Single Negative Test Research Articles

Updated COVID-19 clearance time among patients with cancer in the Delta and Omicron waves.

COVID-19 infection delays therapy and in-person evaluation for oncology patients, but clinic clearance criteria are not clearly defined. We conducted a retrospective review of oncology patients with COVID-19 at a tertiary care center during the Delta and Omicron waves and compared clearance strategies. Median clearance by two consecutive negative tests was 32.0 days (Interquartile Range [IQR] 22.0-42.5, n = 153) and was prolonged in hematologic malignancy versus solid tumors (35.0 days for hematologic malignancy, 27.5 days for solid tumors, p = 0.01) and in patients receiving B-cell depletion versus other therapies. Median clearance by single negative test was reduced to 23.0 days (IQR 16.0-33.0), with recurrent positive rate 25.4% in hematologic malignancy versus 10.6% in solid tumors (p = 0.02). Clearance by a predefined waiting period required 41 days until an 80% negative rate. COVID-19 clearance remains prolonged in oncology patients. Single-negative test clearance can balance delays in care with risk of infection in patients with solid tumors.

COVID-19 clearance among patients with cancer during the Delta and Omicron waves.

42 Background: COVID-19 presents a particular challenge in oncology, as in-person visits and treatments can be delayed during infection and patients are at risk for prolonged viral shedding. Our center uses two consecutive negative PCR tests for patients to return to clinic. As vaccination rates increase, we questioned the need for this strategy vs a time-based clearance approach. Methods: We identified cancer patients who tested positive for COVID-19 from 10/1/2021 to 3/31/2022 at a single tertiary care center and performed chart review under an IRB-approved protocol. Subgroups were compared using the Welch’s t-test and Welch’s ANOVA for 2 or > 2 groups, respectively. Results: 169 patients were identified. 153 had documented clearance defined as two consecutive negative PCR tests. The mean clearance time was 35.7 days (95% CI 32.3-39.0). There was a trend toward longer clearance time in patients with hematologic vs solid tumors (39.6 vs 33.2, p =.06) and a significant increase in patients treated with B cell depletion (58.0) vs chemo/targeted therapy (35.7, p =.01) or immunotherapy (29.0, p =.004). No significant difference was found by vaccination status or between the Delta and Omicron waves. If defined as one negative test, mean clearance time was 25.9 days (95% CI 23.6-28.1), and there was a significant difference in patients with hematologic vs solid tumors and in those treated with B cell depletion vs other therapies. However, 16.0% (27/169) of patients had a subsequent positive test after a first negative result, with increased incidence in patients with hematologic malignancy (26.2%, 16/61) and stem cell/adoptive cell transplant (46.2%, 6/13). Conclusions: COVID-19 is a significant barrier to oncologic care, and clearance times remain longer than reported for the general population. In this single center study, clearance time was > 1 month and further increased in patients with hematologic malignancy or on B cell depleting therapy. While adjusting clearance criteria to a single negative test or specific timeframe may be an attractive option to reduce delays, a large proportion of patients may have further positive PCR testing.[Table: see text]

The dilemma of routine testing for calcitonin thyroid nodule’s patients to detect or exclude medullary carcinoma: one single negative test should be valuable as rule-out strategy to avoid further calcitonin measurements over time

PurposeWhile calcitonin (CT) measurement is recognized as the most accurate tool to diagnose medullary thyroid carcinoma (MTC), its routine use in patients with thyroid nodule (TN) is not universally accepted. The present study raised the question whether a TN patient with an initial normal CT can have suspicious CT levels (i.e., at least >20 pg/ml) later during his follow-up.MethodsThe historical database of our institution was searched to select TN patients undergone multiple CT tests, having an initial normal CT, and clinically followed up for years. The event of a CT above 20 pg/ml (mild-to-moderate suspicion) and 100 pg/ml (high suspicion) was searched in the follow-up of the included patients.ResultsAccording to the study design, the study sample encompassed 170 patients (131 female, 39 male) with initial CT value ≤10 pg/ml. On the first CT test, patients were 54.8 years and median CT was 2.1 pg/ml in both females and males. Over a period of 14.5 years and a median clinical follow-up of patients of 53.0 (23.9–102.5) months, MTC could be excluded by histology or cytology in 109 (64%) and clinically in the remaining ones. On the follow-up over time, no patients had CT >20 pg/ml and only two cases had CT just above 10 pg/ml.ConclusionAccording to the present results, one single CT testing with normal value could be reasonably used as a rule-out strategy in patients with TN to avoid further CT measurements.

