Keywords
COVID 19 - crazy pavement pattern - ground glass opacity - HRCT
Introduction
Globally, high resolution computed tomography (HRCT) chest is currently underutilized
for the evaluation and management of patients affected with COVID-19. HRCT is used
in many developed countries for severe cases of COVID pneumonia primarily to assess
the status of the lung and not in the clinical context of treating the patients. Pulmonary
damage is the most important causes of morbidity and mortality globally although SARS
CoV-2 has extra pulmonary manifestations including sepsis syndrome.
The high sensitivity of HRCT in patients infected by SARS-CoV-2 makes it suitable
for inclusion in clinical management protocols[[1]] The majority of patents with COVID 19 are in the mild to moderate spectrum. The
clinical management of these patients, who may be symptomatic or asymptomatic, is
important from the clinical perspective of the individual patient as well as from
a public health perspective of breaking or controlling the potential transmission
of the virus. HRCT chest can help to guide clinical management in mild & moderate
cases of COVID pneumonia, provide useful information to triage for home quarantine
or hospital admissions and prevent the worsening of patients to more severe states.
In this article, we describe the patterns of lung involvement, using HRCT, in patients,
categorized as mild to moderate to severe. The outcomes of early initiation of steroid
and anticoagulant administration in HRCT positive mild and moderate cases with Inflammatory
markers and D-Dimer elevation including reduction of transitions to more severe stages
and hospital stay and costs for patients with moderate lung involvement are presented.
Material and Methods
A cross sectional study design was conducted from May 15 2020 to August 30 2020, at
five healthcare centers in Trichy district of South Tamilnadu in India. The study
centers included Magnum Imaging & Diagnostics, which was responsible for the imaging
and diagnostic testing of COVID suspected patients, and ABC hospital, GVN Hospital
Singarathope, Sundaram Hospital, Saravana Hospital & Retna Global Hospital, which
were responsible for the clinical care management of patients with COVID-19.
Patients aged 10 to 70 years, suspected to have COVID related symptoms and exposure
to infected persons were included in the study. Patients with pre-surgical conditions,
Diabetes, Hypertension and Renal Failure who were referred for radiology examinations
and were found to have findings suggestive of COVID-19 on examination, were also included
in the study.COVID-related symptoms were considered to include one or more of the
following viz., fever, sore throat, body pain, diarrhea and breathlessness. Patients
with pre-existing interstitial lung disease, unilateral destroyed lung post Tuberculosis,
previous history of heart diseases, previous history of asthma, known primary lung
malignancy or lung metastatic malignancies, readmissions, patients with >60% lung
involvement, irrespective of lung involvement pattern, pleural effusion or pneumothorax
or pneumomediastinum identified in HRCT were excluded from the study. Patients who
were lost to follow up were also excluded from the study.
Every patient underwent evaluation with HRCT chest, Inflammatory markers (LDH/Ferritin)
and D-Dimer assay. The diagnostic test findings were correlated with clinical staging
by SaO2 in room air and the physician’s decision to admit the patient. On follow up,
patients were assessed for oxygen, steroid and anticoagulant therapy, clinical recovery
or progression. Details on mortality were also collected. The post recovery CT chest
or progression to fibrosis or sequelae were not included in the scope of this study.
CT protocol
Multidetector CT scanners (GE128 slice & Siemens 16 slice) were used for the examinations.
Scanning parameters were identical to the manufacturer’s standard recommended pre-setting
for a thorax routine. Images were reconstructed with a 0.625 mm slice thickness in
all cases using the classic filtered back-projection method with a soft tissue kernel
of B20 and a lung kernel of B60. Coronal and sagittal multiplanar reconstructions
were also available in all cases.
Implementation of appropriate infection prevention and control measures, for the healthcare
workers and the CT room, were arranged in all suspected COVID cases undergoing CT
and included prompt sanitation of CT facility and patient’s isolation. Appropriate,
recommended social distancing guidelines were followed and included minimal waiting
times and dedicated patient routes.
