Autor : Freire-Chávez, Jorge L.1, Cordovilla-Zamora, Mónica J.2, Sols-Aramayo, Marco A.1, Quadrelli, Silvia1
1 Servicio de NeumonologÃa, Sanatorio Gemes
2Servicio de ReumatologÃa, Hospital Ramos MeÃja, Ciudad Autónoma de Buenos Aires, Argentina.
https://doi.org/10.56538/ramr.UXJV9747
Correspondencia : Jorge Freire-Chvez. E-mail: freirejorge01@gmail.com
ABSTRACT
atients with COVID-19 have a
broad spectrum of clinical presentations, and mortality rates are relatively
high in severe cases. Early identification of risk factors that are related to
the severity of the disease is of vital importance.
In order to correlate the initial
symptoms of COVID-19 with disease severity, the present retrospective,
cross-sectional, observational cohort study was conducted, including 413
patients diagnosed with COVID-19 between January and March, 2021. Of all the
initial symptoms that were studied, dyspnea (p < 001), fever (p 0.001),
cough (p 0.002), odynophagia (p 0.01), headache (p 0.01), and gastrointestinal
symptoms (p 0.03) were associated with the development of severe illness. The
comorbidities that were associated with the worst prognoses were: arterial
hypertension (p < 0.001), obesity (p < 0.001), COPD (chronic obstructive
pulmonary disease) (p < 0.001), former smoking (p < 0.001), diabetes (p
0.01), previous cardiovascular disease (p 0.03), and active oncological disease
(p 0.04).
In conclusion, patients diagnosed
with COVID-19 whose initial manifestations include dyspnea, fever, cough,
odynophagia, headache, and gastrointestinal symptoms should be closely
monitored to prevent disease deterioration.
Key words: SARS-CoV-2 Infection, COVID-19, Clinical Presentation, Severity
RESUMEN
Los pacientes con COVID-19 tienen un amplio espectro de
presentación clínica y las tasas de mortalidad en los casos
graves son relativamente altas. La identificación temprana de los
factores de riesgo que se relacionan con la gravedad de la enfermedad es de
vital importancia.
Con el objetivo de correlacionar los síntomas
iniciales de COVID-19 con la gravedad de la enfermedad, se realizó el
presente estudio de cohorte transversal retrospectivo y observacional de 413
pacientes con diagnóstico de COVID-19 entre enero y marzo 2021. De todos
los síntomas iniciales estudiados, la disnea (p < 001), fiebre (p
0.001), tos (p 0.002), odinofagia (p 0.01), cefalea (p 0.01) y síntomas
gastrointestinales (p 0.03), se asociaron con el desarrollo de una enfermedad
grave. Las comorbilidades que se asociaron con peor pronóstico fueron:
hipertensión arterial (p < 0.001), obesidad (p <0.001), EPOC (p
< 0.001), ex tabaquismo (p < 0.001), diabetes (p 0.01), enfermedad
cardiovascular previa (p 0.03), y enfermedad oncológica activa (p 0.04).
En conclusión, los pacientes con
diagnóstico de COVID-19, cuya manifestación inicial es disnea,
fiebre, tos, odinofagia, cefalea y síntomas gastrointestinales, deben
ser monitoreados de cerca para prevenir el deterioro de la enfermedad.
Palabras clave: Infección por SARS-CoV-2, COVID-19, Presentación
Clínica, Gravedad
Recibido: 05/20/2022
Aceptado: 02/12/2023
INTRODUCTION
Coronavirus disease 2019
(COVID-19) is an infectious disease caused by a strain of coronavirus called
severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).1
The first cases were seen in Wuhan, China, in late December 2019,
and from there it has spread practically all over the world. It was officially
recognized as a pandemic by the World Health Organization (WHO) on March 11,
2020.1-3
According to PAHO (Pan American
Health Organization) as of April 1, 2021, the number of confirmed cases
worldwide reached 128 million, and more than 2 million deaths. In Argentina,
the data available up to now indicated 2,348,821 cases and 55,858 deaths
associated with COVID-19.