The impact of the COVID-19 outbreak on liver transplantation programs in Northern Italy.

In January 2020, Novel Coronavirus Disease 2019 (COVID‐19) resulted in a global pandemic, creating uncertainty toward the management of liver transplantation (LT) programs. Lombardy has been the most affected region in Italy: the current mortality rate of COVID‐19 patients is 18.3% (10 022 deaths; April 10th) with hospitals in Lombardy having to expand the total number of ICU beds from 724 to 1381 to accommodate infected patients. There has been a drastic decrease in liver donors. From February 23rd until April 10th, 17 LTs were performed in Lombardy. Mean donor age was 49 years (range 18‐74) whereas mean recipient age was 55 (13‐69); mean MELD score was 12 (6‐24). All donors underwent screening for SARS‐CoV‐2 prior to LT. Two patients tested positive after LT, and one patient died for COVID on POD 30. Sixteen patients are alive after an average of 30 days post‐LT (range 3‐46). 10 patients have been discharged. This study has found no specific reason concerning the safety of recipients, to stop LT programs. Several key lessons from our experience are reported. However, due to the complex circumstances which surround the viral outbreak, the cessation or a reduction in LT activity is a pragmatic requirement.

A Bayesian analysis of strategies to rule out COVID19 using reverse transcriptase-polymerase chain reaction (RT-PCR).

To the Editor.—The coronavirus disease 2019 (COVID-19) pandemic may overwhelm health care capacity in parts of the United States and United Kingdom in the coming months.1 Erroneously ruling out COVID-19 based on a false-negative diagnostic test poses a public health hazard. The probability of such an error is quantified by the false omission rate (FOR). The FOR = false negatives/(true negatives + false negatives), and this value depends on the prevalence of disease and operating characteristics of the diagnostic test. Preliminary data suggest the sensitivity of the COVID-19 reverse transcriptase–polymerase chain reaction (RT-PCR) may be 70% for nasopharyngeal (NP) and sputum samples, and 90% for bronchoalveolar lavage (BAL).2–4 We examined strategies to rule out COVID-19 by RT-PCR with an acceptably low FOR in hospitalized patients suspected of having COVID-19.We calculated the FORs of 4 strategies to rule out COVID-19 using RT-PCR across the range of prevalence rates in hospitalized patients. Strategy 1 was a single negative test result with a sensitivity of 70%, such as a single NP swab or sputum sample. Strategy 2 was a series of 2 negative tests, each with a sensitivity of 70%. Strategy 3 was a series of 2 negative tests in which the first had a sensitivity of 70% and the second a sensitivity of 90%, such as an NP swab followed by BAL. Strategy 4 was a series of 3 negative tests, each with a sensitivity of 70%. Specificity was assumed to be 99% in all calculations. We recalculated strategy 4 using a sensitivity of 50% to explore the effect lower sensitivity would have on FORs. We defined a false omission rate of ≤5% as acceptable.Results are presented in the Table and the Figure. The FORs were unacceptable at prevalence rates ≥20% for strategy 1 and at prevalence rates ≥50% for strategy 2. The FORs were acceptable at prevalence rates up to 90% for strategies 3 and 4, but reducing sensitivity to 50% in strategy 4 increased FORs 3-fold.The prevalence of COVID-19 among patients admitted with pneumonia exceeds 50% in some areas of the United States and United Kingdom, as was previously reported from Wuhan, China.3 The FORs of all diagnostic strategies rise with prevalence, and they have reached unacceptable levels for strategies 1 and 2 in many localities. Strategies 3 and 4 may retain acceptable FORs at prevalence rates <90% if we have not overestimated sensitivity. Strategy 3 incorporates BAL, which has the highest reported sensitivity (3) but may aerosolize infectious particles. (The sensitivity of sputum obtained from intubated patients by deep tracheal suctioning through a closed ventilator circuit has not been reported, but it may present a practical alternative to BAL.) Sensitivity and FOR can be optimized by employing proper techniques for collecting, handling, and testing of clinical specimens,5 but clinicians who feel an individual patient has very high pretest probability might reasonably decide not to completely rule out COVID-19, even after negative results using the best diagnostic strategies we modeled.Our analysis relates to patients admitted with a clinical-radiographic syndrome consistent with pneumonia and is not generalizable to outpatients. Significant variation between patients in day-to-day viral shedding has been observed,4 and our model does not account for the possibility that COVID-19 patients with initial false-negative results may be more likely to have repeated false-negative results. Despite limitations, our modeling should help clinicians recognize that FOR increases with disease prevalence and make more objective decisions about how to interpret COVID RT-PCR test results when considering the discontinuation of infection control precautions in patients suspected of having COVID-19.

