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\begin{document}

\title{Evaluation of the relationship between laboratory parameters and
pulmonary function tests in COVID-19 patients}



\author[1]{Buğra  Kerget}%
\author[2]{Alperen Aksakal}%
\author[2]{Ferhan Kerget}%
\affil[1]{Ataturk Universitesi}%
\affil[2]{Affiliation not available}%


\vspace{-1em}



  
  \date{May 28, 2024}


\begingroup
\let\center\flushleft
\let\endcenter\endflushleft
\maketitle
\endgroup





\selectlanguage{english}
\begin{abstract}
Objective: The novel coronavirus SARS-CoV-2 (COVID-19) rapidly escalated
from its origin in an animal market in Wuhan, China in December 2019 to
a global pandemic, and the lungs are the most frequently affected organ.
The aim of this study was to investigate the relationship between
pulmonary function test parameters and laboratory parameters in
COVID-19. Method: A total of 60 patients who were admitted to the chest
diseases department and intensive care unit of our hospital and were
diagnosed with COVID-19 by real-time PCR analysis of nasopharyngeal
swabs were evaluated. Pulmonary function tests and laboratory parameters
at admission and on day 7 of treatment were analyzed. Results: On day 7
of treatment, white blood cell count, CRP, and fibrinogen level were
significantly lower than at admission (p=0.002, 0.001, and 0.001,
respectively), while forced expiratory volume in the first second (FEV1)
and forced vital capacity (FVC) values were significantly higher
compared to admitting values (p=0.001 for both). Correlation analysis of
the changes in respiratory function values and laboratory parameters
during follow-up (day 1 to day 7 of treatment) revealed that CRP level
was positively correlated with FEV1 (r=0.616, p=0.01) and FVC values
(r=0.51, p=0.01). Fibrinogen level was also positively correlated with
FEV1 (r=0.345, p=0.01) and FVC (r=0.357, p=0.01). Conclusion: Fibrinogen
and CRP levels are easily accessible parameters that may help identify
improvement or deterioration in pulmonary function in COVID-19 patients
during follow-up and discharge while reducing the risk of transmission.%
\end{abstract}%



\sloppy


\textbf{Evaluation of the relationship between laboratory parameters and
pulmonary function tests in COVID-19 patients}

\textbf{Short title:} Laboratory parameters and pulmonary function tests
in COVID-19

Bu\selectlanguage{polish}ğ\selectlanguage{english}ra Kerget\textsuperscript{1}, Alperen Aksakal\textsuperscript{2},
Ferhan Kerget\textsuperscript{3}

\textsuperscript{1} Depertment of Pulmonary Diseases, Ataturk University
School of Medicine, Yakutiye, Erzurum, Turkey

\textsuperscript{2} Depertmant of Pulmonary Diseases, Health Sciences
University Erzurum Regional Education and Research Hospital, Yakutiye,
Erzurum, Turkey

\textsuperscript{3} Depertmant of Infection Diseases and Clinical
Microbiology, Health Sciences University Erzurum Regional Education and
Research Hospital, Yakutiye, Erzurum, Turkey

All authors disclosure no Conflict of Interest.

*Corresponding Author:

Bu\selectlanguage{polish}ğ\selectlanguage{english}ra Kerget,MD

Yakutiye Medical Research Center

Chest Disease Department

25240, Yakutiye

Erzurum, TURKEY

Tel: +904423447446

Fax: +904423446528

bjkerget1903@gmail.com

\textbf{Evaluation of the relationship between laboratory parameters and
pulmonary function tests in COVID-19 patients}

\textbf{Abstract}

\textbf{Objective:} The novel coronavirus SARS-CoV-2 (COVID-19) rapidly
escalated from its origin in an animal market in Wuhan, China in
December 2019 to a global pandemic, and the lungs are the most
frequently affected organ. The aim of this study was to investigate the
relationship between pulmonary function test parameters and laboratory
parameters in COVID-19.

\textbf{Method} : A total of 60 patients who were admitted to the chest
diseases department and intensive care unit of our hospital and were
diagnosed with COVID-19 by real-time PCR analysis of nasopharyngeal
swabs were evaluated. Pulmonary function tests and laboratory parameters
at admission and on day 7 of treatment were analyzed.

