Diagnostic test

Could long Covid’s signs of immune dysregulation in the blood lead to a diagnostic test?

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Blood samples. -- health coverage from STAT

Long Covid has long eluded scientists looking for its cause. Not knowing what triggers its persistent and distressing symptoms makes the condition challenging to treat; it’s hard to even say definitively who has it. New research published Thursday in Science has identified proteins present in the blood of people with long Covid that could point the way to a much-needed diagnostic test and possibly to future therapeutic targets.

Scientists at the University of Zurich discovered high levels of proteins involved in the complement system — an important part of the immune system bridging innate and adaptive responses — that were disrupted in people with long Covid symptoms, but not in those who got better after the initial Covid-19 infection or in those who had recovered from long Covid symptoms after six months. The team also found damaged red blood cells and platelets as well as signs of harm to the endothelial cells that line blood vessels.

These biomarkers appeared after the researchers performed high-throughput analyses of more than 6,500 proteins found in the blood serum of 113 people infected with Covid, including 40 people who developed long Covid, and controls who were not infected.

Starting in 2020, a team led by Carlo Cervia-Hasler of University Hospital Zurich and the University of Zurich continued to take samples for a year. Their results were later validated against a larger cohort from Mount Sinai in New York.

Cervia-Hasler told STAT the striking difference in complement proteins was very surprising at first. But then, “it started to make sense because in all these hypotheses that are out there on long Covid, somehow you could connect them a bit with the complement system in the middle. So it will be very interesting further on to see how everything fits under one hat.”

Those hypotheses about the cause of long Covid include the possibility that there are viral reservoirs where SARS-CoV-2 lingers; that inflammation sparked by the infection doesn’t subside; and that the infection triggers autoimmunity, in which the immune system attacks its own cells instead of invaders. Other studies, including one published in November 2023 in Science Translational Medicine, have identified immune signatures in the blood of people with long Covid.

In Thursday’s study, certain complement components went up and down in people with long Covid, changes that could be a clue to why long Covid lingers, Cervia-Hasler said. First there is a cascade of complement proteins in response to the virus. Then complement components subside, leaving the blood and entering healthy cells. The complement system is supposed to fight infected cells and get rid of damaged ones, but when the system is too active, it can also damage healthy cells and renew the battle.

“We could be looking at a vicious cycle,” he said. “After infection or tissue damage where complement is involved, usually it’s not activated anymore after a certain time. The question is, why is it still active in long Covid? Could we block it with certain complement therapy?”

Nadia Roan, a senior investigator at the Gladstone Institute and a professor at University of California, San Francisco, who was not involved with the study, leads a lab that studies immune cells and human viruses, including long Covid. She called the Science study “quite fascinating” in an interview.

“The dysregulation they observed is a bit complex, as some complement components go up and others go down, but overall the results suggest that complement pathways are abnormal in people with long Covid,” said Roan, the senior author of a Nature Immunology paper published earlier in January on immune response in long Covid. “It was also interesting that complement dysregulation seems to normalize in those with long Covid that subsequently recover from the condition.”

The Zurich team’s protein analysis revealed something other researchers have noted: Antibodies against prior herpesvirus infections were reactivated. That finding further supports the idea that people with long Covid are living with immune dysregulation, including increased inflammation, altered autoantibody profiles, and elevated herpesvirus antibody responses, Roan said.

Cervia-Hasler hopes these changes in complement activation could become enough of a long Covid signature in blood samples to develop a diagnostic based on them. Such a test would also look at three other factors: age, body mass index, and signs of abnormal blood clotting with inflammation.

“We really wanted to find something we could use to give patients because many are stigmatized as psychiatric patients who need treatment. Or the care they get, it’s often the wrong one because it’s difficult to objectify what they are reporting,” he said. “And now as Covid tests are even less performed, it’s even more difficult to get a proper diagnosis.”

What’s next? More and larger trials, Cervia-Hesler said, to go into further detail and confirm what they found, looking even longer after the initial Covid-19 infection to understand how it might change over time. And while there are drugs to treat forms of complement dysregulation found in certain genetic diseases, he said much more work needs to be done to establish the mechanism by which the complement system works in long Covid. “Of course, not every Covid patient is the same.”