A comparison of a fluorescence enzyme immunoassay versus indirect immunofluorescence for initial screening of connective tissue diseases: Systematic literature review and meta-analysis of diagnostic test accuracy studies.

The aim was to compare indirect immunofluorescence (IIF) and fluorescence enzyme immunoassay (FEIA) for initial screening of connective tissue diseases (CTDs) and to evaluate whether combining IIF with FEIA adds value. A comprehensive systematic literature review was conducted to identify fully paired, cross-sectional or case-control studies on ANA screening of CTD reporting results for IIF and FEIA. Study quality was assessed using the QUADAS-2 checklist. The reference standard was assessed against established classification criteria. The meta-analysis used hierarchical, bivariate and mixed-effects models to allow test results to vary within and across studies. Eighteen studies of good to fair quality were included in the review. IIF had a higher sensitivity than FEIA [cut-off 1:160, 7 studies, 3251 patients, 0.83 (95% CI 0.75-0.89) versus 0.73 (95% CI 0.64-0.80); cut-off 1:80, 7 studies, 12,311 patients, 0.89 (95% CI 0.84-0.93) versus 0.78 (95% CI 0.71-0.84)] but lower specificity [1:160, 0.81 (95% CI 0.73-0.87) versus 0.94 (95% CI 0.91-0.95); 1:80, 0.72 (95% CI 0.62-0.81) versus 0.94 (95% CI 0.90-0.96)]. A double-positive test had a higher likelihood ratio (LR) for CTD (26.2 (95% CI 23.0-29.9)) than a single positive test (14.4 (95% CI 13.1-15.9) FEIA+, 5.1 (95% CI 4.8-5.4) IIF+). A double-negative test result had more clinical value for ruling out CTD than a single negative test (LR 0.15 (95% CI 0.12-0.18) versus 0.21 (95% CI 0.18-0.25) IIF; 0.33 (95% CI 0.29-0.37) FEIA-). A FEIA+/IIF- discordant result had a higher LR than an IIF+/FEIA- discordant result (LR 2.4 (95% CI 1.7-3.4) versus 1.4 (95% CI 1.2-1.7)). Because of the comparatively higher specificity of FEIA and higher sensitivity of IIF, the combination of FEIA and IIF increases the diagnostic value. Clinicians should be acquainted with the clinical presentation of CTD and aware of the advantages and disadvantages of FEIA and IIF to avoid misinterpretation.

Gastrointestinal disorders in Down syndrome.

Gastrointestinal disorders in Down syndrome.

