Cebu Institute of Medicine
F. Ramos St., Cebu City
Critical Appraisal of Journal Article
What is the effect of Tocilizumab in the prevention of mortality or in the clinical
improvement of adult patients with COVID-19?
Submitted by: PBL 3 Group 9
Cabahug, Kurt Raymond Y.
Israel, Goldameir
Kho, Rachelle
Layese, Charcel Lex T.
Sales, Gene Robert
Talili, Pauline Julia C.
Urgel, Mary Angeli
Valmoria, Tiaramaria
Ymbong, Au Bain Marie M.
Submitted to:
Dr. Maria Philina Villamor
Clinical Question: Is Tociluzumab effective in treating patients with severe COVID-19
infection?
Citation: Xiaoling Xu, Mingfeng Han, Tiantian Ali, Wei Sun, et al. Effective Treatment of
Severe COVID-19 Patients with Tocilizumab [Internet]. 2020 [cited 2020Mar30];
Available from: https://www.ser.es/wp-content/uploads/2020/03/TCZ-and-COVID19.pdf
A. Study Characteristics
1. Patients included: 21 patients with severe or critical COVID-19 infections who were
admitted at Anhui Provincial Hospital and Anhui Fuyang Second People’s Hospital.
2. Interventions observed: 400 mg of Tocilizumab once through an intravenous drip.
3. Outcomes monitored: relief of clinical symptoms, significant change of the
percentage of total WBC, specific lymphocyte, procalcitonin, and CRP levels, along
with CT scan results before and after treatment.
B. Validity Criteria
1. Were patients randomized to treatment groups?
o No, the patients were not randomized to treatment groups nor
were they assigned to control groups.
2. Was randomization concealed?
○ No/not applicable, randomization was not concealed since the 21
patients in question were not randomized to treatment groups
through the duration of the study.
3. Was follow-up adequate?
○ There were no reported drop-outs in the study, so it can be said that
follow up through the study was adequate in that sense.
○ Patients discharged from the hospital as a result from administration
had no reports of subsequent pulmonary infection, illness
deterioration, nor death. Patients not discharged during the course
of the study were also reported as recovering well without
subsequent infections, deterioration, nor deaths. No adverse drug
reactions were also reported.
4.
Were patients analyzed in the groups to which they are randomized?
○ No/not applicable, since they were not assigned to randomized
groups to begin with.
5. Were patients blinded to group allocation?
○ No, All 21 patients who met the severe or critical criteria defined by
the Diagnosis and Treatment Protocol for Novel Coronavirus
Pneumonia (6th interim edition) were made aware of their
participation in the clinical trial and had signed a document of
informed consent before they were given tocilizumab and agreed to
publish the case series. All patients received standard care,
according to the Diagnosis and Treatment Protocol for Novel
Coronavirus. This included lopinavir, methylprednisolone, other
symptom relievers and oxygen therapy, and added with tocilizumab,
prescribed 400 mg once through an intravenous drip.
○ Clinical features including body temperature, oxygen saturations,
etc, were recorded. A whole blood white cell count was performed
repeatedly. All patients had been spiral computerized tomography
(CT) scanned on admission and a week later after the beginning of
tocilizumab treatment, using a 64-row spiral Optima CT680 scanner
(GE Healthcare, USA) in a whole-lung, low-dosage exposure,
scanning with 5mm slices.
6. Were clinicians blinded to group allocation?
○ No, clinicians were not blinded to group allocation and were made
aware of the 21 patients who received the Tocilizumab therapy.
7. Were outcome assessors blinded to group allocation?
○ No, outcome assessors were not blinded to group allocation and
were made aware of the 21 patients who received the Tocilizumab
therapy. Treatment data were collected through chart and figure
review, including gender, age, coexisting diseases, clinical symptoms,
and peripheral oxygen saturations. The researchers focused on
changes in body temperature, respiratory function, and CT findings
before and after treatment with tocilizumab.
8. Were patients in the treatment and control groups similar with respect to known
prognostic factors?
○ Yes, all 21 patients who received Tocilizumab therapy were
compared with patients who also met the severe or critical criteria
defined by the Diagnosis and Treatment Protocol for Novel
Coronavirus Pneumonia (6th interim edition). A severe cases was
diagnosed if any of the following conditions were met: (1) respiratory
rate ≥ 30 breaths/min; (2) SpO2 ≤ 93% while breathing room air; (3)
PaO2/FiO2 ≤ 300 mmHg. A critical case was diagnosed if any of the
following conditions were met: (1) respiratory failure requiring
mechanical ventilation; (2) shock; (3) presence of organ failure, and
the patient would need to be admitted to the ICU.
