An-Najah National University

Faculty of Medicine & Health Sciences

Histology-2 (7103102)
Dr. Malek Al-Quab

Histopathology of COVID-19
Lung Damage

Made by:
12112402 ‫يوسف يعقوب خليل شيخ إبراهيم‬
12143839 ‫أسعد أنور محمد دقة‬
12143867 ‫رامز مهند عبد العزيز عقل‬
12112210 ‫أحمد رائد رضا شيخ إبراهيم‬
12144064 ‫حمزة رزق حسين بشارات‬
12144108 ‫أحمد لؤي أحمد عواد‬
 Histopathology of COVID-19 Lung Damage

Introduction

The emergence of COVID-19 in 2019 marked a critical juncture in global health, originating in Wuhan, China,
and swiftly evolving into a widespread pandemic. This novel coronavirus, officially known as SARS-CoV-2
(severe acute respiratory syndrome coronavirus 2), shares genetic similarities with the virus responsible for the
2002 SARS outbreak. Its transmission primarily occurs through respiratory droplets, introducing the virus to the
respiratory system, where it infiltrates and damages the crucial air sacs or alveoli.
Central to the peril associated with COVID-19 is the risk of respiratory failure, notably stemming from acute
respiratory distress syndrome (ARDS). The histopathological investigation of affected lungs consistently
reveals a distinctive pattern known as diffuse alveolar damage (DAD). This pattern unfolds in two sequential
phases, contingent upon the duration of the viral infection. The initial acute or exudative phase manifests within
the first week of pulmonary infection, succeeded by the organizing or proliferative stage.
Unraveling the histological nuances of these stages is vital for comprehending the disease's pathophysiology.
Additionally, this examination may uncover supplementary features such as vascular thrombosis, endothelial
inflammation, and angiogenesis, providing a deeper understanding of the intricate manifestations of the disease.
This introduction sets the groundwork for an exploration into the histopathological landscape of COVID-19-
affected lungs, aiming to enhance our grasp of the disease and potentially guide tailored therapeutic
interventions.

Case study
A 77-year-old Middle-Eastern woman with a medical history of hypertension and hyperlipidemia was admitted
to the emergency department (ED) from a daycare facility apartment. Two individuals at the facility had tested
positive for COVID-19, although she had no direct contact with them. Five days before her admission, the
patient developed a fever with a temperature of 102°F at home. Her primary medical doctor referred her to the
ED due to persistent symptoms. In the ED, bilateral opacities were observed on her chest X-ray, and she
continued to experience intermittent fevers along with generalized weakness, cough, lethargy, and dyspnea.
Subsequently, she underwent testing for COVID-19 and was then transferred to our facility for further
management. Upon arrival at our facility, her vital signs were recorded as a temperature of 101.7°F, blood
pressure of 148/76 mm Hg, heart rate of 99 beats per minute, respiratory rate of 18 per minute, and oxygen
saturation of 93% in room air.
The physical examination revealed a dry cough and bilateral rales upon
auscultation of the lung fields bilaterally but was otherwise unremarkable. A chest
X-ray (Fig. 1) indicated bilateral opacities throughout the lung fields,
predominantly in the lower lung lobes. The patient was admitted with isolation
precautions for suspected COVID-19 and initiated on oxygen via nasal cannula.

Fig.1 Chest X-ray showing bilateral infiltrates worsened in

the lower lung fields.
 Treatment included intravenous administration of 1-gram ceftazidime every 8 hours and oral 500 mg
azithromycin daily. A chest CT scan (Fig. 2) displayed a bilateral ground glass appearance throughout the lungs,
with a predominance in the peripheral lower lobes. Despite a negative respiratory viral panel and a repeat
COVID-19 test (Table 1), the patient's condition deteriorated within two days of admission. She became hypoxic
with an oxygen saturation of 85% on the nasal cannula and continued to experience fevers peaking at 103.4°F.
Subsequently, she was intubated and transferred to the intensive care unit (ICU) for further management.
Treatment was adjusted to ceftriaxone 1 g intravenously daily, azithromycin 500 mg via orogastric tube daily,
and initiation of hydroxychloroquine with a 400 mg loading dose followed by 200 mg twice daily for a 7-day
course.

Fig.2 CT scan of the chest showing bilateral ground glass

Table.1 Respiratory viral panel testing by PCR.
opacities, worsening in the lower lung fields.

