26 research outputs found
Glucose-6-phosphate dehydrogenase deficiency near-patient tests for tafenoquine or primaquine use with Plasmodium vivax malaria
Objectives
This is a protocol for a Cochrane Review (diagnostic). The objectives are as follows:
To assess the diagnostic accuracy of nearâpatient tests for G6PD deficiency in people undergoing treatment or prophylaxis with primaquine or tafenoquine for malaria; or in people at risk of or susceptible to malaria.
Secondary objectives
To investigate sources of heterogeneity, namely the following.
Age: adults versus children
Sex: male versus female
Reported prevalence of G6PD (high versus low)
Malaria endemicity (endemic versus nonâendemic)
Geographic location (continent of residence; that is, Africa, Asia, or other continent)
Reference standard used (adjusted male median, median G6PD, laboratory standard)
Type of blood used (venous versus capillary)
To compare the accuracy of each type of test
Spatial transcriptomic characterization of COVID-19 pneumonitis identifies immune circuits related to tissue injury
Severe lung damage resulting from COVID-19 involves complex interactions between diverse populations of immune and stromal cells. In this study, we used a spatial transcriptomics approach to delineate the cells, pathways, and genes present across the spectrum of histopathological damage in COVID-19âaffected lung tissue. We applied correlation networkâbased approaches to deconvolve gene expression data from 46 areas of interest covering more than 62,000 cells within well-preserved lung samples from 3 patients. Despite substantial interpatient heterogeneity, we discovered evidence for a common immune-cell signaling circuit in areas of severe tissue that involves crosstalk between cytotoxic lymphocytes and pro-inflammatory macrophages. Expression of IFNG by cytotoxic lymphocytes was associated with induction of chemokines, including CXCL9, CXCL10, and CXCL11, which are known to promote the recruitment of CXCR3+ immune cells. The TNF superfamily members BAFF (TNFSF13B) and TRAIL (TNFSF10) were consistently upregulated in the areas with severe tissue damage. We used published spatial and single-cell SARS-CoV-2 data sets to validate our findings in the lung tissue from additional cohorts of patients with COVID-19. The resulting model of severe COVID-19 immune-mediated tissue pathology may inform future therapeutic strategies
Single cell spatial analysis reveals inflammatory foci of immature neutrophil and CD8 T cells in COVID-19 lungs
Single cell spatial interrogation of the immune-structural interactions in COVID â19 lungs is challenging, mainly because of the marked cellular infiltrate and architecturally distorted microstructure. To address this, we develop a suite of mathematical tools to search for statistically significant co-locations amongst immune and structural cells identified using 37-plex imaging mass cytometry. This unbiased method reveals a cellular map interleaved with an inflammatory network of immature neutrophils, cytotoxic CD8 T cells, megakaryocytes and monocytes co-located with regenerating alveolar progenitors and endothelium. Of note, a highly active cluster of immature neutrophils and CD8 T cells, is found spatially linked with alveolar progenitor cells, and temporally with the diffuse alveolar damage stage. These findings offer further insights into how immune cells interact in the lungs of severe COVID-19 disease. We provide our pipeline [Spatial Omics Oxford Pipeline (SpOOx)] and visual-analytical tool, Multi-Dimensional Viewer (MDV) software, as a resource for spatial analysis
Antibody tests for identification of current and past infection with SARS-CoV-2
Background
The diagnostic challenges associated with the COVIDâ19 pandemic resulted in rapid development of diagnostic test methods for detecting SARSâCoVâ2 infection. Serology tests to detect the presence of antibodies to SARSâCoVâ2 enable detection of past infection and may detect cases of SARSâCoVâ2 infection that were missed by earlier diagnostic tests. Understanding the diagnostic accuracy of serology tests for SARSâCoVâ2 infection may enable development of effective diagnostic and management pathways, inform public health management decisions and understanding of SARSâCoVâ2 epidemiology.
Objectives
To assess the accuracy of antibody tests, firstly, to determine if a person presenting in the community, or in primary or secondary care has current SARSâCoVâ2 infection according to time after onset of infection and, secondly, to determine if a person has previously been infected with SARSâCoVâ2. Sources of heterogeneity investigated included: timing of test, test method, SARSâCoVâ2 antigen used, test brand, and reference standard for nonâSARSâCoVâ2 cases.
