Determinants of COVID-19 Pneumonia (MC-19)
Condition: Pneumonia, Viral; Pneumonia, Bacterial; Coronavirus Infection; Obstructive Lung Disease
MeSH terms: Pneumonia; Coronavirus Infections; Pneumonia, Viral; Pneumonia, Bacterial; Lung Diseases; Lung Diseases, Obstructive
Study type: Observational

Summary: 
      Molecular testing (e.g PCR) of respiratory tract samples is the recommended method for the
      identification and laboratory confirmation of COVID-19 cases.

      Recent evidence reported that the diagnostic accuracy of many of the available RT-PCR tests
      for detecting SARS-CoV2 may be lower than optimal.

      Of course, the economical and clinical implications of diagnostic errors are of foremost
      significance and in case of infectious outbreaks, namely pandemics, the repercussions are
      amplified. False positives and false-negative results may jeopardize the health of a single
      patient and may affect the efficacy of containment of the outbreak and of public health
      policies.

      In particular, false-negative results contribute to the ongoing of the infection causing
      further spread of the virus within the community, masking also other potentially infected
      people.
    

Detailed description: 
      As demonstrated by a study conducted by Ai et al., including 1014 suspect COVID-19 cases who
      underwent multiple RT-PCR testing and chest-CT, overall 88% of patients had positive CT scans
      while RT-PCR positivity was found only in 59% of all cases. Also, as reported by Yang et al,
      the total positive rate of RT-PCR for throat swab samples was reported to be about 30% to 60%
      at initial presentation. Thus, a negative result does not exclude the possibility of
      infection and should not be used as the only criterion for treatment of patient and
      management decisions.

      Reasons for false negative RT-PCR may include the lack of identification or inadequate
      procedures for specimen collection, handling and storage, as well as active viral
      recombination or testing carried out of the diagnostic window.

      From preliminary studies has emerged that patients may show very early but significant CT
      changes even before RT-PCR studies. Hence, the necessity for developing a combined approach
      for the diagnosis of these particular patients who present with negative RT-PCR test results.

      The investigators hypotheses is that several patients who presented with pneumonia confirmed
      at CT scan during the Coronavirus outbreak, and who tested negative for SARS-CoV2 at RT-PCR
      could probably be affected by the disease and need to be carefully observed.

      Primary end-point The primary end-point of our prospective, observational study is to assess
      if inpatients who presented with pneumonia but had a negative test for Covid-19 are positive
      at the serology for SARS-CoV-2.

      Secondary end-points Among the other secondary end-points, the investigators aim is to find
      if the combination of CT scan and serology could help in the identification of those patients
      who were initially negative at laboratory testing alone.

      Other secondary end-points are the efficacy of different pharmaceutical treatments against
      Covid-19 that were empirically started in those highly suspicious cases and the development
      of an approach useful for those patients who initially tested negative for Covid-19
      infection.

      Methods Before starting the study, the protocol will be submitted to and approved by the
      local Ethical Committees at the Fondazione Policlinico Universitario A. Gemelli IRCCS,
      Catholic University, Rome, Italy. Before enrollment each subject will sign the informed
      consent.

      Inclusion criteria: hospitalized subjects of both sexes aged 18 years or older with diagnosis
      of pneumonia, confirmed by chest imaging and oxygen saturation (SaO2) ≤ 94% in ambient air,
      Covid-19 test negative, given informed consent to data collection from the patient or from
      the patient's legal representative if the patient is too unwell to provide consent.

      Exclusion criteria: age lower than 18 years, pregnancy or breast-feeding. Nasopharyngeal swab
      samples will be taken for quantitative real-time polymerase chain reaction to make diagnosis
      of Covid19 (2 repeated tests).

      Data collected include time of symptoms (cough, fever, dyspnea, conjunctivitis, diarrhea,
      asthenia, arthralgia) age, sex, height, weight, education, alcohol and smoking habits,
      morbidities, plasma glucose, creatinine, transaminases, γ-GT, total cholesterol,
      HDL-cholesterol, triglycerides, complete blood count, D-dimer, lactic acid dehydrogenase
      (LDH), high-sensitivity C-reactive protein (hs-CRP), creatinkinase (CK), ferritin, HbA1c,
      chest X rays, chest CT scan, cultures, therapy for pneumonia, other treatments including
      anti-hypertensive and anti-hyperglycemic agents, body temperature, blood pressure, and oxygen
      flow rate or other types of oxygen treatment.

      Five ml of plasma divided in aliquots of 1 ml each will be also obtained and stored at -80°C
      in anonymized way for future analysis, including third parties.

      Sample size If there is truly no difference between the standard and experimental treatment
      (16% in both groups), then 260 patients are required to be 90% sure that the limits of a
      two-sided 90% confidence interval will exclude a difference between the standard and
      experimental group of more than 15% Significance (α) = 0.05 Power (1-β)= 90% Percentage
      deaths in both control and experimental group = 16% Equivalence limit = 15%

      Calculation based on the formula:

      n = 2 × f(α, β/2) × π × (100 - π) / d2 where π is the true percent 'success' in both the
      control and experimental treatment groups, and f(α, β) = [Φ-1(α) + Φ-1(β)]2 Φ-1 is the
      cumulative distribution function of a standardised normal deviate.

      Statistics The association between recovery and patient groups will be tested by means of a
      Fisher exact test. A Cox Proportional-Hazard regression will be used to compare survival
      curves (times to improvement) among the studied groups by correcting for the administered
      therapy and for all the quantitative collected variables. Quantitative variables, measured at
      hospital admission, will be compared among groups using ANOVA. In univariable analyses,
      categorical variables, as gender, education, alcohol consumption and smoke habits will be
      analysed by means of a Chi-Squared test to study their association with the recovery, while a
      logistic regression model will be used to test possible quantitative predictors of recovery.
      A multivariable logistic model, with a stepwise selection procedure, will be then used to
      test all the variables that are significant in a univariable analysis.
    

Intervention name(s): Serology for Covid-19
Intervention type(s): Diagnostic Test
Intervention description(s): Antibody tests designed to provide results to individuals or healthcare providers can show whether someone was previously infected with SARS-CoV-2 being the RT-PCR negative for the population of patients
Observational model: Case-Control
Time perspective: Prospective
Sampling method: Non-Probability Sample
Study population: 
        Subjects hospitalized for pneumonia who tested negative at RT-PCR
      
Biospecimen description: 
      plasma samples