction (23.9%; oxygen desaturation, renal failure, severe jaundice, encephalopathy, cardiac failure) (OR = 1.2, 95% CI = 1.0-1.5 per day delay, P = 0.046; adjusted for age and rickettsia biogroup) and prolonged hospitalization > 10 days (25%) (OR = 1.4, 95% CI = 1.1-1.9 per day delay, P = 0.014). Treatment with fluoroquinolone/clarithromycin did not correlate with clinical outcomes (P > 0.05). Early empirical doxycycline therapy should be considered if clinico-epidemiologic signs of rickettsial infections are present.

Thresholds of risk factors for ischemic stroke in type 2 diabetic patients with and without albuminuria: a non-linear approach.

OBJECTIVES: Multiple risk factors in type 2 diabetes may explain their high risk for ischemic stroke (IS). However, it remains unknown whether these risk factors exhibit threshold characteristics and whether these relationships are influenced by albuminuria. The study aims to investigate whether risk factors exhibit any albuminuria specific threshold for IS. PATIENTS AND METHODS: This is a prospective cohort study with 6969 Chinese type 2 diabetic patients without history of stroke after a median follow-up of 5.36 years. We identified thresholds of risk factors for IS using hazard ratio plots followed by confirmation using traditional Cox regression analysis. RESULTS: In the non-albuminuric group (n=4008), IS risk started to increase rapidly at a body mass index threshold of 24 kg/m(2). The risk of IS declined with increasing blood hemoglobin reaching a threshold value of 14 g/dl. Using these threshold values as cutoff point, body mass index > or =24 kg/m(2) and hemoglobin <14 g/dl were associated with 2-fold increased risk of IS in these subjects. In the albuminuric group (n=2961). IS risk started to increase rapidly from a systolic blood pressure threshold of 135 mmHg and declined with increasing estimated glomerular filtration rate (eGFR) reaching a trough of 115 ml/min per 1.73 m(2). Using these values as cutoff points, patients with systolic blood pressure > or =135 mmHg and eGFR <115 ml/min per 1.73 m(2) had 2-fold increased risk of IS. CONCLUSION: In type 2 diabetic patients, body mass index, hemoglobin, systolic blood pressure and eGFR exhibit different risk relationships and thresholds for IS contingent upon presence or absence of albuminuria.

A novel CASR gene mutation in an octogenarian with asymptomatic hypercalcaemia.

An increasing number of patients are diagnosed with primary hyperparathyroidism after having hypercalcaemia detected incidentally during routine biochemical screening. Many are asymptomatic at the time of diagnosis. An 80-year-old woman was found to have asymptomatic hypercalcaemia. Initial investigations suggested a diagnosis of primary hyperparathyroidism. Subsequent investigations revealed that, in fact, she had familial hypocalciuric hypercalcaemia. Direct DNA sequencing of the calcium-sensing receptor (CASR) gene confirmed that the patient was heterozygous for c.2501delC, a novel frame shift mutation predicted to cause loss of function of the CASR gene. Several other family members were subsequently found to carry the same mutation. Suspected cases of hypocalciuric hypercalcaemia should be confirmed by detection of mutations within the CASR gene. Establishing the correct diagnosis will enable the patient and family members to avoid unnecessary investigations or operations.

Independent associations of alanine aminotransferase (ALT) levels with cardiovascular risk factor clustering in Chinese adolescents.

