Combining symptoms, signs and laboratory tests best for diagnosing giant cell arteritis

26th August 2020

Giant cell arteritis (GCA) is described as a ‘do not miss’ diagnosis in that any delays can lead to loss of vision.

According to a new systematic review, researchers from the Department of Rheumatology and Clinical Immunology, University of Groningen, found that a combination of clinical laboratory markers provides the most accurate way of diagnosing GCA.

They identified a total of 68 studies including 14,037 patients and calculated positive likelihood ratios (PLRs), that is, higher values indicate a higher probability that a factor increasing the risk of a disease, for a range of clinical symptoms and laboratory markers.

The results showed that significant clinical symptoms which, if present, should upgrade the level of suspicion for GCA were limb (PLR = 6.01) and jaw (PLR = 4.90) claudication, temporal artery thickening (PLR = 4.70) and temporal artery loss of pulse (PLR = 3.25). Significant laboratory markers included a platelet count of greater than 400 x 103/micro/litre (PLR = 3.75), erythrocyte sedimentation rates (ESR) of greater than 100mm/h (PLR = 3.11). In contrast, significant negative likelihood ratios included patients aged less than 70 years (LR = 0.48) and the absence of a C-reactive protein level of 2.5mg/dl or more (LR = 0.38).

The authors concluded that their study had identified the key clinical and laboratory markers which should be assessed when there was a suspicion of GCA.

Reference
Van der Geest KSM et al. Diagnostic accuracy of symptoms, physical signs, and laboratory tests for giant cell arteritis: A systematic review and meta-analysis. JAMA Intern Med 2020; August 17, 2020. doi:10.1001/jamainternmed.2020.3050

School children could play a role in spreading COVID-19

25th August 2020

With the UK government stressing the importance of getting children back to school in September, a new study indicates that children may be a potential source of COVID-19 infection, despite of having either milder disease or a lack of symptoms.

The study by a team from Massachusetts General Hospital, included children aged 0 to 22 years with suspected severe COVID-19, presenting at urgent care clinics or even being hospitalised. A total of 192 enrolled children with a mean age of 10.2 years, of which 49 were diagnosed with COVID-19, 18 had multisystem inflammatory syndrome (MIS) and 125 were COVID-19 negative. Interestingly, there were no differences in the proportion of children who were either COVID-19 positive or negative, reporting a fever, cough, congestion or headache though anosmia was uncommon in COVID-19-negative children.

Further analysis revealed that children carried a high viral load in their upper airways yet displayed relatively mild or no symptoms and infected children had higher ACE2 expression.

The authors also noted that the symptoms of COVID-19 overlapped with non-COVID related illnesses which makes identifying those with the disease based on symptoms more complex.

The authors suggest that relying on symptoms and temperature checks, may be an ineffective method for identifying infection in children and express concern that infected children might easily pass on the virus to other, possibly vulnerable household members.

Reference
Yonker LM et al. Pediatric SARS-CoV-2: Clinical presentation, infectivity, and immune responses. Pediatrics, 2020; DOI: 10.1016/j.jpeds.2020.08.037

Increased coffee consumption might reduce liver-related mortality

Epidemiological studies have suggested that coffee has a dose-dependent protective effect on liver-related mortality

Now a team from Monash University, Australia have suggested that increasing per capita consumption of coffee to more than two cups a day has the potential to avert hundreds of thousands of liver-related deaths.

Research suggests that coffee improves liver biochemistry and potentially slows progression to cirrhosis. Using data from the global burden of disease which included information from 112 countries, the researchers estimated that there were 1,240,201 deaths due to liver disease in 2016 among those older than 15 years of age.

The team calculated that if everyone drank more than two cups of coffee per day, the liver-related death rate would reduce by approximately half a million (524,413) and by drinking four or more cups per day, per capita, could avert up to 723,287 deaths.

However, estimates of lives saved varied by geographical region. For example, Europeans already drink more than two cups/day, hence the expected reduction in deaths would be lower. In contrast, populations in South-East Asia, Sub-Saharan Africa and Latin America have much to gain from drinking more coffee.

While these estimates were based on observational data, the authors called for further research to confirm the benefits and cost-effectiveness of coffee consumption on liver-related mortality.

Reference
Gow P et al. Estimates of the global reduction in liver disease-related mortality with increased coffee consumption: an analysis of the Global Burden of Disease Dataset. Aliment Pharmacol Ther 2020; July 16: doi: 10.1111/apt.16020

eNose technology helps to diagnose interstitial lung disease

Analysing exhaled breath using an artificial sensory system, the electronic nose (eNose), has enabled researchers to accurately differentiate between those interstitial lung disease (ILD) and healthy controls.

The eNose compares exhaled breath to previously obtained specific breath ‘signature’ for a particular condition held in a database.

