COVID: ?reinfection cases, and risk calculator

A Swiss report of 2 cases suggested reinfection or reactivation of Covid-19 pneumonia (see https://www.ncbi.nlm.nih.gov/research/coronavirus/publication/32389787 )

 

Details:

Case 1: 81-year-old woman transferred from a psychiatric institution because of fever and cough

-- past history of non-insulin dependent diabetes, CAD, atrial fibrillation, bipolar disorder

-- March 9: admitted with labs including leukocytosis of 11.4, CRP of 100 mg/L

-- nasopharyngeal swab positive for SARS-CoV-2

-- patient hospitalized, fever resolved on day 3 of hospitalization,

-- health improved during the following 2 weeks and oxygen saturation was 95%

-- discharged on March 24 after negative PCR test

-- April 18 (5 weeks after fever resolved!!): she was readmitted for dyspnea, fever, and confusion; this was after a PCR on April 14 was positive for SARS-CoV-2

-- per family physician, these symptoms were new and gradually increased over 4 to 5 days

-- admission labs showed a CRP of 175, creatinine 1.3, and sodium of 167 mmol per liter; CT showed infiltrates of the right upper lobe as well as bilateral pleural effusions

-- the patient died April 22

 

Case 2: 77-year-old woman received a transfemoral aortic valve replacement on March 23, sustaining an ischemic stroke during the procedure

-- she developed cough and fever and tested positive for SARS-CoV-2 during the hospitalization

-- chest CT on March 28 was normal, and she was transferred to the above hospital

-- on admission she was afebrile, hemodynamically stable; labs showed a CRP of 13 and LDH of 685.

-- Fever and respiratory symptoms resolved, repeat nasopharyngeal swabs on April 2 and 3^rd were negative and the patient was discharged to rehab on April 8

-- April 22 (4 weeks after fever resolved): patient was readmitted to their hospital from the rehab due to nonproductive cough for 4 days and positive PCR

-- on admission she had lymphopenia, CRP 47, and LDH 615. Arterial blood gases showed she was hypoxic. CT showed ubiquitous groundglass opacities predominantly in the right upper lobe. She remained hospitalized at the time of this publication

 

Commentary:

-- these researchers felt that this was a reactivation of SARS-CoV-2 based on the fact that reinfection was unlikely given the low rates of Covid-19 infection in their local area [though, these 2 patients somehow did get infected...]

    -- However, this is hard to know for sure: genetic fingerprints of the viruses would have been useful to see if these were basically the same virus or a new infection

-- but this does raise issues in either case:

    -- if this were a reinfection (which sounds pretty likely to me given the long lag between clinical Covid diagnoses), this questions the effectiveness of immunity from an initial infection which appears to have resolved, both clinically and by PCR, and only several weeks later

    -- if this were a reactivation, it raises questions about potential infectivity of patients who were believed to have had a completed Covid course, infectivity both to others as well as themselves

--in any event, this does reinforce the WHO admonition to not assume that those previously infected are protected from second infections: see http://gmodestmedblogs.blogspot.com/2020/05/covid-who-dont-trust-antibody-testing.html

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Based on Chinese data, researchers developed a risk calculator to predict the probability that a Covid-19 patient will develop critical illness (see covid risk calculator in dropbox, or doi:10.1001/jamainternmed.2020.2033)

 

Details:

-- development cohort: 1590 patients, mean age 49, 57% men

    -- critical illness eventually developed in 8%, and 3% died

-- validation cohort: 710 patients, mean age of 48, 54% men

    -- critical illness eventually developed in 12% of these patients, and 1% died

-- they assessed an array of 72 parameters collected in 575 Chinese hospitals in 31 provincial administrative regions, as of January 31:

    -- age, incubation period, admission vital signs, sex, smoking status

    -- symptoms: fever, congestion, headache, dry or productive cough, sore throat, fatigue, hemoptysis, shortness of breath, nausea/vomiting, diarrhea, myalgias/arthralgia, chills

    -- signs: throat congestion, tonsil swelling, enlarged lymph nodes, rash, unconsciousness

    -- comorbidities: COPD, diabetes, hypertension, cardiovascular disease, cerebrovascular disease, hepatitis B infection, malignancy, chronic kidney disease, immunodeficiency, abnormal chest x-ray, abnormal chest CT, residence in Hubei province, exposure to Wuhan (they also included the number of comorbidities, and the severity of abnormalities on chest x-ray or chest CT)