C. Results
The trial consisted of 21 patients, all treated with Tocilizumab. However, no control
group was used in the study. Therefore, dichotomous measurement of effectiveness
cannot be applied.
The treatment outcome of 19 of the 21 patients admitted being discharged with
remarkably improved condition cannot be properly validated as there is no other group
to compare these outcomes with. It is also clinically important to note that 19 of the 21
patients reported absorption of lung opacities on CT scans. Once again however, there
is no valid control group to compare these outcomes to.
An analysis was made, however, regarding the changes in lab values throughout the
duration of the study. For this, we assigned the pre-Tocilizumab tests as the mean
control value.
Mean C
Mean T
Difference
Day 1
6.3
8.05
-1.75
Day 3
6.3
6.02
0..28
Day 5
6.3
5.25
1.05
Day 1
15.52
11.78
3.74
Day 3
15.52
16.93
-1.41
Day 5
15.52
22.6
-7.08
Day 1
75.06
38.13
36.93
Day 3
75.06
10.61
64.45
Day 5
75.06
2.72
72.34
WBC count
Lymphocyte
percentage
CRP
Procalcitonin
Mean C
Mean T
Difference
Day 1
0.33
0.21
0.12
Day 3
0.33
0.09
0.24
Day 5
0.33
0.12
0.21
D. Applicability Issues
➔ Directness
◆ P - adult patients with Severe COVID Infection
◆ E - 400mg of Tocilizumab through intravenous drip
◆ O - improvement in clinical outcome
➔ Biologic issues
1. Sex:
● The study consisted of 18 males & 3 females as patients.
However, methods and results did not discriminate between
males and females, therefore no data is provided to state a
significant difference between both genders.
2. Co-morbidities:
● The study did not mention specific comorbidities of the subjects
who were only assessed as to whether they belonged to the
severe and/or critical COVID-19 infection classification. Although,
the study did state that the treatment data were collected
through a chart and figure review of the patients which included
their co-existing diseases however these were not further
expounded nor were they considered in the discussion of the
results.
3. Race:
● The study did not discriminate between races and only
mentioned that they were patients in the aforementioned
hospitals. Therefore no significant difference in race was
observed. This is critical since there may be certain racial
attributes (e.g. metabolism, clinical effectiveness, and side-effect
profiles) that may affect the results of the study.
4. Age:
● The average age of the patients included in the study was 56.8 ±
16.5 years, ages ranged from 25 to 88 years. Although, in the
discussion of results, the patients were not distinguished by age.
5. Pathology:
The study did not focus on differing pathologies, therefore no
information could be extracted.
➔ Socioeconomic issues
In this research, all 21 patients had a history of routine treatment
for a week before tocilizumab. Apart from the standard care that
included lopinavir, methylprednisolone, other symptom relievers
and oxygen therapy according to the Diagnosis and Treatment
Protocol for Novel Coronavirus Pneumonia (6th interim edition),
tocilizumab was added to the said standard regimen which would
add up to the overall cost of treatment for the patients.
➔ Consideration of clinically relevant outcomes
Considering the lung tissue damage, a sufficient time for
repairing is needed and a remission delay in CT scan can be
anticipated. During the treatment, no adverse drug reactions and
subsequent pulmonary infection were reported. Clinical
symptoms of all patients improved remarkably with good
prognosis after the treatment. Nevertheless, there are several
shortcomings in this study. The number of patients were rather
limited and it was a single observation study and a significant bias
could possibly exist.
E.
Conclusion
Therefore, according to this study, tocilizumab is an effective treatment in
patients with critically severe symptoms of COVID-19. Clinical data showed that the
clinical symptoms, hypoxemia, and CT opacity changes were improved immediately
after the treatment in most of the patients. No adverse drug reactions and subsequent
pulmonary infections were reported. However, due to the limited number of subjects
and other shortcomings of the study, more trials are needed to enhance evidence
strength.
However, it is very important to note the shortcomings of the study due to its
single observation nature with a very strong possibility of existing bias. We would
recommended using this study as the basis of a more thought randomized clinical trial.