The disease mainly affects
tissues that express high levels of ACE2 (angiotensin converting enzyme 2
receptor), including the lungs, heart, and gastrointestinal tract.2 The presence
of underlying comorbidities is associated with a
higher risk of progressing to severe COVID-19. Advanced age, cardiovascular disease, diabetes mellitus, arterial
hypertension, chronic obstructive pulmonary disease (COPD), cancer (especially
hematologic neoplasms, lung cancer, and metastatic disease), chronic kidney
disease, obesity, and smoking have been mentioned as the main risk factors for
developing severe disease.1, 2, 4, 5
Numerous studies have
highlighted the clinical characteristics of the disease, showing that 80% of
patients with COVID-19 present mild disease with an overall mortality rate of
2-5%.1, 5, 6, 7, 8, 9 However, a subset of
approximately 15% of patients showed moderate lung involvement and required
hospitalization, and 5% had severe respiratory failure, resulting in death in
half of these cases.1, 6, 7, 9, 10
The analytical
alterations that have been associated with the worst prognoses include: lymphopenia,
elevation of liver enzymes, of LDH (lactate dehydrogenase), of inflammatory
markers such as PCR and ferritin, D-dimer, troponin, and CPK (creatine
phosphate kinase), prolonged prothrombin time, and acute kidney injury. Coagulation
test alterations have also been observed, with a state of hypercoagulability
that conditions a tendency to thrombosis.1,
6, 11
Mortality rates of
severe forms of the disease are relatively high (half of the cases)1, 6, 7, 9, 10, so early
identification of risk factors related to the severity of the disease could
facilitate the implementation of timely interventions and probably help reduce
the fatality rate.
In this context, the
present research was conducted with the purpose of correlating the initial
symptoms of COVID-19 with the severity of the disease. Also, to determine the
main comorbidities associated with a poor prognosis and describe the main
elevated biomarkers in COVID-19.
MATERIALS AND METHODS
A retrospective, cross-sectional,
observational cohort study was conducted in patients diagnosed with COVID-19
who attended the Emergency Department of the Sanatorio Güemes between
January 1st and March 31st, 2021, whose diagnosis had been confirmed by
reverse transcription polymerase chain reaction (RT-PCR).
Sanatorio Güemes
is a high-complexity private healthcare institution located in the Autonomous
City of Buenos Aires, with a unique information repository for each patient,
which is centralized through an Electronic Health Record (EHR). All patients,
upon admission to the institution, have voluntarily and officially signed
informed consent for the use of their data for research purposes. The
information of this study was obtained from the EHR database and was entered into
an electronic form designed specifically for this purpose, which was accessible
only to the authors of the study, thus preserving the anonymity of all
participants.
Inclusion criteria:
the study included individuals over 18 years of age with a diagnosis of
COVID-19 confirmed by RT-PCR in throat and nasopharyngeal swab.
Exclusion criteria: individuals with suspected COVID-19 without confirmation at the time of the
analysis and those with positive COVID-19 antibodies (but without RT-PCR or
with negative RT-PCR) were excluded. Additionally, patients whose medical
records didnt include demographic data, comorbidities, and initial symptoms of
the disease, and those who hadnt been followed up by the Sanatorio Güemes
until the time of medical discharge were excluded.
Clinical information,
laboratory data, and assessment of disease severity correspond to data obtained
upon hospital admission. Initial symptoms were defined as the first symptoms
to appear at the onset of the illness. Lymphopenia was defined as a lymphocyte
count < 1000/μL or a percentage of less than 20%. Thrombocytopenia
was defined as a platelet count < 100,000/mm3 ;
and thrombocytosis, as a count > 450,000/mm3.
A PCR value of ≥ 10 mg/l was considered elevated; D-dimer was considered
elevated with a value of ≥ 0.5 mg/l; LDH was considered elevated with
values of > 250 U/L, and for ferritin, it was defined as elevated with
values of > 300 ng/mL in men and > 150 ng/mL in women.