She necessitated a100% fraction of inspired oxygen (FiO2) and a positive end-expiratory pressure (PEEP) of 12
to maintain an oxygen saturation above 90%. After 12 hours, the COVID-19 test from the initial facility returned
positive results. On the third day of hospitalization, she commenced a regimen of 6 g of IV ascorbic acid twice
daily and received a single dose of 8 mg per kg (567 mg) of tocilizumab, an anti-interleukin-6 monoclonal
antibody. Due to a shortage of vitamin C in the hospital, her dosage was reduced to 1 g IV daily on the sixth day
of hospitalization, and she received another dose of tocilizumab. By the seventh day, her PEEP was raised from
12 to 16 due to deteriorating oxygen saturation and increased requirements despite 100% FiO2. Because of
severe acute respiratory distress syndrome (ARDS), the decision was made to prone the patient for 18 hours a
day. She completed her course of antibiotics and hydroxychloroquine but continued vitamin C and zinc.
Approval for remdesivir was obtained from Gilead Sciences Inc, and she received a loading dose of 200 mg on
day 10. However, due to worsening oxygen saturation, her PEEP was again increased to 18 on the same day. On
day 11, the patient was unable to tolerate being prone due to significant desaturation to 65% on pulse oximetry
and remained supine.
Eventually, she required levophed to maintain hemodynamic stability, and her creatinine levels increased from a
baseline of 0.5-0.6 since admission until day 10 to 2.65 on day 12. Due to this renal impairment, remdesivir was
discontinued, and nephrology was consulted. They recommended continuous veno-venous hemodialysis
(CVVHD), which was initiated on day 13. On day 14, her PEEP requirement increased again to 20 while on
100% FiO2 to maintain an oxygen saturation above 90%. Despite aggressive management in the ICU, her
condition remained critical. Ultimately, the family decided to pursue comfort measures, and the patient passed
away.
Diagnosis of COVID-19 Lung Damage
It might be difficult to diagnose COVID-19 lung damage because symptoms can differ from person to person
and be minor to severe. Nevertheless, a variety of tests and assessments can be utilized by medical professionals
to identify COVID-19-related lung damage. The following methods are used to diagnose COVID-19 lung
damage:
 Health history: Medical professionals will inquire about the patient's past medical history,
encompassing any COVID-19 diagnoses, symptoms, or contact with COVID-19-positive
individuals.
 Physical examination: Medical professionals will do a physical examination to look for
indications of lung damage, such as coughing, joint discomfort, chest or stomach pain, and
shortness of breath.
 Pulmonary function test: This test measures lung function and identifies any abnormalities
brought on by COVID-19.
 Imaging studies: To see the lungs and find any COVID-19-related damage, imaging tests like
CT scans or chest X-rays can be performed.
 Blood tests: These can be used to look for signs of inflammation and other indications of
COVID-19-related lung injury.
It is noteworthy that COVID-19 can result in lung damage that is both short- and long-term, and that some
individuals may continue to have symptoms for a considerable amount of time after the few weeks that most
people need to recover. To make sure that patients with COVID-19 lung damage receive the right care and
therapy, healthcare providers may need to keep a close eye on them for a considerable amount of time. To
diagnose long-term COVID conditions, there is no test. Since symptoms differ from person to person, it can be
difficult to rule out other medical conditions as a potential cause of your symptoms. Your healthcare provider
will base their diagnosis of long-term COVID conditions on your medical history, any COVID-19 diagnoses
you may have had (positive test, symptoms, or exposure), as well as an overall physical examination.

Histopathological findings
Diffuse Alveolar Damage (DAD), which is a characteristic histopathological pattern observed in patients with
acute lung injury (ALI) and acute respiratory distress syndrome (ARDS), is the most consistently observed
result.
The length of the disease's clinical course can affect how severe and structured DAD is i.e., the histological
features of DAD differ according to the time a biopsy is taken when the illness is still active. Based on this
DAD is divided into 2 phases:
 During the first week following a pulmonary injury, there is an acute/exudative phase. Furthermore,
shows interstitial expansion and intra-alveolar edema on day 2. 4-5 days after the initial insult, hyaline
membranes may start appearing at this point and peak. While they can be visible focally, hyaline
membranes are usually diffuse (Fig. 3).
  Organizing/proliferative phase, which is distinguished in the hematoxylin-
eosin section by cellular fibroblastic proliferation that appears loose and
myxoid (Fig. 4). Along with type 2 pneumocyte hyperplasia, this is also
linked to squamous metaplasia, which can occasionally be noticeable.
Hyaline membranes also disappear and merge with the alveolar septa.