BACKGROUND/AIMS: To establish the prevalence of elevated serum alanine aminotransferase (ALT) concentrations in Chinese adolescents, and to explore the nature of associations amongst ALT, obesity and cardiovascular risk factors. METHODS: Anthropometric measurements and fasting plasma glucose, insulin, lipids and ALT were measured in 2102 Chinese adolescents, aged 12-18 years, randomly selected from 14 secondary schools in Hong Kong. RESULTS: The prevalence of elevated ALT levels was 3.2% and 5.9% if abnormal ALT levels were defined as >40 IU/L and >30 IU/L respectively. Using the <25th, 25-75th and >75th percentile values of ALT, all subjects were divided into 3 ALT strata. Using the lowest ALT stratum as referent, the top ALT stratum was associated with obesity and clustering of cardiometabolic-inflammatory risk markers in both genders. After adjusting for age and body mass index (BMI), the highest ALT stratum remained independently associated with diastolic blood pressure and insulin resistance (fasting insulin and Homeostasis Model Assessment, HOMA-IR, HOMA-beta) in boys (p<0.05); and serum triglyceride and HOMA-beta (p=0.008 and 0.014, respectively) in girls. Repeat analysis after excluding subjects with ALT>30 (n=123) or >40 IU/L (n=67) yielded comparable results. CONCLUSIONS: In adolescents, top ALT stratum, albeit within normal range, is associated with clustering of cardiovascular risk factors, independent of obesity.

Predicting values of lipids and white blood cell count for all-site cancer in type 2 diabetes.

Type 2 diabetic patients have increased cancer risk. We developed and validated an all-site cancer risk score in a prospective cohort of 7374 Chinese type 2 diabetic patients free of known history of cancer at enrolment, using split-half validation. Spline Cox model was used to detect common risk factors of cancer and to guide linear transformation of non-linear risk factors. After a median follow-up period of 5.45 years, 365 patients (4.95%) developed cancer. Body mass index (BMI; <24.0 or > or =27.6 kg/m2), triglyceride (> or =0.81 to <1.41 mmol/l), high-density lipoprotein cholesterol (<0.9 or > or =1.8 mmol/l), total cholesterol (<4.3 mmol/l) and white blood cell (WBC) count (<5.8x10(9) count per litre) were associated with increased cancer risks and exhibited non-linear relationships. We further linear transformed these terms for selection using backward Cox regression (P<0.05 for stay) in the training dataset. In the test dataset, calibration was checked using Hosmer-Lemeshow test and discrimination checked using area under receiver operating characteristic curve. In addition to age and current smoking, only linear-transformed total cholesterol and WBC count were selected. The risk score was 0.0488xage (years)-0.5810xtotal cholesterol (mmol/l, coded to 4.3 if >4.3)-0.3596xWBC count (10(9) counts/l, 5.8 if >5.8)+0.6390xcurrent smoking status (1 if yes). The 5-year probability of cancer was 1-0.9590(EXP(0.9382x(RISK SCORE+1.5903))). The predicted cancer probability was not significantly different from the observed cancer probability during the 5-year follow-up. The adjusted area under receiver operating characteristic curve was 0.712. In conclusion, BMI, lipids and WBC count have predicting values for cancer.

Development and validation of a risk score for hospitalization for heart failure in patients with Type 2 diabetes mellitus.

BACKGROUND: There are no risk scores available for predicting heart failure in Type 2 diabetes mellitus (T2DM). Based on the Hong Kong Diabetes Registry, this study aimed to develop and validate a risk score for predicting heart failure that needs hospitalisation in T2DM. METHODS: 7067 Hong Kong Chinese diabetes patients without history of heart failure, and without history and clinical evidence of coronary heart disease at baseline were analyzed. The subjects have been followed up for a median period of 5.5 years. Data were randomly and evenly assigned to a training dataset and a test dataset. Sex-stratified Cox proportional hazard regression was used to obtain predictors of HF-related hospitalization in the training dataset. Calibration was assessed using Hosmer-Lemeshow test and discrimination was examined using the area under receiver's operating characteristic curve (aROC) in the test dataset. RESULTS: During the follow-up, 274 patients developed heart failure event/s that needed hospitalisation. Age, body mass index (BMI), spot urinary albumin to creatinine ratio (ACR), HbA1c, blood haemoglobin (Hb) at baseline and coronary heart disease during follow-up were predictors of HF-related hospitalization in the training dataset. HF-related hospitalization risk score = 0.0709 x age (year) + 0.0627 x BMI (kg/m2) + 0.1363 x HbA1c(%) + 0.9915 x Log10(1+ACR) (mg/mmol) - 0.3606 x Blood Hb(g/dL) + 0.8161 x CHD during follow-up (1 if yes). The 5-year probability of heart failure = 1-S0(5)EXP{0.9744 x (Risk Score - 2.3961)}. Where S0(5) = 0.9888 if male and 0.9809 if female. The predicted and observed 5-year probabilities of HF-related hospitalization were similar (p > 0.20) and the adjusted aROC was 0.920 for 5 years of follow-up. CONCLUSION: The risk score had adequate performance. Further validations in other cohorts of patients with T2DM are needed before clinical use.