Based on the National
Institutes of Health (NIH) guidelines, individuals who test positive for
SARS-CoV-2 but dont have symptoms compatible with COVID-19 are considered to
have an asymptomatic infection. Mild disease: individuals who have any of the
various signs and symptoms of COVID-19 but do not show breathing difficulty,
dyspnea, or abnormal chest imaging. Moderate disease: individuals who show
evidence of lower airways illness during clinical evaluation or imaging and
have an oxygen saturation (SpO2)
≥ 94% on room air at sea level. Severe disease: individuals who have SpO2 < 94%, arterial oxygen
partial pressure/fraction of inspired oxygen (PaO2/FiO2) ratio of < 300 mmHg,
respiratory rate > 30 breaths/min, or pulmonary infiltrates > 50%.
Critical disease: people who have respiratory failure, septic shock, and/or
multi-organ dysfunction.4 In
order to perform statistical analysis with practical relevance for the studys
objectives, the population was divided into three groups: mild disease
(asymptomatic and mild cases), moderate disease, and severe disease (severe and
critical cases).
Descriptive
statistics were used to analyze the median (interquartile range [IQR]),
frequencies, and proportions. Categorical variables were compared using the
Chi-square test and Fishers exact test when the expected frequencies were less
than 5. Odds ratio (OR) and 95% confidence interval (CI) were used to estimate
the association between initial symptoms, comorbidities, and severe COVID-19 (p
<0.05 was considered statistically significant). Statistical analyses were
performed using SPSS software (version 26.0).
RESULTS
A total of 413
patients with diagnosis of COVID-19 confirmed by RT-PCR were included. The
median age was 37 years ([IQR] 28-48), 228 cases (55.2%) were female, and 185
(44.8%) were male. A total of 154 cases (37.3%) presented with one or more
comorbidities at the time of diagnosis (Table 1).
Among the main
comorbidities, 9.9% were hypertensive, 8.2% former smokers, 6.3% current
smokers, 4.6% asthmatic, and 4.6% obese. The remaining characteristics are
detailed in Table 1.
The initial clinical
presentation was characterized by the presence of fever and headache, each in
43.6% of cases; 39.5% had odynophagia, 34.9% cough, 29.1% myalgia, 20.8%
anosmia, 13.1% dysgeusia, 8.5% rhinitis/nasal congestion, 7.7% gastrointestinal
symptoms, and only 1% dyspnea.
Regarding laboratory
findings, these were requested according to the treating physicians criteria,
so we do not have data on all patients. LDH was requested in 73 cases, of which
91.8% had elevated LDH; the PCR was elevated in 85.7% of 77 patients; elevated
ferritin was found in 85.1% of 47 cases; D-dimer was elevated in 42.3% of 26
patients; lymphopenia was found in 31.1% of 90 cases; thrombocytopenia was
present in 3.4% of 89 patients, and no evidence of thrombocytosis was found in
any of the studies.
Of the 413 patients,
82.6% (341) were indicated home medical care and daily telephone follow-up;
16.9% required hospitalization in a general ward, and 0.5% had to be
hospitalized at the intensive care unit (ICU) upon their admission to the institution.
The median time from symptom onset to medical consultation was 3 days (IQR
2-4).
81.1% developed mild
disease, 12.8% moderate disease, and 6.1% severe disease. When correlating
initial symptoms with severe COVID-19, the severity of the disease was
significantly associated with dyspnea (OR = 1.19, CI: 1.003-1.41, p <
0.001), fever (OR = 4.46, CI: 1.74-11.43, p 0.001), cough (OR = 3.61, CI:
1.55-8.39, p 0.002), odynophagia (OR =3.42, CI: 1.19-9.79, p 0.01), headache
(OR = 3.09, CI: 1.18-8.07), and gastrointestinal symptoms (OR = 3.34, CI: 1.16-9.60,
p 0.03) (Table 2).