\textbf{Results:} On day 7 of treatment, white blood cell count, CRP,
and fibrinogen level were significantly lower than at admission
(p=0.002, 0.001, and 0.001, respectively), while forced expiratory
volume in the first second (FEV\textsubscript{1}) and forced vital
capacity (FVC) values were significantly higher compared to admitting
values (p=0.001 for both). Correlation analysis of the changes in
respiratory function values and laboratory parameters during follow-up
(day 1 to day 7 of treatment) revealed that CRP level was positively
correlated with FEV\textsubscript{1} (r=0.616, p=0.01) and FVC values
(r=0.51, p=0.01). Fibrinogen level was also positively correlated with
FEV\textsubscript{1} (r=0.345, p=0.01) and FVC (r=0.357, p=0.01).

\textbf{Conclusion:} Fibrinogen and CRP levels are easily accessible
parameters that may help identify improvement or deterioration in
pulmonary function in COVID-19 patients during follow-up and discharge
while reducing the risk of transmission.

\textbf{Keywords:} COVID-19, laboratory parameters, pulmonary function
tests

\textbf{What's already known about this topic?}

It was also reported that pulmonary function tests performed at
discharge revealed no significant difference in forced expiratory volume
in the first second (FEV1) or forced vital capacity (FVC) values between
COVID-19 patients with mild, moderate, and severe pneumonia, whereas
diffusion capacity decreased in correlation with disease severity.
Pulmonary function testing is often not recommended for patients with
active COVID-19 infection in order to prevent excessive transmission.
However, despite clinical improvement in this patient group, ongoing
hypoxia and persistent radiological findings cause considerable
difficulty in predicting the extent of improvement in pulmonary
function.

\textbf{What does this article add?}

While evaluating the laboratory parameters and radiological findings in
patients with COVID-19 has become an easily accessible method, the
inability to evaluate the pulmonary function capacities of patients in
order to prevent contamination has become the most important problem in
follow-up and discharge. Therefore, in our study in which easily
accessible parameters were evaluated for guidance, we think that the
combined decrease in CRP and fibrinogen levels may be related to
increased pulmonary functional capacity.

\textbf{Introduction}

COVID-19 has infected over 70 million people since it appeared just over
a year ago in December 2019, and this number continues to grow daily.
The clinical course ranges from asymptomatic or mild (loss of smell and
taste, anorexia, muscle and joint pain, fatigue) to severe, particularly
in older patients, patients with comorbidities such as hypertension,
diabetes mellitus, or chronic kidney disease, pregnant women, and
immunocompromised patients \textsuperscript{1}.

Acute respiratory failure and macrophage activation syndrome are the
most common severe clinical manifestations of COVID-19. Both are
characterized by overproduction of proinflammatory cytokines which can
lead to endothelial dysfunction in several vital organs, especially the
lungs. Recent studies have shown that COVID-19 causes extensive alveolar
epithelial destruction, capillary damage/bleeding, hyaline membrane
formation, alveolar septal fibrous proliferation, and pulmonary
consolidation. Pulmonary function tests have been the most concrete
indicator of this lung damage \textsuperscript{2,3}.

Studies involving 2-year follow-up of pulmonary function values in
patients with severe acute respiratory syndrome (SARS) and Middle East
respiratory syndrome (MERS) demonstrated that the main pathology was
reduced diffusion capacity (15.5--43.6\%), followed by decreased total
lung capacity (5.2--10.9\%) \textsuperscript{4,5}. It was also reported
that pulmonary function tests performed at discharge revealed no
significant difference in forced expiratory volume in the first second
(FEV\textsubscript{1}) or forced vital capacity (FVC) values between
COVID-19 patients with mild, moderate, and severe pneumonia, whereas
diffusion capacity decreased in correlation with disease severity.
Pulmonary function testing is often not recommended for patients with
active COVID-19 infection in order to prevent excessive
transmission\textsuperscript{6}. However, despite clinical improvement
in this patient group, ongoing hypoxia and persistent radiological
findings cause considerable difficulty in predicting the extent of
improvement in pulmonary function.

The aim of this study was to determine the relationship between
pulmonary function tests and laboratory parameters for the demonstration
of pulmonary dysfunction, which is an important problem for COVID-19
patients.