Gladstone’s Roan takes a similarly cautious view of both treatment and testing. “I think it will be crucial to determine the extent to which dysregulated complement is an actual cause of long Covid, and therefore a potential therapeutic target,” she said. “The extent to which this serves as a useful biomarker of long Covid, however, will require validation in larger cohorts, and it is unlikely that a single biomarker can be used to diagnose long Covid given the heterogeneity of the condition.”

Wolfram Ruf, scientific director of the Center for Thrombosis and Hemostasis at Johannes Gutenberg University in Mainz, Germany, leans more toward a possible diagnostic than a treatment. “Although therapeutic interventions with coagulation and complement inhibitors in acute Covid-19 produced mixed results, the pathological features specific for long Covid suggest potential interventions for clinical testing,” he wrote in a related Science commentary.

Cervia-Hesler hopes other research groups will look in more detail at pathways that may have been overlooked. “I look forward also to seeing where the field moves, hopefully toward a diagnostic tool or therapeutic solution as early as possible.”

Changes in exhaled 13CO2/12CO2 breath delta value as an early indicator of infection in intensive care unit patients

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BACKGROUND We have developed a new, noninvasive predictive marker for onset of infection in surgical intensive care unit (ICU) patients. The exhaled 13CO2/12CO2 ratio, or breath delta value (BDV), has been shown to be an early marker for infection in a proof of concept human study and in animal models of bacterial peritonitis. In these studies, the BDV changes during onset and progression of infection, and these changes precede physiological changes associated with infection. Earlier diagnosis and treatment will significantly reduce morbidity, mortality, hospitalization costs, and length of stay. The objective of this prospective, observational, multicenter study was to determine the predictive value of the BDV as an early diagnostic marker of infection.

METHODS Critically ill adults after trauma or acute care surgery with an expected length of stay longer than 5 days were enrolled. The BDV was obtained every 4 hours for 7 days and correlated to clinical infection diagnosis, serum C-reactive protein, and procalcitonin levels. Clinical infection diagnosis was made by an independent endpoint committee. This trial was registered at the US National Institutes of Health (ClinicalTrials.gov) NCT02327130.

RESULTS Groups were demographically similar (n = 20). Clinical infection diagnosis was confirmed on day 3.9 ± 0.63. Clinical suspicion of infection (defined by SIRS criteria and/or new antibiotic therapy) was on day 2.1 ± 0.5 in all infected patients. However, 5 (56%) of 9 noninfected subjects also met clinical suspicion criteria. The BDV significantly increased by 1‰ to 1.7‰ on day 2.1 after enrollment (p < 0.05) in subjects who developed infections, while it remained at baseline (± 0.5‰) for subjects without infections.

CONCLUSION A BDV greater than 1.4‰ accurately differentiates subjects who develop infections from those who do not and predicts the presence of infection up to 48 hours before clinical confirmation. The BDV may predict the onset of infection and aid in distinguishing SIRS from infection, which could prompt earlier diagnosis, earlier appropriate treatment, and improve outcomes.

LEVEL OF EVIDENCE Diagnostic test, level III.

If You Can Smell This, You May Not Have Alzheimer’s.

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A new diagnostic test involves a dollop of peanut butter.

Peanut Butter

You may not have heard of “the peanut butter test,” but it could become a fantastically low-cost and non-invasive way to test for Alzheimer’s. After all, what’s less invasive than asking someone to smell some delicious peanut butter?

“The ability to smell is associated with the first cranial nerve and is often one of the first things to be affected in cognitive decline,” reads this release from the University of Florida, researchers from which conducted the experiment. But with Alzheimer’s patients, the sense of smell is affected in a very particular way: The left nostril is significantly more impaired than the right. Weird! But true.

The experiment involved capping one nostril and measuring the distance at which the patient could detect about a tablespoon of peanut butter. In Alzheimer’s patients, the left nostril was impaired so thoroughly that, on average, it had 10 centimeters less range than the right, in terms of odor detection. That’s specific to Alzheimer’s patients; neither control patients (those not suffering from cognitive decline) nor those with other types of cognitive impairment (like dementia) demonstrated that nostril difference.