Researchers from the Erasmus Medical Centre, The Netherlands, undertook a cross-sectional study in 322 patients with a diagnosis of ILD patients and 48 healthy controls with a mean age of 61.6 years (59.9% male), of whom, 5.3% were current smokers.

The eNose is first ‘trained’ to recognise ILD breath signatures of those with the condition the ILD subgroups, for example, idiopathic pulmonary fibrosis (IPF), sarcoidosis, connective-tissue related ILD etc. Researchers then compared the area under the curves (AUCs) results obtained from the training phase to the breath samples obtained from the study patients. The results showed a high level of comparability between the study patients and the breath signatures obtained through training the eNose. For example, in the training phase, the AUC for patients with IPF was 0.91 compared to other subtypes and 0.87 (95% CI 0.77–0.96) in the testing phase.

The authors concluded that using the eNose represents a potentially novel biomarker in ILD, which enables diagnosis of the condition and the different ILD subgroups.

Reference
Moor CC et al. Exhaled breath analysis by use of eNose technology: a novel diagnostic tool for interstitial lung disease. Eur Respir J 2020; July 30: doi:10.1183/13993003.02042-2020

COVID-19 antibody levels vary considerably in those with mild disease

Results from a new study in patients who had a mild COVID-19 infection, suggest that there is a wide variation in the level of neutralising antibodies (NAbs) produced.

Researchers from the Shanghai Public Health Clinical Centre, China, examined the association between mild infection with COVID-19 and the subsequent development of antibodies in a cohort of 175 patients with a mean age of 50 years (53% female) with mild disease and testing positive for the virus. Patients were hospitalised between January to February 2020 for a median of 16 days and had a median disease duration of 22 days.

At discharge, levels of NAbs, which are necessary for viral clearance, varied substantially and were even undetectable in ten patients and very low in 30% of patients. A total of 117 patients were available for a two-week follow-up appointment at which time, NAbs levels had decreased significantly compared to the levels at discharge and were still undetectable the ten patients. An interesting find from the study was the Nabs were significantly higher in older compared with younger patients and the former group also had higher C-reactive protein levels and lower lymphocyte levels at the time of admission.

The authors concluded that the clinical implications of their findings, especially in relation to the development of a vaccine, are currently unknown.

Reference
Wu F et al. Evaluating the association of clinical characteristics with neutralizing antibody levels in patients who have recovered from mild COVID-19 in Shanghai, China. JAMA Intern Med 2020; August 18: doi:10.1001/jamainternmed.2020.4616

Contact tracing apps unlikely to reduce the spread of COVID-19

According to a new systematic review of available studies, researchers from University College London, Institute of Health Informatics, suggest that contact tracing apps for COVID-19 are unlikely to be effective without both proper uptake.

The team defined their primary outcome as the number or proportion of contacts (or subsequent cases) identified from the tracing apps.

In a review of 15 studies, they identified seven which used automated contact tracing which were all mathematical modelling studies, five of which addressed smartphone apps specifically. However, none of these studies contained data on the primary outcome. Five studies based on partially automated systems were observational in nature or case studies and three of these using automated contact detection looked at other diseases such as Ebola virus. Finally, the authors found three studies involving contact detection but without subsequent tracing or contact notification and there were no studies directly comparing manual to automated contact-tracing systems.

In discussing their findings, the authors noted that there is still a lack of evidence for the effectiveness of automated system tracing and that the success of any automated system depends on population uptake of the app and that manual contact tracing is still likely to be required in most cases.

Reference
Braithwaite I et al. Automated and partly automated contact tracing: a systematic review to inform the control of COVID. Lancet Digital Health 2020; DOI: 10.1016/S2589-7500(20)30184-9

Tape-stripping identifies a distinct biomarker to differentiate eczema from psoriasis

17th August 2020

Using tape-stripping researchers from Mount Sinai School of Medicine, New York, have identified a single gene biomarker that accurately distinguishes atopic eczema from psoriasis.

The team evaluated the tape strips from both normal and lesional skin in 20 adults with either moderate to severe eczema and psoriasis or healthy controls and subjected the samples to RNA sequencing for analysis. The results showed huge differences in the genes expressed in lesional compared to normal skin for both diseases. For instance, in eczema patients, there were 4123 differentially expressed genes (DEGs) in lesional skin compared to 1498 DEGs in normal skin. Similarly, there were 5390 DEGs in lesional skin compared to 1135 in normal skin. There were also importance differences related to expression of immune system T cells with eczema patient samples showing a skewing towards T-2 helper cells and psoriasis samples, T-17 helper cells. In addition, there were differences in gene expression related to epidermal barrier function which also allowed for a distinction between the two skin conditions.

However, more relevant was the finding that nitric oxide synthetase2 was a single gene biomarker that distinguished between the conditions. The gene produces nitrous oxide subsequent to stimulation by pro-inflammatory cytokines and was only present in psoriasis.

They concluded that as a minimally invasive approach, tape-stripping can be used to monitor biomarkers of disease activity in clinical trials.