Image analysis
Definitions of radiological terms like ground glass opacity (GGO), crazy-paving pattern,
and pulmonary consolidation were based on the standard glossary for thoracic imaging
reported by the Fleischner Society.[[2]] Based on two separate publications by Hansell & Salehi,[[3], [4]] the diagnosis of a suspected SARS-CoV-2 pneumonia was established considering the
following chest CT patterns: GGO, crazy-paving, and consolidation and the diagnostic
confidence of COVID lung was determined based on CORADS.[[5]]
Once the CT was classified as CORADS 4 or 5 (High or Very High Suspicion), Radiological
Severity Classification was made on the percentage of Lung Involvement (Using Automated
software) into mild, moderate and severe, which is <30%, 30-60% and >60%, respectively
[[Figure 1], [2], [3]].
Figure 1 (A and B): A and B: 3D segmentation Volume images showing Mild and Moderate
lung involvement, for segmentation and percentage analysis with the software
Figure 2: Volume of lung involvement by segmentation, Qualification and Analysis
Figure 3 (A and B): A and B: Severe Disease by coronal CT & Segmentation analysis
A 62 year-old male 75% lung involvement - “M” pattern, hospitalised with breathlessness
SaO2 85% in room air with elevated inflammatory markers and D-Dimer
We evaluated the pattern of percentage lung involvement, which we could assess by
HRCT chest, along with D-Dimer & inflammatory markers (LDH & Ferritin) to predict
the possibility of worsening of the disease condition, as the important clinical problems
were the severity of inflammation, rhabdomyolysis and thrombogenesis.
The HRCT Lung in COVID cases were reported with mention of predominant pattern, viz.,
“G”, when there was predominant Ground glass opacities, “C”, when there was predominant
Crazy-paving or consolidation & “M” for mixed pattern or those pattern that could
not be properly evaluated or categorized as only G or C. For example, if there is
30-60% lung involvement with predominant crazy-paving pattern, it was reported as
“CORADS 5 - Moderate Disease -C” [[Figures 4A] and [4B]]
Figure 4 (A and B): A and B: Axial and Coronal - Crazy paving pattern - moderate disease
(CORADS -5 - Moderate Disease -“C” Pattern
Informed consent is routinely obtained from every patient presenting for diagnostic
imaging, lab tests and clinical assessments at the study centers. Data were entered
into a spreadsheet and analyzed further with respect to the main outcomes. A Chi-square
test was used to determine statistical significance of important associations and
a P value <0.05 was considered as statistically significant.
Results Analysis
The study included 7,340 patients with suspected COVID and 3,963 (53.9%) patients
had lung involvement based on HRCT. The majority of these 3,963 subjects were aged
30 to 50 years (n = -1741, 43.93%) and 2241 (56.55%) were males. Among the 3,963 patients with a positive
HRCT, Mild Lung involvement was identified in 1,783 (43%), moderate lung involvement
in 1,268 (32%) and severe lung involvement in 912 (25%). [[Table 1]] shows the RT PCR status in these 3,963 patients.
Table 1
RT PCR status in the 3,963 patients with identifiable lung involvement in HRCT
RT PCR status
|
CT Positive
|
Positive
|
2,940 (74.1%)
|
Negative
|
1,023 (25.9%)
|
The predominant HRCT pattern in this population was Crazy Pavement pattern (n = 2022, 51.0%) and GGO was found in 1,941 (49.0%) patients in the study. Severe lung
involvement was more common in the Crazy Pavement pattern of lung involvement [[Table 2]] Patients with GGO and moderate lung involvement were significantly more likely
to recover faster compared to patients with Crazy Pavement pattern (Chi-square test,
P value <0.001) [[Table 3]].