Peanut butter was used because it’s a so-called “pure odorant.” Generally our sense of smell actually incorporates two distinct sensations: the olfactory sense, or smell, as well as a trigeminal sense, which is like a more physical burning or stinging sort of sense. Peanut butter has no trigeminal element; it’s only olfactory, which makes it ideal for testing, as the link to Alzheimer’s is specifically dealing with the olfactory sense.

This could be a great, inexpensive, early warning system for those with Alzheimer’s; the illness is not easy to detect, requiring neurological examination as well as mental, and has to be carried out by a professional. The peanut butter test? Much easier.

Galactomannan and PCR versus culture and histology for directing use of antifungal treatment for invasive aspergillosis in high-risk haematology patients: a randomised controlled trial.

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Background

Empirical treatment with antifungal drugs is often used in haematology patients at high risk of invasive aspergillosis. We compared a standard diagnostic strategy (culture and histology) with a rapid biomarker-based diagnostic strategy (aspergillus galactomannan and PCR) for directing the use of antifungal treatment in this group of patients.

Methods

In this open-label, parallel-group, randomised controlled trial, eligible patients were adults undergoing allogeneic stem-cell transplantation or chemotherapy for acute leukaemia, with no history of invasive fungal disease. Enrolled patients were randomly assigned (1:1) by a computer-generated schedule to follow either a standard diagnostic strategy (based on culture and histology) or a biomarker-based diagnostic strategy (aspergillus galactomannan and PCR) to direct treatment with antifungal drugs. Patients, were followed up for 26 weeks or until death. Masking of the use of different diagnostic tests was not possible for patients, treating physicians, or investigators. The primary endpoint was empirical treatment with antifungal drugs in the 26 weeks after enrolment (for the biomarker-based diagnostic strategy, a single postive galactomannan or PCR result was deemed insufficient to confirm invasive aspergillosis, so treatment in this context was classified as empirical). This outcome was assessed by an independent data review committee from which the study allocations were masked. Analyses were by intention to treat and included all enrolled patients. This study is registered withClinicalTrial.gov, number NCT00163722.

Findings

240 eligible patients were recruited from six Australian centres between Sept 30, 2005, and Nov 19, 2009. 122 were assigned the standard diagnostic strategy and 118 the biomarker-based diagnostic strategy. 39 patients (32%) in the standard diagnosis group and 18 (15%) in the biomarker diagnosis group received empirical antifungal treatment (difference 17%, 95% CI 4—26; p=0·002). The numbers of patients who had hepatotoxic and nephrotoxic effects did not differ significantly between the standard diagnosis and biomarker diagnosis groups (hepatotoxic effects: 21 [17%] vs 12 [10%], p=0·11; nephrotoxic effects: 52 [43%] vs 60 [51%], p=0·20).

Interpretation

Use of aspergillus galactomannan and PCR to direct treatment reduced use of empirical antifungal treatment. This approach is an effective strategy for the management of invasive aspergillosis in high-risk haematology patients.

Source: lancet

Wireless Motility Capsule Versus Other Diagnostic Technologies for Evaluating Gastroparesis and Constipation: A Comparative Effectiveness Review..

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To systematically review the evidence comparing wireless motility capsule (WMC) with other diagnostic tests used for the evaluation of gastroparesis and slow-transit constipation, in terms of diagnostic accuracy, accuracy of motility assessment, effect on treatment decisions, effect on patient-centered outcomes, harms, and effect on resource utilization. Data sources. We searched Medline ® and Embase ® from inception through July 2012. Additionally, we scanned reference lists of relevant articles and queried experts. Review methods. We included studies in any language that compared WMC with other diagnostic tests among patients with suspected gastroparesis or slow-transit constipation. Two reviewers independently assessed articles for eligibility, serially abstracted data from relevant articles, independently evaluated study quality, and graded the strength of the evidence (SOE). We summarized results qualitatively rather than quantitatively because of the heterogeneity of studies. Results. We included 12 studies (18 publications). Seven studies evaluated diagnosis of gastric emptying delay; we found low SOE that WMC alone was comparable to scintigraphy for diagnostic accuracy, accuracy of motility assessment, effect on treatment decisions, and effect on resource utilization. Sensitivity of WMC compared with gastric scintigraphy ranged from 59 to 86 percent and specificity ranged from 64 to 81 percent. We found two studies evaluating WMC as an add-on to other testing. The SOE was low for diagnostic accuracy and for the accuracy of motility assessment by WMC in combination with other modalities. The addition of WMC increased diagnostic yield. Nine studies analyzed colon transit disorders and provided moderate SOE for diagnostic accuracy, accuracy of motility assessment, and harms. WMC was comparable to radiopaque markers (ROM), with concordance ranging between 64 percent and 87 percent. Few harms were reported. The evidence was insufficient to justify conclusions about effects of WMC on treatment decisions and resource utilization. Conclusions. WMC is comparable in accuracy to current modalities in use for detection of slowtransit constipation and gastric emptying delay, and is therefore another viable diagnostic modality. Little data are available to determine the optimal timing of WMC for diagnostic algorithms.