\textbf{Materials and Methods}

Study design

The study included patients who presented to the emergency department of
Atat\selectlanguage{ngerman}ürk University with complaints such as recent onset fever, cough,
dyspnea, malaise, and sudden loss of taste and smell, and history of
international travel or contact with a suspected COVID-19 patient in the
last 14 days. Patients (or their relatives) were informed in detail
about the aim of the study and all participants provided informed
consent forms before being included. Approval was obtained from the
local ethics committee prior to study initiation.

Study population

All patients assessed as high risk for COVID-19 underwent
high-resolution computed tomography (HRCT) examination. Patients with
HRCT findings suggesting COVID-19 and those with atypical radiologic
findings but consistent clinical symptoms were admitted. Diagnosis of
COVID-19 was based on real-time polymerase chain reaction (PCR) testing
of nasopharyngeal swab samples. The study included 60 patients admitted
to the Erzurum Regional Training and Research Hospital due to COVID-19
during December 2020 who did not develop acute respiratory distress and
macrophage activation syndrome and had a ratio of arterial partial
pressure of oxygen to fraction of inspired oxygen
(PO\textsubscript{2}/FiO\textsubscript{2}) above 200 at admission and on
day 7 of treatment.

Starting at admission to the ward, the patients' hematological
parameters, biochemical parameters including liver and kidney function
tests, coagulation parameters, ferritin, D-dimer, troponin-I, and
C-reactive protein (CRP) levels were evaluated daily.

Exclusion criteria

Patients with any potential contraindications to pulmonary function
testing (recent myocardial infarction, pulmonary embolism, cerebral
aneurysm, active hemoptysis, pneumothorax, nausea/vomiting, recent
thoracic, abdominal, or ocular surgery) were excluded before conducting
the tests. In addition, patients who developed acute respiratory
distress or macrophage activation syndrome associated with secondary
bacterial infections during the 7-day follow-up were also excluded.

Pulmonary function testing

Pulmonary function tests were performed in a negative-pressure room by a
technician wearing protective equipment to prevent transmission. The
patients' age, height, and weight were measured and recorded. Before
testing, patients were instructed to abstain from smoking (24 hours),
alcohol (4 hours), strenuous exercise (30 minutes), and heavy meals (2
hours). Tests were performed with the patients lightly dressed. BTPS
correction was performed according to room air and barometric pressure.
The technician explained the desired maneuvers to the patients and they
performed 3 acceptable spirograms. Tests that met the reproducibility
and acceptability criteria were included in our analysis. All spirometry
was performed by the same technician using a Plusmed MIR Spirolab III
device.

Definitions and Diagnosis

Fever was defined as an axillary temperature of 37.3°C or above.
Secondary bacterial infection was diagnosed based on signs and symptoms
of bacteremia or pneumonia with identification of a new bacterial
pathogen in endotracheal aspirate or lower respiratory tract sputum
culture. For patients diagnosed as having ventilator-associated or
hospital-acquired pneumonia, treatment was planned according to
available guidelines. Acute respiratory distress was diagnosed and
graded according to the Berlin 2015 diagnostic criteria. Patients with
daily cardiac-specific troponin levels above normal range underwent
echocardiographic evaluation for emerging cardiac pathologies.
Coagulopathy was defined as prothrombin time 3 s longer than normal and
activated partial thromboplastin time 5 s longer than normal. Treatment
strategy was determined based on disease severity in accordance with the
COVID-19 adult diagnosis and treatment guidelines issued by the Turkish
Ministry of Health. Macrophage activation syndrome was presumed in
patients who despite treatment exhibited findings such as refractory
fever, persistently high or increasing CRP and ferritin levels, elevated
D-dimer level, lymphopenia or thrombocytopenia, abnormal liver function
indicators, hypofibrinogenemia, or elevated triglyceride levels. If
daily follow-up of these parameters showed continued deterioration that
could not be explained by secondary bacterial infection, 400 mg
tocilizumab for macrophage activation syndrome was administered if not
contraindicated. Another dose of 400 mg tocilizumab was administered if
no significant improvement in laboratory parameters and vital signs was
observed after 24 hours.

Biochemical markers

Venous blood samples were obtained from all patients from an antecubital
vein after at least 15 min of semisupine rest. Blood samples were
collected into tubes containing ethylenediaminetetraacetic acid (EDTA)
to prevent coagulation. Troponin-I levels were measured by
chemiluminescent immunoassay using an Immulite 2500 device (Siemens
Medical Solutions, Erlangen, Germany).