Search methods
The COVIDâ19 Open Access Project living evidence database from the University of Bern (which includes daily updates from PubMed and Embase and preprints from medRxiv and bioRxiv) was searched on 30 September 2020. We included additional publications from the Evidence for Policy and Practice Information and Coâordinating Centre (EPPIâCentre) âCOVIDâ19: Living map of the evidenceâ and the Norwegian Institute of Public Health âNIPH systematic and living map on COVIDâ19 evidenceâ. We did not apply language restrictions.
Selection criteria
We included test accuracy studies of any design that evaluated commercially produced serology tests, targeting IgG, IgM, IgA alone, or in combination. Studies must have provided data for sensitivity, that could be allocated to a predefined time period after onset of symptoms, or after a positive RTâPCR test. Small studies with fewer than 25 SARSâCoVâ2 infection cases were excluded. We included any reference standard to define the presence or absence of SARSâCoVâ2 (including reverse transcription polymerase chain reaction tests (RTâPCR), clinical diagnostic criteria, and preâpandemic samples).
Data collection and analysis
We use standard screening procedures with three reviewers. Quality assessment (using the QUADASâ2 tool) and numeric study results were extracted independently by two people. Other study characteristics were extracted by one reviewer and checked by a second. We present sensitivity and specificity with 95% confidence intervals (CIs) for each test and, for metaâanalysis, we fitted univariate randomâeffects logistic regression models for sensitivity by eligible time period and for specificity by reference standard group. Heterogeneity was investigated by including indicator variables in the randomâeffects logistic regression models. We tabulated results by test manufacturer and summarised results for tests that were evaluated in 200 or more samples and that met a modification of UK Medicines and Healthcare products Regulatory Agency (MHRA) target performance criteria.
Main results
We included 178 separate studies (described in 177 study reports, with 45 as preâprints) providing 527 test evaluations. The studies included 64,688 samples including 25,724 from people with confirmed SARSâCoVâ2; most compared the accuracy of two or more assays (102/178, 57%). Participants with confirmed SARSâCoVâ2 infection were most commonly hospital inpatients (78/178, 44%), and preâpandemic samples were used by 45% (81/178) to estimate specificity. Over twoâthirds of studies recruited participants based on known SARSâCoVâ2 infection status (123/178, 69%). All studies were conducted prior to the introduction of SARSâCoVâ2 vaccines and present data for naturally acquired antibody responses. Seventyânine percent (141/178) of studies reported sensitivity by week after symptom onset and 66% (117/178) for convalescent phase infection. Studies evaluated enzymeâlinked immunosorbent assays (ELISA) (165/527; 31%), chemiluminescent assays (CLIA) (167/527; 32%) or lateral flow assays (LFA) (188/527; 36%).
Risk of bias was high because of participant selection (172, 97%); application and interpretation of the index test (35, 20%); weaknesses in the reference standard (38, 21%); and issues related to participant flow and timing (148, 82%). We judged that there were high concerns about the applicability of the evidence related to participants in 170 (96%) studies, and about the applicability of the reference standard in 162 (91%) studies.
Average sensitivities for current SARSâCoVâ2 infection increased by week after onset for all target antibodies. Average sensitivity for the combination of either IgG or IgM was 41.1% in week one (95% CI 38.1 to 44.2; 103 evaluations; 3881 samples, 1593 cases), 74.9% in week two (95% CI 72.4 to 77.3; 96 evaluations, 3948 samples, 2904 cases) and 88.0% by week three after onset of symptoms (95% CI 86.3 to 89.5; 103 evaluations, 2929 samples, 2571 cases). Average sensitivity during the convalescent phase of infection (up to a maximum of 100 days since onset of symptoms, where reported) was 89.8% for IgG (95% CI 88.5 to 90.9; 253 evaluations, 16,846 samples, 14,183 cases), 92.9% for IgG or IgM combined (95% CI 91.0 to 94.4; 108 evaluations, 3571 samples, 3206 cases) and 94.3% for total antibodies (95% CI 92.8 to 95.5; 58 evaluations, 7063 samples, 6652 cases). Average sensitivities for IgM alone followed a similar pattern but were of a lower test accuracy in every time slot.