Reference
He H et al. Tape strips detect distinct immune and barrier profiles in atopic dermatitis and psoriasis. J Allergy Clin Immunol 2020; doi.org/10.1016/j.jaci.2020.05.048.

Public Health England revises definition of COVID-19-related deaths

The way in which the daily COVID-19-related deaths is calculated is to be changed according to Public Health England (PHE).

The daily death totals on the PHE dashboard and which are reported in media over the last few months, have included all recorded deaths in those who have tested positive for COVID-19. This process is at variance with the recording of COVID-19 deaths in the devolved nations, in which deaths are only counted if an individual dies within 28 days of a positive test result and accounts for the lower number of recorded deaths in these nations.

Because PHE has recorded all deaths in which someone had a positive COVID-19 test result at any time-point, the actual COVID-19-related death tally in England might have been over-estimated. After undertaking review of the data collection methods, the COVID-19-related death totals in England will now be based on a) deaths among COVID-19 positive patients that occurred within 28 days of the test and b) deaths within 60 days of a positive test AND deaths after 60 days but only where COVID-19 is recorded on the death certificate.

Using these definitions, England has now had 36,695 deaths compared to the previously reported 42,072, a drop of 5377. Using this revised measure will hopefully provide a more accurate measure of COVID-19-related deaths and allow for tracking death rates over time.

Reference
Public Health England. https://assets.publishing.service.gov.uk/government/uploads/system/uploads/attachment_data/file/908781/Technical_Summary_PHE_Data_Series_COVID-19_Deaths_20200812.pdf

Earlier mammograms associated with a reduction in breast cancer mortality

A new randomised, follow-up trial has revealed how breast cancer screening from age 40, leads to a 25% reduction in breast cancer mortality after 10 years.

A team from the Wolfson Institute of Preventative Medicine, University of London, began recruiting women between 1990 and 1997. A total of 53,883 women were randomised to the intervention group (that is, annual screening at 40 years of age) and 106,953 to the control arm, in which mammography screening began at the currently recommended age of 50 years.

The primary outcome was mortality from breast cancer diagnosed during the trial period but before the woman’s first invitation for the usual care breast screening programme. Participants were recruited for a median of 22.8 years during which time there were 10,439 deaths, 683 (7%) of which were due to breast cancer diagnosed during the study period.

After 10 years, there were 83 breast cancer deaths in the intervention group compared to 219 in the control group with a relative risk, RR = 0.75 (95% CI 0.58-0.97, p = 0.029). However, when considering mortality beyond 10 years, there was no significant difference between the two groups. Put another way, the results suggest that screening 1150 women age 40-49 would prevent one breast cancer death.

The authors concluded that breast cancer screening from an earlier age, could potentially reduce breast cancer mortality.

Reference
Duffy SW et al. Effect of mammographic screening from age 40 years on breast cancer mortality (UK Age trial): final results of a randomised, controlled trial. Lancet Oncol 2020; August 12, 2020. https://doi.org/10.1016/ S1470-2045(20)30398-3

Gut enzyme could lead to new disease biomarker

Researchers at the University of Birmingham and Newcastle University have successfully identified and characterised one of the key enzymes involved in mucus breakdown in the gut.

They demonstrated it enables bacteria to break down and feed off sugars in the layers of mucus lining the gut.

The research offers a significant step forward in the understanding of the complex co-dependent relationships at work in the gut, about which little is currently known. Because the mechanism used by the enzyme is particularly distinctive, the researchers anticipate it can be used in the development of new diagnostics for intestinal diseases.

The molecules in mucus, called mucin, are constantly produced by the body to generate the layer of mucus in the gut that provides a barrier between the gut’s complex populations of bacteria and the rest of the body. Mucin contain sugars (glycans), and these also provide an essential source of nutrients for bacteria.

The team investigated how this enzyme sits on the outside of the bacterial cell and clips away parts of the mucin molecule, taking them inside the bacterial cell to be consumed.

Because glycans are known to change when certain diseases are present in the body, the researchers anticipate it will be possible to use the enzymes to take a snapshot of the glycans within a biopsy and use that as a biomarker for early detection of the disease.

The team have investigated this process in three different diseases. They examined tissue from adults suffering from ulcerative colitis and colorectal cancer, and from preterm infants with necrotising enterocolitis, a serious illness in which the gut becomes inflamed and can start to die. They found that by adding the enzyme to the samples and labelling the glycans with a fluorescent dye, they were able to get useful information about the glycan structure.

Lead researcher, Dr Lucy Crouch, of the University of Birmingham’s School of Biosciences, explains: “Although we still don’t fully understand what the glycan structures are made from and how these vary between different tissue types, we can see that the differences in structure between health and non-healthy tissue is quite distinctive. We hope to be able to use these enzymes to start producing better diagnostics for the very early stages of these diseases.”