Figure. 3 Fig.4 Intra-alveolar fibrin and

patchy areas of organization.
(a) Acute lung injury with intra-alveolar hyaline membranes, fibrin plugs, and interstitial
inflammation.
(b) Patchy intra-alveolar plugs of fibrin and interstitial inflammation.

Most DAD survivors still

have some residual functional impairment, however, some instances recover gradually after the organizing
phase (Fig.5), while others have interstitial fibrosis with interstitial remodeling.
Additionally, certain COVID-19 patients exhibit pulmonary vascular endothelialitis (Fig. 6), thrombosis, and
angiogenesis, indicating pulmonary vascular injury. In contrast to individuals experiencing influenza-
associated respiratory failure, COVID-19 patients exhibit a higher prevalence of endothelial damage,
microthrombi, and angiogenesis. Additionally, some research has indicated that the first step toward
microvasculopathy may be pericyte loss, which could be brought on by SARS-CoV-2's direct impacts.

Fig.5 Organizing acute lung Fig.6 Endothelialitis and acute

injury with interstitial lung injury. Remodeling.

Pathophysiology
SARS-CoV-2 is the virus that causes COVID-19. This virus can enter an individual's body through the
respiratory system, especially the lungs when they are infected. Because the surface of epithelial cells in the
lungs contains a protein known as ACE2, the virus adheres to these cells. Once within the cells, the virus
begins to proliferate and disperse.

Lung tissue may sustain damage from the virus as it spreads. Inflammation and the development of fluid-
filled patches in the lungs called "ground glass opacities" may result from this. A chest CT scan can reveal
these alterations.
One tool in the fight against the virus is the immune system. T cells and B cells— two types of immune cells
 —are triggered to identify and eliminate the virus. But occasionally, an overactive immune response can result
in excessive inflammation. This may result in acute respiratory distress syndrome (ARDS), a condition that
causes significant lung damage and a decrease in blood oxygen levels.

Moreover, COVID-19 can impact additional body organs. Blood clot risk can rise as a result of the virus's
ability to damage blood vessels and enter the bloodstream. Complications like heart attacks or strokes may
arise from this.

It is essential to remember that COVID-19 symptoms can range greatly in intensity. While certain individuals
may only show minor symptoms like a fever, cough, and exhaustion, others may endure severe respiratory
distress and even organ failure.

All things considered, COVID-19 is a complicated illness that impacts several bodily systems, most notably
the respiratory system. Numerous symptoms and problems can arise from lung injury, inflammation, and
immune system dysregulation caused by the virus.

Treatment
The management of complications and support are the major goals of treating the lung injury caused by
COVID-19. There are a few essential treatment parameters:
To help patients breathe, they may require mechanical ventilation or oxygen therapy.
Treatment for inflammation: By controlling the immune response and reducing inflammation, corticosteroids
like dexamethasone have demonstrated advantages in lowering mortality for severe COVID-19 cases.
Anticoagulation therapy may be required to prevent or treat blood clots due to the elevated risk of blood
clotting associated with COVID-19.
Supportive care includes maintaining equilibrium, offering dietary assistance, and managing any potential
further infections.

References
 Lewis KL, Helgeson SA, Tatari MM, Mallea JM, Baig HZ, Patel NM: COVID-19 and the effects on pulmonary function following
infection: a retrospective analysis. EClinicalMedicine. 2021, 39:101079. 10.1016/j.eclinm.2021.101079
https://pubmed.ncbi.nlm.nih.gov/34405138/

 Silva Andrade B, Siqueira S, de Assis Soares WR, et al.: Long-COVID and post-COVID health complications: an up-to-date review on
clinical conditions and their possible molecular mechanisms. Viruses. 2021, 13:700. 10.3390/v13040700
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8072585/
 Montero-Fernández, M. A., & Pardo-Garcia, R. (2020). Histopathology features of the lung in COVID-19 patients. Diagnostic
Histopathology. https://doi.org/10.1016/j.mpdhp.2020.11.009

 Douedi, S., & Miskoff, J. (2020). Novel coronavirus 2019 (COVID-19). Medicine, 99(19), e20207.
https://doi.org/10.1097/md.0000000000020207

 Pannone, G., Caponio, V.C.A., De Stefano, I.S. et al. Lung histopathological findings in COVID-19 disease – a systematic
review. Infect Agents Cancer 16, 34 (2021). https://doi.org/10.1186/s13027-021-00369-0