As for comorbidities,
those significantly associated with severe disease were arterial hypertension
(OR = 11.42, CI: 4.78 - 27.30, p < 0.001), obesity (OR = 21.26, CI: 7.59 -
59.56, p < 0.001), COPD (OR = 60.95, CI: 11.53 - 322.2, p < 0.001),
former smoking (OR = 12.46, CI: 5.09 - 30.51, p < 0.001), diabetes (OR =
5.96, CI: 1.77-0.09, p 0.01), previous cardiovascular disease (OR = 5.74, CI:
1.45- 22.72, p 0.03), and active oncological disease (OR = 8.34, CI: 1.45 -
47.97, p 0.04) (Table 2).
All patients who
received home hospitalization completed their telephone follow-up without any
reported deaths or need for hospitalization. Among the patients who required
hospitalization (72 cases), the median length of hospital stay was 6 days (IQR
3.25-9.75). Of those initially hospitalized in a general ward (70 cases), 11.4%
subsequently required ICU care. Mortality among hospitalized patients was 8.3%
(6 cases). All 6 deceased patients required ICU stay and mechanical
ventilation, and they all showed symptoms and comorbidities associated with
greater severity. The overall mortality rate was 1.5% (6/413 patients).
DISCUSSION
Our work describes the main
clinical characteristics, comorbidities, and commonly requested laboratory
tests in cases of COVID-19 and the association between initial symptoms and
comorbidities that are related to the severity of the disease. As relevant
data, 37.3% showed comorbidities at the time of
diagnosis, with arterial hypertension being the main one, followed by a history
of past smoking, current smoking, and obesity; similar to what has been
observed in national studies such as that of Pulido et al.12 The
first symptoms to appear were fever and headache in 43.6% of cases, followed
by odynophagia and cough. These data are consistent with several studies
published in the literature.3, 5-7, 13, 14
Out of our entire
population, 81.1% developed a mild disease, 12.8% moderate, and 6.1% had severe
disease. These data are related to several studies that showed that 80% of
patients with COVID-19 show mild disease.1, 5-8 15% of patients had
moderate lung involvement, which required hospitalization, and 5% had severe
respiratory failure, which resulted in death in half of these cases.1,
6,7, 9, 10
As a relevant finding
of our study, we found that the initial symptoms of COVID-19 that are
associated with the development of severe disease are: dyspnea (p < 0.001),
fever (p 0.001), cough (p 0.002), odynophagia (p 0.01), headache (p 0.01), and
gastrointestinal symptoms (p 0.03). Likewise, comorbidities associated with the
worst prognoses were: arterial hypertension (p < 0.001), obesity (p <
0.001), COPD (p < 0.001), former smoking (p < 0.001), diabetes (p 0.01),
previous cardiovascular disease (p 0.03), and active oncological disease (p
0.04).
As of the writing of
this study, there are no national publications that assess the initial symptoms
and their relationship with the severity of the disease. When comparing our
results with the international literature, we saw that He et al3
found in a population of 3,326 patients (selected from 20 articles, all based
on the Chinese population), that from the initial symptoms, cough (p <
0.001), fever (p < 0.001), dyspnea (< 0.001), diarrhea (p < 0.001),
fatigue (p < 0.01), expectoration (p < 0.01), myalgia (p < 0.001),
hemoptysis (p < 0.001), abdominal pain (p < 0.001), and anorexia (p <
0.001) were associated with the risk of progressing to severe disease.
Rubio et al7
conducted a cluster analysis of the Spanish SEMI-COVID-19 registry including 11
phenotypic variables in a cohort of 12,066 hospitalized patients. The study
identified 4 phenotypic groups that predicted hospital prognosis. The groups
associated with poor prognosis were C1 (cases that showed the isolated triad of
fever, cough, and dyspnea) and C4 (diarrhea, vomiting, and/or abdominal pain).