    -- lab tests: total urine volume, PaO₂, FiO₂, neutrophil count, lymphocyte count, platelet count, hemoglobin, CRP, pro-calcitonin, LDH, aminotransferases, bilirubin, CK, creatinine, high-sensitivity troponin I, albumin, sodium, potassium, chloride, d-dimer, PT, aPTT, neutrophil-lymphocyte ratio

 

Results:

-- based on 72 potential predictors, 10 variables were found to be independent predictive factors and were included in the risk score:

    -- chest x-ray abnormal, OR 3.39 (2.14-5.38)

    -- age, OR 1.03 (1.01-1.05)

    -- hemoptysis, OR 4.53 (1.36-15.15)

    -- dyspnea, OR 1.88 (1.18-3.01)

    -- unconsciousness, OR 4.71 (1.39-15.98)

    -- number of comorbidities, OR 1.60 (1.27-2.00)

    -- cancer history, OR 4.07 (1.23-13.43)

    -- neutrophil-lymphocyte ratio, or 1.06 (1.02-1.10)

    -- lactic dehydrogenase, OR 1.002 (1.001-1.004)

    -- direct bilirubin, OR 1.15 (1.06-1.24)

-- the AUC (area under the curve) for both the development and the validation cohort were 0.88

    -- there were very small differences in the AUC for patients in the epicenter of Hubei vs outside Hubei

-- based on the above, they developed an online risk calculator, available to the public at http://118.126.104.170/ 

 

Commentary:

-- as an overall perspective, the WHO reported a total of about 2 million Covid-19 cases globally as of April 16, with an average mortality of 6.6%; per the NY times today, now at 4.3+ million with 296,684 deaths (no doubt undercounted...)

-- the Chinese Center for Disease Control and Prevention found that of 72,314 cases: 81% were classified as mild, 14% were severe, and 5% were considered critical; the average case fatality rate was 2.3%, but increasing to 49% in patients with critical illness

-- this risk calculator performed reasonably well, with remarkably similar performance in the development as well as the validation cohorts

-- it was noted that the 10 variables required for the calculator are generally available at hospital admission

-- the basis for the this risk model did not include a few parameters found to be important in other studies including IL-6, or CD3+-CD8+ T cells <75/mL.  And, they did not find that either male sex or lymphopenia by itself were significant

-- the Mass General Hospital has a grid of Covid-19 risk factors, including some of the above, but also ferritin >500, obesity, use of biologics, see  https://www.massgeneral.org/assets/MGH/pdf/news/coronavirus/risk-factors-for-severe-COVID-19.pdf

-- a few other comments:

    -- it has been unclear (to me) what the relative risk of severe Covid-19 is with increasing age. is it age itself and its own ravages on the immune and other systems? or the increasing comorbidities associated with aging? it was notable in their sorting through 72 potential risk factors that age was only a minimal independent one (3% of increased risk attributable independently to age), suggesting that higher risk was mostly from other easily measured factors and not so much to age itself. (Several other variables also had minimal contribution to the risk score, including LDH, neutrophil to lymphocyte ratio, and direct bilirubin)

    -- it would be really interesting to combine the last 2 blogs: having a large cohort of patients have their risk assessed, then (per yesterday's blog http://gmodestmedblogs.blogspot.com/2020/05/covid-early-use-of-lopinavirritonavir.html ) try some medication in an RCT that is more likely to be effective early in the disease (eg the combo yesterday, or remdesivir, or...) and see how the different subgroups fare (those predicted to have more severe disease as well, to see if bad consequences could be avoided by early treatment). which also means really easy access to testing early so that patients can be identified early....  and, this really makes sense: treating early may be much more effective than waiting for compassionate use of remdesivir in extremely sick patients with multi-organ dysfunction

 

Limitations of the generalizability of the study:

-- modest sample size with small validation cohort

-- relying entirely on a Chinese cohort

-- they did not include several lab tests or symptoms that have emerged as potentially useful predictors (eg IL-6, or anosmia), and may either have displaced some of the ones that they did include or adding them might have reinforced the accuracy/generalizability of their model

 

So,

--it is useful to have an accurate risk predictor, to help guide clinical decision-making both outpatient and at the time of an emergency room visit, which may allow for different degrees of monitoring: eg more aggressive monitoring in some people with some defined cutpoint in risk score

--though, we really do need more data from other countries (would be great to have aggregate data from the US, the leader by far in cases globally, but we have no large databank or consistency in approach to allow the needed datamining)

geoff

 

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