Development and validation of an all-cause mortality risk score in type 2 diabetes.

BACKGROUND: Diabetes reduces life expectancy by 10 to 12 years, but whether death can be predicted in type 2 diabetes mellitus remains uncertain. METHODS: A prospective cohort of 7583 type 2 diabetic patients enrolled since 1995 were censored on July 30, 2005, or after 6 years of follow-up, whichever came first. A restricted cubic spline model was used to check data linearity and to develop linear-transforming formulas. Data were randomly assigned to a training data set and to a test data set. A Cox model was used to develop risk scores in the test data set. Calibration and discrimination were assessed in the test data set. RESULTS: A total of 619 patients died during a median follow-up period of 5.51 years, resulting in a mortality rate of 18.69 per 1000 person-years. Age, sex, peripheral arterial disease, cancer history, insulin use, blood hemoglobin levels, linear-transformed body mass index, random spot urinary albumin-creatinine ratio, and estimated glomerular filtration rate at enrollment were predictors of all-cause death. A risk score for all-cause mortality was developed using these predictors. The predicted and observed death rates in the test data set were similar (P > .70). The area under the receiver operating characteristic curve was 0.85 for 5 years of follow-up. Using the risk score in ranking cause-specific deaths, the area under the receiver operating characteristic curve was 0.95 for genitourinary death, 0.85 for circulatory death, 0.85 for respiratory death, and 0.71 for neoplasm death. CONCLUSIONS: Death in type 2 diabetes mellitus can be predicted using a risk score consisting of commonly measured clinical and biochemical variables. Further validation is needed before clinical use.

Development and validation of a total coronary heart disease risk score in type 2 diabetes mellitus.

There are no validated risk scores for predicting coronary heart disease (CHD) in Chinese patients with type 2 diabetes mellitus. This study aimed to validate the UKPDS risk engine and, if indicated, develop CHD risk scores. A total of 7,067 patients without CHD at baseline were analyzed. Data were randomly assigned to a training data set and a test data set. Cox models were used to develop risk scores to predict total CHD in the training data set. Calibration was assessed using the Hosmer-Lemeshow test, and discrimination was examined using the area under the receiver-operating characteristic curve in the test data set. During a median follow-up of 5.40 years, 4.97% of patients (n = 351) developed incident CHD. The UKPDS CHD risk engine overestimated the risk of CHD with suboptimal discrimination, and a new total CHD risk score was developed. The developed total CHD risk score was 0.0267 x age (years) - 0.3536 x sex (1 if female) + 0.4373 x current smoking status (1 if yes) + 0.0403 x duration of diabetes (years) - 0.4808 x Log(10) (estimated glomerular filtration rate [ml/min/1.73 m(2)]) + 0.1232 x Log(10) (1 + spot urinary albumin-creatinine ratio [mg/mmol]) + 0.2644 x non-high-density lipoprotein cholesterol (mmol/L). The 5-year probability of CHD = 1 - 0.9616(EXP(0.9440 x [RISK SCORE - 0.7082])). Predicted CHD probability was not significantly different from observed total CHD probability, and the adjusted area under the receiver-operating characteristic curve was 0.74 during 5 years of follow-up. In conclusion, the UKPDS CHD risk engine overestimated the risk of Chinese patients with type 2 diabetes mellitus and the newly developed total CHD risk score performed well in the test data set. External validations are required in other Chinese populations.