Average specificities were consistently high and precise, particularly for preâpandemic samples which provide the least biased estimates of specificity (ranging from 98.6% for IgM to 99.8% for total antibodies).
Subgroup analyses suggested small differences in sensitivity and specificity by test technology however heterogeneity in study results, timing of sample collection, and smaller sample numbers in some groups made comparisons difficult. For IgG, CLIAs were the most sensitive (convalescentâphase infection) and specific (preâpandemic samples) compared to both ELISAs and LFAs (P < 0.001 for differences across test methods). The antigen(s) used (whether from the Spikeâprotein or nucleocapsid) appeared to have some effect on average sensitivity in the first weeks after onset but there was no clear evidence of an effect during convalescentâphase infection.
Investigations of test performance by brand showed considerable variation in sensitivity between tests, and in results between studies evaluating the same test. For tests that were evaluated in 200 or more samples, the lower bound of the 95% CI for sensitivity was 90% or more for only a small number of tests (IgG, n = 5; IgG or IgM, n = 1; total antibodies, n = 4). More test brands met the MHRA minimum criteria for specificity of 98% or above (IgG, n = 16; IgG or IgM, n = 5; total antibodies, n = 7). Seven assays met the specified criteria for both sensitivity and specificity.
In a lowâprevalence (2%) setting, where antibody testing is used to diagnose COVIDâ19 in people with symptoms but who have had a negative PCR test, we would anticipate that 1 (1 to 2) case would be missed and 8 (5 to 15) would be falsely positive in 1000 people undergoing IgG or IgM testing in week three after onset of SARSâCoVâ2 infection.
In a seroprevalence survey, where prevalence of prior infection is 50%, we would anticipate that 51 (46 to 58) cases would be missed and 6 (5 to 7) would be falsely positive in 1000 people having IgG tests during the convalescent phase (21 to 100 days postâsymptom onset or postâpositive PCR) of SARSâCoVâ2 infection.
Authors' conclusions
Some antibody tests could be a useful diagnostic tool for those in whom molecularâ or antigenâbased tests have failed to detect the SARSâCoVâ2 virus, including in those with ongoing symptoms of acute infection (from week three onwards) or those presenting with postâacute sequelae of COVIDâ19. However, antibody tests have an increasing likelihood of detecting an immune response to infection as time since onset of infection progresses and have demonstrated adequate performance for detection of prior infection for seroâepidemiological purposes. The applicability of results for detection of vaccinationâinduced antibodies is uncertain
Cytomegalovirus induced refractory TTP in an immunocompetent individual: a case report
Abstract Background Thrombotic thrombocytopenic purpura (TTP) is a rare, potentially fatal disease with multisystem involvement. Cytomegalovirus (CMV) infection as a cause of refractory TTP, has been reported only in immunocompromised individuals. We report a case of CMV-induced refractory TTP in an immunocompetent individual. Case presentation A 35-year-old, previously healthy Sri Lankan man, presented with fever for 3âdays with gum bleeding and progressive drowsiness. His Glasgow coma scale score was 10/15. He did not have papilloedema or neck stiffness. Laboratory evaluation showed a severe thrombocytopenia with microangiopathic haemolytic anaemia. There was marginal renal impairment and normal coagulation profile. Non-contrast CT scan of brain was normal. A diagnosis of thrombotic thrombocytopenic purpura was made. Despite daily plasma exchanges and high-dose steroids, he failed to achieve the expected therapeutic response, thus demonstrating refractory TTP. On exploring for possible causes of refractoriness to treatment, a clinically significant PCR titre of CMV was detected. Treatment of CMV infection lead to complete recovery of TTP. His disease course was further complicated with spontaneous spinal haemorrhage leading to neurological sequelae. Discussion and conclusions This is the first report of CMV induced refractory TTP in an immunocompetent adult. It is also the first report of clinically significant spontaneous spinal haematoma in TTP. These two rare occurrences should be considered when patients with refractory TTP do not improve as expected
Unilateral Osler nodes, Janeway lesions and splinter haemorrhages associated with surgical arterio-venous fistula infection: a case report