\textbf{Statistical Analysis}

Data were analyzed using IBM SPSS Statistics version 24.0 software (IBM
Corp., Armonk, IL). Categorical variables were expressed as number and
percentage; numerical variables were expressed as mean and standard
deviation. Kolmogorov--Smirnov test was used to test whether the data
were normally distributed. Repeated measures were compared using
Friedman test and Wilcoxon test with Bonferroni correction for
non-normally distributed numerical data. Pearson correlation analysis
was used to assess the relationship between changes in laboratory
parameters and changes in pulmonary function tests. Results with p value
\textless{}0.05 were considered statistically significant.

\textbf{Results}

The mean age of the patients was 51.4 ± 18.2 years. Forty-two (70\%) of
the patients were men and 18 (30\%) were women. The mean ages of the
male and female patients were 55.1 ± 12.5 years and 50.1 ± 10.4 years,
respectively (p=0.04). The mean height and weight of the patients were
168.8 ± 9.1 cm and 82.3 ± 11.4 kg, respectively. Three of the patients
had previously known coronary artery disease, 5 had diabetes mellitus,
and 1 had asthma.

The patients' laboratory values and pulmonary function test results at
admission and on day 7 of treatment are shown in Table 1. White blood
cell count, CRP, and fibrinogen values on day 7 of treatment were
significantly lower compared to admitting values (p=0.002, 0.001, 0.001,
respectively). FEV\textsubscript{1} and FVC values on day 7 were
significantly higher than those at admission (p=0.001 for both) (Figure
1). Statistical analysis of the patients' pulmonary function values
based on the lower limits of normal (LLN) demonstrated that
FEV\textsubscript{1} and FVC were significantly reduced at the start of
treatment (p=0.05 for both) and higher but not significantly on day 7 of
treatment (Figure 1).

Correlation analysis between the changes in respiratory function values
and changes in laboratory parameters during follow-up (day 1 to day 7 of
treatment) revealed that CRP level was positively correlated with
FEV\textsubscript{1} (r=0.616, p=0.01) and FVC values (r=0.51, p=0.01)
(Figure 2). Fibrinogen level was also positively correlated with
FEV\textsubscript{1} (r=0.345, p=0.01) and FVC (r=0.357, p=0.01) (Figure
3). Among the laboratory parameters, CRP was found to be correlated with
fibrinogen (r=0.609, p=0.01) and ferritin (r=0.308, p=0.017).

\textbf{Discussion}

Our study showed that COVID-19 patients' CRP, ferritin, and fibrinogen
levels decreased with treatment, consistent with previous studies, while
FEV\textsubscript{1} and FVC values increased. The symptoms of
restrictive lung disease observed at the start of treatment were
improved on day 7 of treatment. Correlation analysis between the 7-day
changes in laboratory parameters and pulmonary function tests showed
that FEV\textsubscript{1} and FVC values increased in correlation with
the change in CRP and fibrinogen levels.

On March 11, 2020, the World Health Organization (WHO) declared the
COVID-19 a pandemic and as of December 15, 2020, more than 72 million
cases had been confirmed worldwide {[}1{]}. Large-scale studies on
COVID-19 have documented extensive lung damage both during and after the
disease. In a recent report it was determined that COVID-19 pneumonia
patients still showed abnormalities in lung CT scans after discharge,
with ground-glass opacities being the most common pulmonary
sequelae\textsuperscript{7}. Survivors of other coronavirus pneumonias
(SARS and MERS) are known to have pulmonary function and exercise
capacity impairments persisting for months or even
years\textsuperscript{5,8-10}. To date, however, there have been few
studies examining loss of pulmonary function in discharged COVID-19
patients.

SARS-CoV-2 infects the human airway and the vascular and immune cells,
potentially leading to severe damage to the respiratory tract,
especially within the lungs. Disease severity depends on the
effectiveness of the immune system. Current evidence suggests that in
some cases, viral infection can cause an exaggerated immune reaction in
the host that is severe enough to be classified as the hyperinflammatory
condition referred to as macrophage activation
syndrome\textsuperscript{11}.