Source: AHRQ Comparative Effectiveness Review.

Use of serum C reactive protein and procalcitonin concentrations in addition to symptoms and signs to predict pneumonia in patients presenting to primary care with acute cough: diagnostic study.

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Abstract

Objectives To quantify the diagnostic accuracy of selected inflammatory markers in addition to symptoms and signs for predicting pneumonia and to derive a diagnostic tool.

Design Diagnostic study performed between 2007 and 2010. Participants had their history taken, underwent physical examination and measurement of C reactive protein (CRP) and procalcitonin in venous blood on the day they first consulted, and underwent chest radiography within seven days.

Setting Primary care centres in 12 European countries.

Participants Adults presenting with acute cough.

Main outcome measures Pneumonia as determined by radiologists, who were blind to all other information when they judged chest radiographs.

Results Of 3106 eligible patients, 286 were excluded because of missing or inadequate chest radiographs, leaving 2820 patients (mean age 50, 40% men) of whom 140 (5%) had pneumonia. Re-assessment of a subset of 1675 chest radiographs showed agreement in 94% (κ 0.45, 95% confidence interval 0.36 to 0.54). Six published “symptoms and signs models” varied in their discrimination (area under receiver operating characteristics curve (ROC) ranged from 0.55 (95% confidence interval 0.50 to 0.61) to 0.71 (0.66 to 0.76)). The optimal combination of clinical prediction items derived from our patients included absence of runny nose and presence of breathlessness, crackles and diminished breath sounds on auscultation, tachycardia, and fever, with an ROC area of 0.70 (0.65 to 0.75). Addition of CRP at the optimal cut off of >30 mg/L increased the ROC area to 0.77 (0.73 to 0.81) and improved the diagnostic classification (net reclassification improvement 28%). In the 1556 patients classified according to symptoms, signs, and CRP >30 mg/L as “low risk” (<2.5%) for pneumonia, the prevalence of pneumonia was 2%. In the 132 patients classified as “high risk” (>20%), the prevalence of pneumonia was 31%. The positive likelihood ratio of low, intermediate, and high risk for pneumonia was 0.4, 1.2, and 8.6 respectively. Measurement of procalcitonin added no relevant additional diagnostic information. A simplified diagnostic score based on symptoms, signs, and CRP >30 mg/L resulted in proportions of pneumonia of 0.7%, 3.8%, and 18.2% in the low, intermediate, and high risk group respectively.

Conclusions A clinical rule based on symptoms and signs to predict pneumonia in patients presenting to primary care with acute cough performed best in patients with mild or severe clinical presentation. Addition of CRP concentration at the optimal cut off of >30 mg/L improved diagnostic information, but measurement of procalcitonin concentration did not add clinically relevant information in this group.

Discussion

Main findings

Pneumonia was diagnosed by chest x radiography in 140 (5%) of the 2820 patients presenting to primary care with acute cough. The optimal combination of symptoms and signs for predicting pneumonia was absence of runny nose and presence of breathlessness, crackles and diminished breath sounds on auscultation, tachycardia, and fever. Signs and symptoms were useful in correctly identifying patients with a “low” (<2.5%) or “high” (>20%) diagnostic risk in 26% of patients. In the 74% of patients in whom diagnostic doubt remained (estimated risk 2.5%-20%), measurement of C reactive protein (CRP) concentration helped to correctly exclude pneumonia. A simplified diagnostic score based on symptoms, signs, and CRP concentration resulted in proportions of pneumonia of 0.7%, 4%, and 18% in the low, intermediate, and high risk group, respectively. Measurement of procalcitonin concentration had no clinically relevant added value in this setting.