Abstract Background Oslerâs nodes, Janeway lesions and splinter haemorrhages are cutaneous manifestations of infective endocarditis. They occur due to vascular occlusion by septic emboli and a resulting localized vasculitis. They are usually bilateral. We report a case of unilateral Oslerâs nodes, Janeway lesions and splinter haemorrhages due to an ipsilateral surgical arterio-venous fistula infection. Case presentation A fifty-two-year-old Sri Lankan female with end stage kidney disease presented with fever for five days with blurred vision, pain and redness of the right eye. She had a left brachio-cephalic arterio-venous fistula (AVF) created one month back. She complained of a foul-smelling discharge from the surgical site for past three days. Redness of the right eye with a hypopyon was noted. AVF site over the left cubital fossa was infected with a purulent discharge. Oslerâs nodes, Janeway lesions and splinter haemorrhages were noted in the distal fingers, thenar and hypothenar eminences of the left hand. Right hand and both feet were normal. No cardiac murmurs were heard. Blood cultures, vitreous sample cultures and pus cultures from the fistula site were all positive for methicillin sensitive Staphylococcus aureus. Infective endocarditis was excluded by a trans-oesophageal echocardiogram. She was treated with IV flucloxacillin and surgical excision of the AVF. Conclusion Infections of AVF can result in septic emboli formation which can have both anterograde arterial embolization and retrograde venous embolization. Arterial embolization can result in unilateral Oslerâs nodes, Janeway lesions and splinter haemorrhages. Venous embolization can cause metastatic infections in the systemic and pulmonary circulations
Evolution into Takayasu arteritis in a patient presenting with acute pulmonary oedema due to severe aortic regurgitation; a case report
Abstract Background Takayasu arteritis is a rare large vessel vasculitis which predominantly affects young Asian females. Aortic regurgitation and heart failure are well described manifestations which are usually preceded by constitutional symptoms, limb claudication, pulse and blood pressure discrepancies, vascular bruits and features of organ ischaemia. Case presentation A 25-year- old Sri Lankan female presented with a three days history of acute shortness of breath, cough and orthopnoea. On examination she had severe aortic regurgitation resulting in high output cardiac failure. There was no evidence of acute coronary ischaemia or infective endocarditis. The only significant investigation finding was an elevated erythrocyte sedimentation rate (ESR) of 114Â mm/first hour. The patient was treated for pulmonary oedema and empirically for infective endocarditis. Extensive evaluation for an underlying infection, large vessel vasculitis or malignancy did not reveal any abnormalities. Detailed periodic assessment identified reduced blood pressure in left arm (70/40Â mmHg) compared to right (100/70Â mmHg) and reduced pulse volume of left arm with left subclavian bruit more than one year after the initial presentation. Digital subtraction angiography revealed significant stenosis at first part of left subclavian and origin of left vertebral arteries. A diagnosis of Takayasu arteritis was made and patient was started on high dose glucocorticoids. Conclusions Takayasu arteritis can present initially with isolated cardiac involvement even as acute cardiac manifestations and high degree of suspicion with close follow up would allow early detection of development of other classic features and timely diagnosis
Embolizing pulmonary aspergillosis, mycobacterial & aspergillous splenic abscess and cytomegalovirus co-infection following steroid induced immunosuppression: a case report
Abstract Background Aspergillosis is a serious infection particularly affecting the immunodeficient host. Its co-infection with tuberculosis and cytomegalovirus has not been reported before. Embolic events are well recognized with aspergillous endocarditis and aortitis. Splenic abscess is a rare serious complication of disseminated aspergillosis and is difficult to treat. We report the first case of multiple embolic events and splenic abscess in a patient with pulmonary aspergillosis and cytomegaloviral and tuberculous co-infection, without endocarditis or aortitis. Case presentation Thirty-year-old male presented with fever and non-productive cough while on glucocorticoids for glomerulonephritis. He was found to have pulmonary aspergillosis and subsequently developed bilateral lower limb and cerebral fungal emboli and fungal abscess in the spleen. He had IgM and B cell deficiency and cytomegalovirus (CMV) and tuberculous co-infections. He recovered after prolonged course of antimicrobials, splenectomy and cessation of glucocorticoid therapy which also lead to the resolution of immune deficiencies. Conclusion This report illustrates rare combination of B and T cell suppressive effects of glucocorticoids leading to co-infections with CMV, Mycobacterium tuberculosis and Aspergillus and systemic fungal embolization from pulmonary aspergillosis