Table 2
Pattern of lung involvement by severity of lung of involvement
Lung Involvement
|
Ground Glass Opacity n, %
|
Crazy Pavement Pattern n, %
|
Mild
|
963, 49.61%
|
821, 40.60%
|
Moderate
|
712, 31.68%
|
557, 27.54%
|
Severe
|
266, 13.70%
|
644, 31.84%
|
Table 3
Recovery rate by lung pattern involvement in COVID patients with moderate lung involvement
|
Ground glass Opacity n=712
|
Crazy Pavement pattern n=-557
|
Asymptomatic and recovered
|
510 (71.63%)
|
131 (23.52%)
|
Became symptomatic during course of illness
|
202 (28.37%)
|
426 (76.48%)
|
Elevated Inflammatory Markers (LDH/ferritin/D-Dimer) were found in 134 (17.3%) of
patients with GGO and moderate lung involvement and 488 (87.6%) of patients with Crazy
Pavement pattern (Chi square P value <0.001). All these patients were followed up with HRCT after 3 days and showed
increase in Septal thickening/Band atelectasis/Plate atelectasis. All these patients
were started on Anticoagulant & Steroids and HFNO was started in cases of Hypoxemia.
Mortality in Moderate Lung Involvement (Any Pattern total patients 1263) was 18 (1.4%)
irrespective of treatment with Steroids & Anticoagulants. All these patients had pre-existing
conditions such as Diabetes, Hypertension or renal failure. Patients sowing ground
glass opacity with mild and moderate lung involvement by HRCT, were significantly
less likely to need hospitalization compared to those with Crazy Pavement Pattern
(Chi square test, P < 0.001) [[Table 4]].
Table 4
Hospitalization by lung pattern in COVID patients with moderate lung involvement
|
Ground Glass Opacity n=712
|
Crazy Pavement Pattern n=-557
|
Hospitalized
|
109 (15.31%)
|
488 (87.61%)
|
Did not need hospitalization
|
603 (84.69%)
|
69 (12.39%)
|
Discussion
On February 11, 2020, the WHO Director-General, Dr. Tedros Adhanom Ghebreyesus, announced
that the disease caused by this new CoV was a “COVID-19,” which is the acronym of
“coronavirus disease 2019”.[[6]] This new virus initially reported from Wuhan district of China in 2019 is very
contagious and has quickly spread globally. In a meeting on January 30, 2020, per
the International Health Regulations (IHR, 2005), the outbreak was declared by the
WHO a Public Health Emergency of International Concern (PHEIC) as it had spread to
18 countries with four countries reporting human-to-human transmission. An additional
landmark occurred on February 26, 2020, as the first case of the disease, not imported
from China, was recorded in the United States (US).[[6]] After which, COVID-19 quickly crossed the ocean and as of September 15, 2020, about
4.8 million cases with 81,000 deaths has been recorded in India, whereas about 29.2
million with 926,000 deaths has been recorded throughout the world. Although over
time the lethality rate (total number of deaths for a given disease in relation to
the total number of patients) of COVID-19 has been significantly lower than that of
the SARS and MERS epidemics, the transmission of the SARS-CoV-2 virus is much larger
than that of the previous viruses, with a much higher total number of deaths. It has
been estimated that about one in five individuals worldwide could be at increased
risk of severe COVID-19 disease if they become infected, due to underlying health
conditions.[[7]]
CoVs are enveloped, positive-stranded RNA viruses with nucleocapsid the SARS-CoV-2
virus, like the closely related MERS and SARS coronaviruses, effects its cellular
entry via attachment of its virion spike protein (S protein) to the angiotensin-converting
enzyme 2 (ACE2) receptor, which is expressed in the acini. The spike RBD (Receptor-Binding
Domain) allows the binding to the ACE2 receptor in the lungs and other tissues. The
presence within the spike protein of an amino acid site (polybasic site) allows the
functional processing of the same by the human enzyme furin (protease). This process
allows the exposure of the fusion sequences and therefore the fusion of the viral
and cell membranes, a necessary passage for the virus to enter the cell.[[6]] The data so far available seem to indicate that the viral infection is capable
of producing an excessive immune reaction in the host. In some cases, a reaction takes
place which as a whole is labeled a ’cytokine storm’. The effect is extensive tissue
damage with dysfunctional coagulation. The Italian researchers introduced the term
of MicroCLOTS (microvascular COVID-19 lung vessels obstructive thromboinflammatory
syndrome) for underlying the lung viral injury associated with the inflammatory reaction
and the microvascular pulmonary thrombosis.[[8]]
The Lung changes are host response to the virus attachment in the airspace. These
changes are predominantly seen between 5 to 7 days on HRCT. So, it is prudent to do
CT chest between day 5 to 7 from the onset of symptoms, which is the intermediate
phase between late viral disease and early host response. Doing a HRCT chest earlier
may give false sense of wellbeing and a false negative result. But in cases of Suspected
Covid, with preexisting lung disease (COPD/ILD) or prior oxygen dependency or hypoxia
during the 1st visit to hospital, early HRCT may be indicated, to assess the status of underlying
Lung damage.