Follow-up Testing After Colposcopy

Most women referred for colposcopy are not diagnosed with cervical intraepithelial neoplasia grade 2 or worse (CIN 2+) but, nonetheless, are typically asked to return much sooner than their next routine screening interval in 3 to 5 years. An important question is how many subsequent negative Pap results, or negative Pap and human papillomavirus (HPV) cotest results, are needed before returning to an extended retesting interval. We estimated 5-year risks of CIN 2+ for 3 follow-up management strategies after colposcopy (Pap-alone, HPV-alone, and cotesting) for 20,319 women aged 25 years and older screened from 2003 to 2010 at Kaiser Permanente Northern California who were referred for colposcopy but for whom CIN 2+ was not initially diagnosed (i.e., "women with CIN 1/negative colposcopy"). Screening results immediately antecedent to CIN 1/negative colposcopy influenced subsequent 5-year CIN 2+ risk: women with an antecedent HPV-positive/atypical squamous cells of undetermined significance (ASCUS) or low-grade squamous intraepithelial lesion (LSIL) Pap had a lower risk (10%) than those with antecedent atypical squamous cells cannot rule out HSIL (ASC-H; 16%, p < .0001) or high-grade squamous intraepithelial lesion or worse (HSIL+; 24%, p < .0001). For women with an antecedent HPV-positive/ASC-US or LSIL, a single negative cotest approximately 1 year after colposcopy predicted lower subsequent 5-year risk of CIN 2+ (1.1%) than 2 sequential negative HPV tests (1.8%, p = .3) or 2 sequential negative Pap results (4.0%, p < .0001). For those with an antecedent ASC-H or HSIL+ Pap, 1 negative cotest 1 year after colposcopy predicted lower subsequent 5-year risk of CIN 2+ (2.2%) than 1 negative HPV test (4.4%, p = .4) or 1 negative Pap (7.0%, p = .06); insufficient data existed to calculate the risk after sequential negative cotests for women with high-grade antecedent cytology. Women with a CIN 1/negative colposcopy followed by negative postcolposcopy tests did not achieve sufficiently low CIN 2+ risk to return to 5-year routine screening. For women with antecedent HPV-positive/ASC-US or LSIL, a single negative postcolposcopy cotest reduced their risk to a level consistent with a 3-year return. For women with antecedent ASC-H or HSIL+, no single negative test result sufficed to reduce their risk to a level consistent with a 3-year return.

Cervical cancer risk for women undergoing concurrent testing for human papillomavirus and cervical cytology: a population-based study in routine clinical practice

Concurrent testing for human papillomavirus (HPV) and cervical cytology (co-testing) is an approved alternative to cytology alone in women aged 30 years and older. We aimed to assess the safety in routine clinical practice of 3-year screening intervals for women testing negative for HPV with normal cytology and to assess if co-testing can identify women at high risk of cervical cancer or cervical intraepithelial neoplasia grade 3 (CIN3) or worse over 5 years. We assessed the 5-year cumulative incidence, starting in 2003-05, of cervical cancer and CIN3 or worse for 331,818 women aged 30 years and older who enrolled in co-testing at Kaiser Permanente Northern California (Berkeley, CA, USA) and had adequate enrolment co-test results. Follow-up continued until Dec 31, 2009. We defined cumulative incidence to include prevalence at enrolment and incidence after enrolment. Prevalence at enrolment was defined as the ratio of women diagnosed with each outcome on the biopsy visit immediately after their enrolment screening visit to the total enrolled women. At screening visits only HPV test and Pap smear samples were collected, and at biopsy visits colposcopically directed biopsies were taken. To estimate post-enrolment incidence, we used Weibull survival models. In 315,061 women negative by HPV testing, the 5-year cumulative incidence of cancer was 3.8 per 100,000 women per year, slightly higher than for the 306,969 who were both negative by HPV and Pap testing (3.2 per 100,000), and half the cancer risk of the 319,177 who were negative by Pap testing (7.5 per 100,000). 313,465 (99.5%) women negative by HPV testing had either normal cytology or equivocal abnormalities. Abnormal cytology greatly increased cumulative incidence of CIN3 or worse over 5 years for the 16,757 positive by HPV testing (12.1%vs 5.9%; p<0.0001). By contrast, although statistically significant, abnormal cytology did not increase 5-year risk of CIN3 or worse for women negative by HPV testing to a substantial level (0.86%vs 0.16%; p=0.004). 12,208 (73%) of the women positive by HPV testing had no cytological abnormality, and these women had 258 (35%) of 747 CIN3 or adenocarcinoma in situ, [corrected] 25 (29%) of 87 cancers, and 17 (63%) of 27 adenocarcinomas. For women aged 30 years and older in routine clinical practice who are negative by co-testing (both HPV and cytology), 3-year screening intervals were safe because a single negative test for HPV was sufficient to reassure against cervical cancer over 5 years. Incorporating HPV testing with cytology also resulted in earlier identification of women at high risk of cervical cancer, especially adenocarcinoma. Testing for HPV without adjunctive cytology might be sufficiently sensitive for primary screening for cervical cancer. Intramural Research Program of the US National Cancer Institute/NIH/DHHS, and the American Cancer Society.

