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Disparities in care: Two women's stories of Covid 19 misdiagnoses

  • 1.  Disparities in care: Two women's stories of Covid 19 misdiagnoses

    Posted 08-11-2020 10:38

  • 2.  RE: Disparities in care: Two women's stories of Covid 19 misdiagnoses

    Posted 08-11-2020 11:50
    Hi All,

    Helen, I'm so glad you shared this as I heard it yesterday also.  

    I found the exchange below (in highlighted transcript) so worrisome and yet unfortunately predictable given the limitations of the SARS-CoV-2 RT-PCR test:

    1. Here is the link to the IDSA guidance Table 8 showing a false negative rate of at least 25% for each level of pre-test probability: https://www.idsociety.org/globalassets/idsa/practice-guidelines/covid-19/diagnostics/table-8.pdf#Table8; https://www.idsociety.org/practice-guideline/covid-19-guideline-diagnostics/
    2. In Woloshin's NEJM paper (https://www.nejm.org/doi/full/10.1056/NEJMp2015897), with a PCR sensitivity of 70% (the same as in IDSA Guidance), a pre-test probability of 15% or more does not allow COVID-19 to be ruled out to a level below 5% by a negative PCR.
    3. In a Spanish evaluation of outpatients with mild-moderate symptoms (https://pubmed.ncbi.nlm.nih.gov/32651152/), a cohort that most closely matches the experience of the people in this NPR story, 42% o f patients who were negative on PCR were subsequently positive on SARS-CoV-2 antibody testing. 
    4. In a meta-analysis (https://www.acpjournals.org/doi/full/10.7326/m20-1495) of patients, 94% of whom were hospitalized, the maximum sensitivity of PCR was 80% on Day 8 of infection (corresponding to Day 3 of symptoms). 
    I could go on. The issue is not that PCR does not detect low levels of virus. It certainly does and this is what companies report to the FDA (it has a high analytical accuracy). Instead, PCR does not reliably detect virus from the upper pharynx in symptomatic people (it has a relatively low sensitivity). One explanation for this is that that virus simply is not in the upper airway at significant levels (as Wang et al published way back on March 11 in JAMA [https://jamanetwork.com/journals/jama/fullarticle/2762997], finding the sensitivity of bronchoalveolar lavage fluid was 93%, sputum 72%, nasal 63%, and pharyngeal 32%). If this is the case, we likely can't just magically make the test more accurate in the upper airway. 

    IDSA guidance is to repeat PCR testing when pre-test probability is high. This is a nice idea, but as above test sensitivity decays after Day 3 of symptoms. 

    As a nation, we may be looking for our keys under the streetlight (upper airway) when we dropped them in the dark (lower airway or elsewhere).  

    The public is on to this. Please see cartoon here from August 7th.

    COVID test accuracy

    The above does not even address the accuracy of asymptomatic or pre-symptomatic testing. 

    Without an honest discussion about the limitations of testing, and without clinicians being more circumspect about its accuracy, more people will have the experience of the two people interviewed by NPR.

    Testing has a lot to offer at the public health level where you can build in an error rate by merely changing a coefficient based on a false negative rate. We can't do that readily in clinical practice, and patients will suffer without the necessary clinical humility (that has not been emphasized enough by professional societies and guidance).  Current test interpretation(diagnostic error) harms and misleads patients.

    I'd appreciate joining with others here to help address this fundamental problem in the pandemic.  It isn't solving itself. 



    ROBERTS: And the second time they took me to the emergency room, they was like - really like, you don't need a ventilator. We told you that you didn't have COVID. And I'm like, well, something is wrong with me; please help me. So they sent me home again, and they told me to get in touch with my primary doctor.

    NOWELL: So I reached out to my physician again. I don't know if, because I had a negative test, he didn't believe that I was as sick as I was.

    ROBERTS: She didn't help me at all. She was really like, you're not sick. And she told me that I was mimicking what I was seeing on television and that I needed to watch good - Lifetime feel-good movies to get myself out of the funk.

    NOWELL: He said, well, maybe you have a UTI, or maybe it's a stomach infection; let's call it a sinus infection. I was like, OK, so you're not going to be the one to help me get well.

    ROBERTS: You're stressed. You're stressed. She kept saying I was stressed and it was all in my mind.

    Variation in False-Negative Rate of Reverse Transcriptase Polymerase Chain Reaction–Based SARS-CoV-2 Tests by Time Since Exposure [94% were hospitalized.] 


    Probability of a False-Negative Result Among SARS-CoV-2–Positive Patients, by Day Since Exposure

     Over the 4 days of infection before the typical time of symptom onset (day 5), the probability of a false-negative result in an infected person decreases from 100% (95% CI, 100% to 100%) on day 1 to 67% (CI, 27% to 94%) on day 4, although there is considerable uncertainty in these numbers. On the day of symptom onset, the median false-negative rate was 38% (CI, 18% to 65%) (Figure 2, top). This decreased to 20% (CI, 12% to 30%) on day 8 (3 days after symptom onset) then began to increase again, from 21% (CI, 13% to 31%) on day 9 to 66% (CI, 54% to 77%) on day 21.

    Predictive factors of COVID-19 in patients with 
    negative RT-qPCR
    42% of outpatients with symptoms who were negative on SARS-CoV-2 PCR were then positive on antibody testing.

    Objective: To evaluate the factors associated with false negatives in RT-qPCR in patients with mild-moderate symptoms of COVID-19.

    Materials and methods: This was a cross-sectional study that used a random sample of nonhospitalized patients from the primary care management division of the Healthcare Area of Leon (58 RT-qPCR-positive cases and 52 RT-qPCR-negative cases). Information regarding symptoms was collected and all patients were simultaneously tested using two rapid diagnostic tests --- RDTs (Combined --- cRDT and Differentiated --- dRDT). The association between symptoms and SARS-CoV-2 infection was evaluated by non-conditional logistic regression, with estimation of Odds Ratio.

    Results: A total of 110 subjects were studied, 52% of whom were women (mean age: 48.2 ± 11.0 years). There were 42.3% of negative RT-qPCRs that were positive in some RDTs. Fever over 38 ◦C (present in 35.5% of cases) and anosmia (present in 41.8%) were the symptoms most associated with SARS-CoV-2 infection, a relationship that remained statistically significant in patients with negative RT-qPCR and some positive RDT (aOR = 6.64; 95%CI = 1.33---33.13 and aOR = 19.38; 95% CI = 3.69---101.89, respectively).

    Conclusions: RT-qPCR is the technique of choice in the diagnosis of SARS-CoV-2 infection, but it is not exempt from false negatives.

    Stephen Martin
    University of Massachusetts