The knowledge of basic structural and functional unit [[Figure 5A]], is essential in understanding the pathophysiology of inflammatory cascade that
happens in the lung parenchyma which is the underlying cause for the clinical deterioration
of the affected patients. Secondary pulmonary lobules represent a cluster of up to
30 acini[[9]] supplied by a common distal pulmonary artery and bronchiole.[[10], [11], [12]] These clustered acini are bounded by interstitial fibrous septa (interlobular septa)
which outline an irregular polyhedron of varying size between 1 and 2.5 cm2 Peripheral
lobules are larger and cuboidal/pyramidal, while central lobules tend to be smaller
and hexagonal.[[12]] When the airspace is involved by the disease process due to ACE expression in the
acini, the HRCT reveals ground glass opacities (GGO), where there is associated terminal
pulmonary arteritis, giving the dilated vessel sign [[Figure 6]]. When the inflammation progresses through the lobular parenchyma & involves the
septum, crazy-paving pattern is seen, which is due to involvement of Pulmonary veins,
as a part of endothelial dysfunction & the Lymphatic involvement [[Figures 7] and [8]]. These patients showing predominantly septal thickening involving 30 to 60% lung
parenchyma shows elevated inflammatory markers & D-Dimer level [[Chart 1]] The interstitial vasculitis involving the pulmonary veins hampers the oxygen transfer
to the systemic circulation, how much ever oxygen is administered, through that disease
affected lobule. So, these patients were benefitted by Steroid & Anticoagulant administration,
thereby reducing the thrombo-inflammation and effectively managing the patients by
facilitating the transfer of oxygen administered, in cases of hypoxia, into the systemic
circulation.
Figure 5 (A and B): A and B Anatomy of the Lobule of Lung and Pattern of Lung involvement
: Secondary lobule is made up of Centrilobular structures, Lobular parenchyma and
the septal structures. Secondary pulmonary lobules represent a cluster of up to 30
acini[[9]] (Light blue) supplied by a common distal pulmonary artery (blue) and bronchiole.[[10]–[12]] These clustered acini are bounded by interstitial fibrous septa (interlobular septa),
which has lymphatics (yellow) and Pulmonary veins (red) which outline an irregular
polyhedron of varying size between 1 and 2.5 cm. Peripheral lobules are larger and
cuboidal/ pyramidal, while central lobules tend to be smaller and hexagonal[[12]] When the airspace is involved the HRCT reveals ground glass opacities (GGO), with
dilated vessel sign and when the inflammation progresses through the lobular parenchyma
and involves the septum, crazy-paving pattern is seen, which is due to interstitial
vasculitis involving the pulmonary vein (box with arrow)
Figure 6: Ground glass opacities in posterior segments of bilateral upper lobes with
dilated terminal pulmonary artery (blue double head arrow) - (due to airspace inflammation
- Lung response to the Viral disease)
Figure 7: Crazy Paving and areas of consolidation
Figure 8: Crazy paving pattern
Chart 1: Pattens of Lung involvement, its pathophysiology and correlation with Biochemical
parameters
This is also supported by Tian et al.[[13]] who reported histopathological data obtained on the lungs of two patients who underwent
lung lobectomies for adenocarcinoma. These patients were retrospectively found to
have had the infection at the time of surgery in which the authors reported vascular
congestion combined with inflammatory clusters of fibrinoid material and multinucleated
giant cells and hyperplasia of pneumocytes. Zhang et al.[[14]] performed a postmortem transthoracic needle lung biopsy in a patient who died of
COVID-19. Immunostaining showed diffuse alveolar injury and an important alveolar
expression of viral antigens and the authors[[15]] offered a detailed picture of the histological patterns in lung and extrapulmonary
tissues. characterized by capillary congestion, necrosis of pneumocytes, hyaline membrane,
interstitial edema, pneumocyte hyperplasia, reactive atypia and Platelet-fibrin thrombi
in small vessels were the expression of intravascular coagulopathy with findings suggestive
for vascular dysfunction, in lung and other tissues.