On the other hand, patients who belonged to group C2 (dysgeusia and/ or
anosmia) showed the best prognosis, along with group C3 (arthromyalgia,
headache, and odynophagia).
Regarding
comorbidities, several studies on different population groups have described
that the presence of these comorbidities is associated with a higher risk of progressing to
severe COVID-19. Advanced age, cardiovascular
disease, diabetes mellitus, arterial hypertension, COPD, cancer, chronic kidney
disease, obesity, and smoking are the main risk factors associated with severe
COVID-19.1, 2, 4, 5 Our findings mostly agree with published data,
however; in contrast, former smoking (p < 0.001) was associated with a risk
of severe disease. This result is consistent with what was published by Zhang
et al15 in a meta-analysis of 25 articles, which suggested that
there was a significant relationship between former smokers and the risk of
severe COVID-19, compared to current smokers (combined OR: 1.85, 95% CI:
1.33-2.55, I2 = 67.7%, p < 0.001).
Different studies
have identified the main biomarkers that are associated with a higher risk of
developing a worse course of the disease. In this regard, Tjendra et al5
conducted a review of 43 cohort studies and 11 systematic reviews (including
the meta-analysis) where they found that upon admission, most patients showed
lymphopenia, neutrophilia, thrombocytopenia, prolonged PT, elevated D-dimer,
high lactate levels, lower oxygen saturation, high neutrophil-to-lymphocyte
ratio (> 5.0), and high systemic immune inflammation index (> 500). All
patients had high initial levels of PCR and IL-6 (> 10 pg/ml), and a large
subset of patients had elevated levels of LDH, D-dimer, procalcitonin, and
ferritin. The presence of these abnormalities was associated with critical
illness. Similarly, Zhou et al14 conducted a retrospective cohort
study including 191 patients with COVID-19. In comparison to survivors,
non-survivors more frequently showed high LDH (p < 0.001), high
procalcitonin (p < 0.001), increased levels of serum ferritin (p <
0.001), and elevated IL-6 (p < 0.001). When comparing these results with
those obtained in our study, all patients who developed severe disease had
mainly elevated levels of LDH, PCR, ferritin, and D-dimer.
The overall mortality
rate was 1.5%, similar to what has been reported in different publications that
mention a fatality rate between 1.4% and 4.3%.16,17
Our study has some
limitations. As a retrospective study, collected data comes from electronic
medical records, which are subject to biases that are inherent in data
collection. The results only correspond to the experience of a single hospital
center rather than multiple centers. In addition, several records were excluded
because they did not have the minimum data necessary for the study or medical
follow-up until final discharge. Biomarkers were requested according to the
treating physicians criteria, so we do not have that particular data on all
patients. Although we found significant associations with disease severity,
more multicenter studies are necessary, with a larger number of participants,
to replicate our findings in a large percentage of the national population.
In conclusion, patients diagnosed with COVID-19 whose initial
manifestations include dyspnea, fever, cough, odynophagia, headache, and
gastrointestinal symptoms have higher risk of developing a severe course of the
disease. High blood pressure, obesity, COPD, former smoking, diabetes, previous
cardiovascular disease, and active oncological disease are associated with a
poor prognosis.
In order to prevent
disease deterioration, it is vital to identify initial symptoms and comorbidities
related to poor outcomes as soon as possible.
Conflict of interest
Authors have no
conflict of interest to declare.
REFERENCES
1. Martínez E, Díez A,
Ibáñez L, Ossaba S, Borruel S. Diagnóstico
radiológico del paciente con COVID-19. Radiología 63. 2021;56-73.
https://doi.org/10.1016/j.rx.2020.11.00131
2. Terpos E, Ntanasis-Stathopoulos I, Elalamy
I, et al. Hematological findings and complications
of COVID-19. Am J Hematol. 2020;114.
3. He X, Cheng X,
Feng X, Wan H, Chen S, Xiong M. Clinical Symptom Differences Between Mild and
Severe COVID-19 Patients in China: A Meta-Analysis. Front Public Health.