Strengths and limitations

This is the first study to quantify the independent diagnostic value of symptoms, signs, and additional diagnostic value of inflammatory markers for pneumonia in patients presenting with acute cough in primary care that included an adequate number of cases of pneumonia. All blood samples were analysed in the same laboratory with standardised procedures. Serum CRP and procalcitonin concentrations were measured by conventional venous blood tests in a diagnostic laboratory and not with a point of care test. The added value of CRP might be different and could be lower when measured with a point of care test in general practice. Nonetheless, agreement between point of care test results and a conventional reference test has been shown to be good.44

Given how common lower respiratory tract infections are, many more eligible patients presented during the recruitment period than were approached about participation in this study, and therefore we probably did not achieve the goals of recruiting all consecutive, eligible patients. Nevertheless, we do not believe that there was important clinical selection bias because feedback from recruiting clinicians during and after the study was that the time required to recruit and assess each patient made sequential recruitment of every eligible patient impossible.

Chest radiographs were examined by local radiologists. We attempted to increase uniformity in assessment by implementing a protocol for reporting. While there was some variability between observers, the moderate unweighted κ of 0.45 was similar to that reported in other studies.18 20

We did not attempt to distinguish between bacterial and viral pneumonia as this is not feasible in routine primary care.14 45 All available relevant guidelines advocate identification of patients with pneumonia and treatment with antibiotics without further aetiological testing.14

Comparison with other studies

Absence of a runny nose and presence of dry cough, breathlessness, chest pain, diarrhoea, fever, and crackles have previously been found to have diagnostic value for pneumonia in primary care populations.7 9 “Tachycardia” and “diminished vesicular breathing” have diagnostic value in secondary care populations.3 6 8 11 We were able to confirm the predictive value of most of these items, apart from chest pain and diarrhoea. Differences between our findings and those from previous studies could relate to the difference in prevalence of pneumonia, inclusion criteria, and outcome definition.

Our finding that CRP concentration can be low in people with pneumonia is not new. Flanders and colleagues reported on a small subgroup of patients with pneumonia who had a CRP of less than 11 mg/L.3 In the 54 patients with pneumonia with low CRP in our study, the estimated diagnostic risk of pneumonia was high (n=3) or intermediate (n=51) based on history and physical examination results as defined in our model. These findings emphasise that CRP test results should be interpreted together with clinical findings.

Of the factors known to lower CRP—such as steroid use46 and duration of disease47—only steroid use (including both oral and inhaled steroids) was significantly more prevalent in the group of patients with pneumonia with low CRP concentration. Exclusion of all steroid users from our analyses resulted in a similar association between CRP concentration and pneumonia.

Procalcitonin concentrations in our study were higher in patients with pneumonia and comparable with previous findings in patients with lower respiratory tract infection in primary care.17 48 They did not, however, add meaningful diagnostic information. Holm and colleagues showed a clear association between procalcitonin concentration and radiographic pneumonia as well as bacterial infection,17 but the positive predictive value was too low to be useful in clinical practice. Our findings support this conclusion. Moreover, Holm and colleagues studied a population with a higher prevalence of pneumonia (13%) and did not combine history and physical examination with procalcitonin test results.17

Implications for practice and conclusions

Although the diagnostic “symptoms and signs” model presented in this study assigned an intermediate diagnostic risk of pneumonia to most patients, history taking and physical examination alone enabled general practitioners to correctly identify a small group of patients at high risk. Chest radiography and/or (empirical) antibiotic treatment should therefore be considered in these patients. In these more severely ill patients, point of care tests, including CRP, do not seem to be useful. In patients with a low risk of pneumonia based on symptoms and signs, it seems justified to withhold further diagnostic investigation and not to treat with antibiotics.

CRP has additional diagnostic value in patients with an intermediate diagnostic risk of pneumonia as determined by symptoms and signs alone, especially in appropriately excluding pneumonia. Procalcitonin has no additional diagnostic value in primary care.

The simplified score derived from the regression models is more suitable for uptake in daily care than the regression models. The downside of the simplified score is that it is less precise and contains less diagnostic information. To determine whether our diagnostic model improves clinical outcomes in everyday practice would require an implementation study in which general practitioners use point of care CRP testing with outcomes such as patient recovery and the unnecessary prescription of antibiotics. Further research should also determine the performance of CRP in other settings where pneumonia is more prevalent or where patients are more severely ill.