Legionella spp. and legionellosis in southeastern Italy: disease epidemiology and environmental surveillance in community and health care facilities

BackgroundFollowing the publication of the Italian Guidelines for the control and prevention of legionellosis an environmental and clinical surveillance has been carried out in Southeastern Italy. The aim of the study is to identify the risk factors for the disease, so allowing better programming of the necessary prevention measures.MethodsDuring the period January 2000 - December 2009 the environmental surveillance was carried out by water sampling of 129 health care facilities (73 public and 56 private hospitals) and 533 buildings within the community (63 private apartments, 305 hotels, 19 offices, 4 churches, 116 gyms, 3 swimming pools and 23 schools). Water sampling and microbiological analysis were carried out following the Italian Guidelines. From January 2005, all facilities were subject to risk analysis through the use of a standardized report; the results were classified as good (G), medium (M) and bad (B). As well, all the clinical surveillance forms for legionellosis, which must be compiled by physicians and sent to the Regional Centre for Epidemiology (OER), were analyzed.ResultsLegionella spp. was found in 102 (79.1%) health care facilities and in 238 (44.7%) community buildings. The percentages for the contamination levels < 1,000, 1,000-10,000, > 10,000 cfu/L were respectively 33.1%, 53.4% and 13.5% for samples from health care facilities and 33.5%, 43.3% and 23.2% for samples from the community. Both in hospital and community environments, Legionella pneumophila serogroup (L. pn sg) 2-14 was the most frequently isolate (respectively 54.8% and 40.8% of positive samples), followed by L. pn sg 1 (respectively 31.3% and 33%). The study showed a significant association between M or B score at the risk analysis and Legionella spp. positive microbiological test results (p < 0.001). From clinical surveillance, during the period January 2001 - August 2009, 97 cases of legionellosis were reported to the OER: 88 of community origin and 9 nosocomial. The most frequent symptoms were: fever (93.8%), cough (70.1%), dyspnea (58.8%), shivering (56.7%). Radiological evidence of pneumonia was reported in 68%. The laboratory diagnostic methods used were: urinary antigen (54.3%), single antibody titer (19.8%), only seroconversion (11.1%), other diagnostic methods (14.8%).ConclusionsOur experience suggests that risk analysis and environmental microbiological surveillance should be carried out more frequently to control the environmental spread of Legionella spp. Furthermore, the laboratory diagnosis of legionellosis cannot be excluded only on the basis of a single negative test: some patients were positive to only one of the diagnostic tests.

Molecular Remission to Imatinib in Patients with Chronic Myeloid Leukaemia (CML) Is Less Durable Compared to Patients after Allografting.