Numerous proinflammatory cytokines are released in COVID-19 patients,
primarily tumor necrosis factor alpha, interleukins 1, 2, 6 and 18, and
nitric oxide. These cytokines can increase vascular permeability,
resulting in impaired tissue perfusion, endothelial damage, and
microthrombus formation. Increased vascular permeability causes fluid
accumulation in the lung tissue and interstitial spaces, which manifests
clinically with acute respiratory failure \textsuperscript{2,3}.
Suppression of these proinflammatory cytokines has proven to be
therapeutically beneficial in many inflammatory conditions, including
viral infections. Increased cytokine levels in the lung cause alveolar
epithelial damage, alveolar septal fibrous proliferation, hyaline
membrane formation, and the development of pulmonary
consolidation\textsuperscript{12}. This is the main cause of the
restrictive pathology and reduced diffusion capacity seen in the lungs
of COVID-19 patients. Studies have shown that this process continues in
association with regression even after discharge \textsuperscript{13}.
In a study including 110 COVID-19 patients, evaluation of pulmonary
function tests at discharge showed a reduction in diffusion capacity
that was correlated with disease severity. However, a striking aspect of
the study was that the diffusing capacity of the lung for carbon
monoxide (DLCO) decreased more than the diffusing capacity divided by
alveolar volume (DLCO/VA), suggesting that impairment of the diffusion
membrane was a more important issue than low lung volume
\textsuperscript{6}.

It was also observed that levels of D-dimer and acute phase reactants
such as CRP, ferritin, and fibrinogen were elevated in COVID-19 patients
after intense inflammatory cytokine discharge and that these parameters
may be associated with morbidity and mortality \textsuperscript{14}.
Among these parameters, levels of CRP, fibrinogen, and ferritin levels
were found to be high and inversely correlated with
FEV\textsubscript{1}and FVC levels \textsuperscript{15-17}. These acute
phase reactants are elevated in most inflammatory diseases, and studies
evaluating the relationship with parenchymal fibrosis in interstitial
lung diseases have demonstrated increases in correlation with the extent
of parenchymal fibrosis, highlighting their potential usefulness in
follow-up \textsuperscript{18,19}.

In the present study, we observed that the restrictive pattern initially
presented by COVID-19 patients due to parenchymal infiltration in the
lungs resolved during follow-up with regression of the lung
consolidation. Pulmonary function values increased with the decline in
CRP and fibrinogen levels, suggesting the improvement was secondary to
reduced inflammation. However, consistent with our experience with
COVID-19, fibrosis may be permanent and patients may show a restrictive
pattern with reduced diffusion in long-term follow-up. Plasma fibrogen
level has been associated with increased parenchymal fibrosis in
previous studies. Therefore, the decline in plasma fibrinogen levels
during follow-up in COVID-19 suggests that this parameter may be useful
in evaluating progression to parenchymal fibrosis in this disease, which
is characterized by pathologies also observed in interstitial lung
diseases, such as hyaline membrane formation and alveolar septal fibrous
proliferation.

The most important limitation of our study was the inability to evaluate
diffusion capacities and total lung capacities when evaluating the
etiology of the restrictive pathology observed in pulmonary function
tests. However, this was a result of the fact that only portable
pulmonary function testing equipment could be placed in the negative
pressure room established to minimize the chance of transmission.

In conclusion, although the assessment of laboratory parameters and
radiological findings has become a convenient method for evaluating
COVID-19 patients, the inability to evaluate patients' pulmonary
function due to risk prevention measures has become the biggest problem
in follow-up and discharge. In this study examined the guiding potential
of some of these easily obtained parameters, we observed that decline in
both CRP and fibrinogen levels may be associated with improved pulmonary
functional capacity.

\textbf{References}

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2. Kerget B, Kerget F, Koçak AO, et al. Are Serum Interleukin 6 and
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3. Kerget B, Kerget F, Aksakal A, A\selectlanguage{polish}ş\selectlanguage{english}k\selectlanguage{polish}ı\selectlanguage{english}n S, Sa\selectlanguage{polish}ğ\selectlanguage{english}lam L, Akg\selectlanguage{ngerman}ün M. Evaluation
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\textbf{Figure legends}

\textbf{Figure 1.} Comparison of pulmonary function test parameters in
COVID-19 patients between admission and day 7 of treatment and with
lower limit of normal (LLN) values

\textbf{Figure 2.} Correlation analysis of C-reactive protein level with
pulmonary function values

\textbf{Figure 3.} Correlation analysis of fibrinogen level with
pulmonary function values

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