Since the veins in the septa are obliterated and no metabolite or oxygen transfer
in the capillary level, there is not the lymph exudation, which is the possible reason
why inspire of so much of lung inflammation, Pleural effusion is not the main feature
in Covid Pneumonia, unless there is myocarditis or coronary disease. Since the air
pressure in the Alveoli is less than the pleural pressure when the inflammation resolves,
band atelectasis is the common feature in the post infective sequel.
The Dutch Radiological Society developed CO-RADS based on other efforts for standardization,
such as the Lung Imaging Reporting and Data System or Breast Imaging Reporting and
Data System. CO-RADS assesses the suspicion for pulmonary involvement of COVID-19
on a scale from 1 (very low suspicion) to 5 (very high suspicion). The system is meant
to be used in patients with moderate to severe symptoms of COVID-19. The system was
evaluated by using 105 chest CT scans of patients admitted to the hospital with clinical
suspicion of COVID-19 and in whom reverse transcription-polymerase chain reaction
(RT-PCR) was performed.[[5]] This system gives the diagnostic confidence in Covid lung. However, it does not
provide insight to the pattern of lung involvement or the volume of lung involved
by the disease.
The Radiological Society of North America (RSNA) has released a consensus statement
endorsed by the Society of Thoracic Radiology and the American College of Radiology
(ACR) that classifies the CT appearance of COVID-19 into four categories for standardized
reporting language.[[16]] The typical appearances include peripheral, bilateral, GGO +/- consolidation or
visible intralobular lines (”crazy paving” pattern), multifocal GGO of rounded morphology
+/- consolidation or visible intralobular lines (”crazy paving” pattern) and reverse
halo sign or other findings of organizing pneumonia. The indeterminate appearances
include absence of typical CT findings and the presence of multifocal, diffuse, perihilar,
or unilateral GGO +/- consolidation lacking a specific distribution and are non-rounded
or non-peripheral few very small GGO with a non-rounded and non-peripheral distribution.
Third, the atypical appearances include absence of typical or indeterminate features
and the presence of isolated lobar or segmental consolidation without GGO discrete
small nodules (e.g., centrilobular, tree-in-bud), lung cavitation and smoother interlobular
septal thickening with pleural effusion and finally, negative for pneumonia where
there is no CT features to suggest pneumonia, in particular, absent GGO and consolidation.[[16]]
The segmental and lobar involvement of lung by Covid is given by CT severity score.
CT severity score[[17]] (total score out of 25) does not correlate with the biochemical parameters and
clinical severity in cases of <60% lung involvement, which takes into account only
the percentage of segmental involvement rather than the pattern of disease process.
With Severity score alone, it is unclear, which of these subsets will fare well or
worsen during the course of illness and also there is no clear correlation with the
biochemical worsening. We also cannot ascertain how to triage these patients to home
quarantine or close monitoring or to hospitalize with general CT severity score alone.