What is already known on this topic

  • Studies have evaluated the diagnostic accuracy of signs and symptoms for pneumonia, but there is limited evidence applicable to primary care
  • The added diagnostic value of C reactive protein (CRP) and procalcitonin concentrations to clinical signs and symptoms is unknown
  • Symptoms and signs (absence of runny nose and presence of breathlessness, crackles and diminished breath sounds on auscultation, tachycardia, and fever) have moderate diagnostic accuracy for pneumonia in patients who present in primary care with acute cough
  • CRP concentration at the optimal threshold of >30 mg/L adds some diagnostic information by increasing diagnostic certainty in the patients when doubt remains after history and physical examination
  • Procalcitonin concentration adds no clinically relevant information in primary care

What this study adds

Source: BMj

 

 

Imaging in Acute Cholecystitis.

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Cholescintigraphy is slightly more accurate, but ultrasound is more readily available.

Ultrasound (US) and cholescintigraphy (e.g., hepatobiliary iminodiacetic acid [HIDA] scanning) are used widely to evaluate patients with suspected acute cholecystitis. Additionally, emergency department clinicians sometimes order computed tomography (CT) as the initial test, especially when they are considering both biliary and nonbiliary causes of abdominal pain.

To address the diagnostic accuracy of imaging tests for acute cholecystitis, researchers performed a meta-analysis of 57 studies with explicitly stated criteria for positive tests and with surgery and clinical follow-up as reference standards. Cholescintigraphy was evaluated in 40 studies, and US was evaluated in 26 studies; CT and magnetic resonance imaging were evaluated in only 1 and 3 studies, respectively. For cholescintigraphy, sensitivity was 96% and specificity was 90%; nonvisualization of the gallbladder was the usual criterion for a positive test. For US, sensitivity was 81% and specificity was 83%; criteria for a positive test varied widely, from simple presence of gallstones to combinations of additional findings (e.g., wall thickening, distention, pericholecystic fluid, sonographic Murphy sign).

Comment: Although US might be less accurate than cholescintigraphy, it remains a reasonable initial procedure, because it is simple and inexpensive to perform. The investigators’ figures for sensitivity and specificity of US should be considered only approximations, given the varying criteria for positive tests across studies. Cholescintigraphy should be done when US results are ambiguous. Despite widespread use of CT for initial evaluation of abdominal pain, its accuracy for acute cholecystitis has not been studied adequately.

Source:

Journal Watch General Medicine

Reducing the Rate of Active TB by Targeted Testing and Treatment.

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Such a program, initiated by the Tennessee Department of Health, prevented an estimated 184 cases of active tuberculosis during its first 5 years.

Although the overall number of new tuberculosis (TB) cases has declined in the U.S., the proportion of cases among foreign-born individuals has increased. Most such cases are due to reactivation of latent TB infection (LTBI).

To address this problem, the Tennessee Department of Health initiated a targeted tuberculin testing program in which individuals determined to have any risk factor for TB exposure (or for progression to active TB, once infected) are screened using the tuberculin skin test (TST), and those with positive test results receive treatment for LTBI. Now, researchers have evaluated the results of this program from its initiation, in March 2002, through December 2006.

After initial risk screening of 168,517 people, 125,200 individuals had a TST placed. Of these, 91,332 (73%) were considered to be high risk, including 21,680 (17%) who were foreign born. Among 102,709 recorded TST results, 9090 (9%) were positive. The positive TST rate was 33% for foreign-born persons, compared with 5% for high-risk, U.S.-born individuals and 1% for low-risk individuals. The number needed to test to identify one case of LTBI was 4 for foreign-born individuals, 24 for high-risk, U.S.-born persons, and 85 for low-risk persons. A total of 4780 individuals with positive TST results initiated LTBI therapy, and 1953 (54%) completed it. An estimated 184 cases of active TB were prevented.

Comment: These findings suggest that targeted testing and treatment of persons at high risk for TB, particularly those who are foreign born, can result in marked reductions in TB rates over time.

Source: Journal Watch Infectious Diseases