2021;8:561264. https://doi.org/10.3389/fpubh.2020.561264
4. COVID-19 Treatment
Guidelines Panel. Coronavirus Disease 2019 (COVID-19) Treatment Guidelines.
National Institutes of Health. Available at
https://www.covid19treatmentguidelines.nih.gov/. Accessed [5/12/2021].
5. Tjendra Y, Al Mana AF, Espejo AP, et al. Predicting Disease Severity and Outcome in COVID-19
Patients: A Review of Multiple Biomarkers. Arch Pathol Lab Med. 2020;144:1465-
74. https://doi.org/10.5858/arpa.2020-0471-SA
6. Wang D, Li1 R,
Wang J, et al. Correlation analysis between disease severity and clinical and
biochemical characteristics of 143 cases of COVID-19 in Wuhan, China: a
descriptive study. BMC Infectious Diseases. 2020;20:519.
https://doi.org/10.1186/s12879-020-05242-w
7. Rubio M, Corbella
X, Mora JM, et al. Predicting Clinical Outcome with Phenotypic Clusters in
COVID-19 Pneumonia: An Analysis of 12,066 Hospitalized Patients from the
Spanish Registry SEMI-COVID-19. J. Clin.
Med. 2020;9:3488. https://doi.org/10.3390/jcm9113488
8. Ministerio de Salud de la Nación.
Recomendaciones para equipos de salud. Nuevo Coronavirus COVID-19. Actualizado
al 14/04/2021. Disponible en:
https://www.argentina.gob.ar/coronavirus/equipos-salud.
9. Geng MJ, Wang LP,
Ren X, et al. Risk factors for developing severe COVID‑19 in China: an
analysis of disease surveillance data. Geng et al. Infect Dis Poverty.
2021;10:48 https://doi.org/10.1186/s40249-021-00820-9
10. Bats ML, Rucheton
B, Fleur T, et al. Covichem: A biochemical severity risk score of COVID-19
upon hospital admission. PLoS One. 2021;16:e0250956.
https://doi.org/10.1371/journal.pone.0250956
11. Coté A,
Ternacle J, Pibarot P. Early prediction of the risk of severe coronavirus
disease 2019: A key step in therapeutic decision making. EBioMedicine. 2020;59:102948.
https://doi.org/10.1016/j.ebiom.2020.102948
12. Pulido L, Solís M, Ibarrola M, et
al. Experiencia inicial en la atención de pacientes con COVID-19 en un
hospital privado de alta complejidad de la Ciudad de Buenos Aires. Medicina (B
Aires). 2020;80:433-38.
13. Guan W, Ni Z, Hu Y, et al. Clinical Characteristics of Coronavirus Disease 2019
in China. N Engl J Med. 2020;382:1708- 20.
https://doi.org/10.1056/NEJMoa2002032
14. Zhou F, Yu T, Du
R, et al. Clinical course and risk factors for mortality of adult inpatients
with COVID-19 in Wuhan, China: a retrospective cohort study. Lancet. 2020;395: 1054-62.
https://doi.org/10.1016/S0140-6736(20)30566-3
14. Zhang H, Ma S,
Han T, et al. Association of smoking history with severe and critical outcomes
in COVID-19 patients: A systemic review and meta-analysis. Eur J Integr Med. 2021;43:101313.
https://doi.org/10.1016/j.eujim.2021.101313
16. Du Y, Tu L, Zhu P, et al. Clinical features of 85 fatal cases of COVID-19 from
Wuhan. A retrospective observational study. Am J Respir Crit Care Med.
2020;201:1372-9. https://doi.org/10.1164/rccm.202003-0543OC
17. Guan WJ, Ni ZY, Hu Y, et al. Clinical characteristics of coronavirus disease 2019
in China. N Engl J Med. 2020;382:1708-20.
https://doi.org/10.1056/NEJMoa2002032