Clinically patients are classified as mild, moderate, and severe by oxygen saturation
in room air. Radiological Classification has to be made on the percentage of Lung
Involvement (Preferably using Automated software) into mild, moderate, and severe,
which is <30%, 30-60%, and >60%, respectively with special mention of predominant
pattern G/C/M, as explained earlier in this article. Patients with more than 60% lung
involvement by HRCT, usually have mixed pattern on CT and are predominantly symptomatic
and shows elevated inflammatory markers invariably, who needs hospitalization and
different management plan, including Plasma therapy, Immunomodulators, Free-Radical
scavengers or Ventilation according to the clinical and biochemical parameters.
The major morbidity in this cross-sectional population of Trichy District, South India
are the mild and moderate group, which is attributed to the strain of virus and tropical
climate. When HRCT shows ’C” or “M” pattern, biochemical investigations (Inflammatory
markers and D-Dimer) were ordered and the treatment was initiated based on the biochemical
and clinical parameters. In these cases, HRCT gives us the insight on the possible
pathology, used in guiding these patients for further need for investigations and
appropriate management [[Charts 2] and [3]].
Chart 2: Patterns in cases with Less than 30% Lung involvement on HRCT by Covid-19
with investigation and management protocol
Chart 3: Patterns in cases with Less than 30-60% Lung involvement on HRCT by Covid-19
with investigation and management protocol
A significant proportion of these patients who had moderate disease by HRCT with ’M”
or “C” pattern showed elevated Inflammatory markers and D-Dimer levels and showed
excellent recovery when they were appropriately treated with steroids (dexamethasone)
and Anticoagulants (therapeutic doses Low Molecular Weight Heparin). They do not progress
to severe illness, as steroids and anticoagulants prevent the progressive inflammation
of the lung parenchyma, thereby improving the oxygen delivery and absorption into
systemic circulation. A large-size RCT (the RECOVERY trial) demonstrated that dexamethasone
reduces deaths by one-third among critically ill COVID-19 patients. In the intervention
group, 2,100 patients received dexamethasone (6 mg/day for 10 days) whereas in the
control group patients (n = 4,300) received standard care for the disease.[[18]] Because/COVID-19 patients have a higher incidence of venous thromboembolism and
anticoagulant therapy is associated with reduced ICU mortality, it is suggested that
patients should receive thromboprophylaxis. In the case of known thrombophilia or
thrombosis, full therapeutic-intensity anticoagulation (e.g., enoxaparin 1 mg/kg twice
daily) is indicated[[19]]All patients treated with steroids were monitored with serial blood sugar evaluation
and in case of Hyperglycemia, treatment with insulin initiated, as and when required.
The patients with less than <60% lung involvement are the ones that can be prevented
from progression to severe disease. This will help decrease the burden on the health
care workers and on the medical system in India, which are already overburdened by
the disease. Moreover only 70% of the Covid affected patients show RT-PCR positive
results and the turnover time for the result is longer these days, which makes CT
a dependable tool in quick triaging and guiding the management of patients with Covid
pneumonia.
Conclusion
In this Pandemic era, HRCT chest is a wonderful tool in triaging of patients for Home
quarantine or Close monitoring with expectant management or Hospital Admission in
cases of mild to moderate Lung involvement cases, along with clinical and biochemical
evaluation. The Percentage of Pattern of Lung involvement by Covid on HRCT chest is
important than the overall Severity score. The patients with Moderate Lung involvement
by HRCT with predominantly Crazy paving or consolidation or mixed patterns showed
elevated inflammatory markers and D-Dimer, in which cases, Steroid and Anticoagulants
started early in the disease, showed improvement in symptoms, halting progression
to severe disease, facilitating early recovery, decrease in depletion of finite resources,
thereby can reduce the cost incurred and burden on the health care facilities across
the world.
Declaration of patient consent
The authors certify that they have obtained all appropriate patient consent forms.
In the form the patient(s) has/have given his/her/their consent for his/her/their
images and other clinical information to be reported in the journal. The patients
understand that their names and initials will not be published and due efforts will
be made to conceal their identity, but anonymity cannot be guaranteed.