Objectives: Patients with CML who achieve molecular remission (MR, defined as a RT-PCR negativity for BCR-ABL transcripts) after myeloablative stem cell transplantation (SCT) have a low risk of relapse, and the majority may be cured. The frequency of MR on imatinib varies greatly and the durability of these responses has not been reported. To investigate if MR after SCT and on imatinib are equally stable, we directly compared two cohorts of patients treated with imatinib or SCT, respectively, from the time of their first negative RT-PCR result.Patients and Methods: One hundred and forty-four CML patients in chronic (n=104) or accelerated phase (n=40) treated with standard dose imatinib were routinely monitored by conventional cytogenetics, quantitative RT-PCR (qPCR) and conventional nested PCR in case of negative qPCR results. Nineteen patients (13.2%) had at least 1 negative nested PCR. To assess the level of residual disease in patients with a single negative RT-PCR result, 10 replicate reactions were performed, each corresponding to > 106 white bone marrow cells. Thirty-six samples (median 3, range 1–4) from patients in MR on imatinib and 45 samples (median 2, range 1–3) from patients in MR after SCT were available. Twenty samples from healthy individuals were tested as controls.Results: The first negative result was noted after a median of 16.8 months (range 11.5–36.1) of imatinib therapy and 6.6 months (range 4.7–9.5) after SCT, respectively. The projected risk of molecular relapse at 12 months after the first negative RT-PCR result was 83% in patients on imatinib but only 20% in patients after SCT (P = 0.0001). Only two patients on imatinib remained in molecular remission at 13.8 and 16.6 months. While none of the patients with molecular relapse after allograft lost CCyR, one patient on imatinib progressed to cytogenetic relapse. The replicate assay was positive in 18/36 samples (50%) from patients on imatinib, 8/46 (17.4%) after allografting and 4/20 (20%) from healthy individuals. These differences were significant between patients on imatinib and after allografting (P = 0.003) and between patients on imatinib and healthy individuals (P = 0.005), but not between patients after allografting and healthy individuals (P = 0.9). Negativity by replicate testing was more stable in patients after allografting, although, even in these patients, positive replicate reactions continued to occur with longer follow-up.Conclusion: Imatinib-induced MR is usually not durable, in contrast to MR after transplant. Consistent with this, the level of residual disease in samples negative by single nested PCR is higher in patients on imatinib compared to patients after SCT. These results suggest that disease eradication with imatinib monotherapy may be rare. Patients on imatinib followed by PCR should be made aware of the fact that a single negative test does not have the same significance as in patients after SCT.

Relative Risks of Anticoagulant Treatment of Acute Pulmonary Embolism Based on an Angiographic Diagnosis vs a Ventilation/Perfusion Scan Diagnosis

The purpose of this investigation was to assess the relative risks of antithrombotic treatment following pulmonary angiography vs no angiography in patients with acute pulmonary embolism (PE). Comparisons of risks of diagnosis and therapy were made among patients treated on the basis of a pulmonary angiographic diagnosis vs patients treated on the basis of a ventilation/perfusion (V/Q) scan combined with clinical assessment in the presence of a single negative test for deep venous thrombosis. Calculations of risks assumed major complications of pulmonary angiography equal to 1.3 percent, major bleeding with heparin equal to 4.9 percent (1.1 percent among patients with a low risk of bleeding and 10.8 percent among patients with a high risk of bleeding), and major bleeding with warfarin (international normalized ratio 2 to 3) equal to 1.7 percent. Among patients with a risk of major bleeding from heparin followed by warfarin of 6.6 percent, if the estimated probability of PE was greater than about 80 percent, fewer major complications of diagnosis and treatment would occur if treatment was initiated on the basis of the V/Q scan. If the probability of PE in such patients was less than 80 percent, fewer major complications of diagnosis and treatment would occur if the diagnosis was established by pulmonary angiography. Among patients with a high (12.5 percent) risk of major bleeding, it was shown to be safer to treat on the basis of an angiographic diagnosis if the estimated probability of PE was less than 90 percent. If the patients, however, were at low (2.8 percent) risk of major bleeding, fewer major complications would occur if angiography was reserved for patients with an estimated risk of PE less than about 50 percent. Serial studies of the leg veins may eliminate the need for angiography in such patients.

Chorioepithelioma of the Fallopian tube

Summary An instance of chorioepithelioma of the Fallopian tube, which was treated by operation and radiation, is reported. This seems to be the forty-second case to be recorded in the literature. The modes of origin of extrauterine chorioepitheliomata are discussed, and it is believed that in our patient it developed primarily in the tube subsequent to a tubal pregnancy. The value of tests for the luteinizing hormone in the urine in cases of ehorionic tumors is shown. A persistent positive reaction even in the absence of all signs and symptoms seems to indicate a serious prognosis, while too much reliance should not. be placed in a single negative test. The mortality in the reported cases has been about 93 per cent.