We’re beginning to start to see some information about lung pathology due to COVID-19. But before jumping into that, a little background…
background: lung pathology, DAD, and AFOP
Lung pathology & treatment: the bigger picture
In an ideal world, different insults to the lung would cause specific histologic patterns. These patterns would be related to unique treatments. If you could identify the histologic pattern, this would allow you to know the treatment. Easy-peasy:
The reality of the situation is far more complicated. A more accurate schematic might look more like this:
There are numerous layers of complexity here, including:
- A single pathogen can lead to a variety of different histologic abnormalities. Sometimes these may neatly fit within a single histologic pattern, but not always.
- A single pathogen may lead to different histologic patterns in different people, depending on the interaction between the pathogen and the host immune system.
- The optimal treatments for various histologic patterns are poorly defined. Particularly, for less common patterns, there is no high-quality evidence to guide us.
So before going further, we should appreciate that we’re wading into a very murky area here.
What is Acute Fibrinous and Organizing Pneumonia (AFOP)?
AFOP is an extremely rare histologic pattern of lung inflammation with some similarities to cryptogenic organizing pneumonia (COP, previously known as bronchiolitis obliterans organizing pneumonia or BOOP). Key histologic features of AFOP are:
- Intra-alveolar “fibrin balls” (hence the “acute fibrinous” part)
- Intra-luminal loose connective tissue within alveolar ducts and bronchioles (hence the “organizing pneumonia” part).
AFOP can result from a variety of insults to the lung, including collagen vascular diseases, adverse drug reactions, hematologic malignancy, inhalation injury, and infections (including influenza H1N1 and SARS).1 Clinical manifestations lack specificity, most commonly including dry cough, dyspnea, and constitutional symptoms. Radiographically, patients with more acute and severe disease typically have basilar predominant consolidation and ground-glass opacification.2 Laboratory studies may show elevated inflammatory markers including IL-6, which is again nonspecific.3 Among patients who require intubation for AFOP, the mortality is extremely high.4
Given the rarity of AFOP, there are no RCTs investigating how it should be treated. Nonetheless, corticosteroid is generally felt to be the front-line therapy for AFOP (analogous to cryptogenic organizing pneumonia). Also similar to cryptogenic organizing pneumonia, prolonged steroid courses are often utilized to avoid remission.
What is diffuse alveolar damage (DAD)?
DAD is the classical histology which is most closely associated with ARDS, with diffuse hyaline membrane formation. DAD is commonly involved in ARDS, although not all patients with ARDS have DAD. For example, one approach to sub-classifying ARDS is as follows:
DAD can be caused by essentially all of the things which may cause ARDS (e.g. infection, aspiration, chemical injury). Additionally, ventilator-induced lung injury itself can potentially cause DAD.5
Clinically, DAD behaves as a traditional, quintessential form of ARDS. It often causes reduced compliance and increased dead space on mechanical ventilation, leading to prolonged ventilator courses.
Lung pathology & COVID-19
Chopin MC et al. Time to consider histologic pattern of lung injury to treat critically ill patients with COVID-19 infection (Intensive Care Medicine 2020)
This is a short letter describing autopsy findings in six French patients.6 The first patient died early in the disease course after withdrawal of treatment, five days after the beginning of fever. Histology revealed a lymphocytic viral pneumonia (panel a, below):
The remaining five patients died around 20 days after the beginning of symptoms. These patients were found to have a histologic pattern of acute fibrinous and organizing pneumonia (AFOP), with the following characteristics:
- Extensive intra-alveolar “fibrin balls” (1B above)
- Intra-luminal loose connective tissue within alveolar ducts and bronchioles (organizing pneumonia)(1C above)
- Lack of hyaline membranes (the hallmark of diffuse alveolar damage)
- Vascular injury, including endothelial cell detachment in small to medium-sized pulmonary arteries (1D above)
This case series has numerous limitations. For example, little clinical information is available about the patients and how they were treated (e.g. partially treated eosinophilic pneumonia following steroid administration may resemble AFOP).7 It’s possible that selection bias was involved in the selection of these six patients for autopsy. Interpretation of lung pathology can be subjective, so an external review might have been desirable.
Nonetheless, it is interesting to speculate that these two pathologies encountered at different phases of the disease could fit with our overall schema of disease pathogenesis (above). This could also be consistent with the lung compliance often being higher than would typically be expected for patients with diffuse alveolar damage (DAD).
Hwang DH et al. Pulmonary pathology of severe acute respiratory syndrome in Toronto (2005)
This is a series of 20 autopsies from the Toronto SARS epidemic in 2003 (“SARS-CoV-1”).8 Additionally, matched controls were obtained from patients who died of other causes during the same time period. The mean duration of illness was 27 days (with a range of 5-108 days).
8/20 patients had a histologic pattern with predominantly diffuse alveolar damage (example above). 6/20 patients had a histologic pattern with predominantly AFOP (example below). The remaining patients showed some admixture of DAD and AFOP (emphasizing the possibility that multiple lung injury patterns can occur together). All patients with <10 days illness duration had DAD-predominant pattern, whereas all patients with an AFOP-predominant pattern had an illness duration >20 days. Other pathologic findings included endothelial injury, fibrin thrombi (17/20 patients) and pulmonary infarcts (12/20 patients). Two patients who had been treated with high-dose steroid were found to have aspergillus infection.
It’s unclear to what extent DAD may result from the virus itself versus superimposed ventilator-induced lung injury versus a combination of the virus plus ventilator-induced injury. All twenty patients had some histologic features of DAD, suggesting that the virus may be directly contributing to DAD.
As discussed earlier, the same virus may elicit various response patterns in different patients over time. Thus, it’s possible that some patients respond to SARS with more of an AFOP pattern, whereas others respond with more of a DAD pattern. It's also conceivable that a DAD pattern could evolve into an AFOP pattern over time.7
What are the clinical implications of this?
These case series doesn’t have strong immediate implications. It’s likely that COVID-19 can cause a variety of different patterns on lung pathology. Further data is needed to validate these findings and determine the frequency and context of various histological patterns (e.g. DAD, AFOP, lymphocytic pneumonitis, and perhaps other patterns as well).
If AFOP does emerge as a common histological pattern, this would provide indirect support for the use of steroid in COVID-19 patients with hypoxemic respiratory failure. Performing surgical lung biopsies in patients with COVID-19 is logistically and clinically almost impossible (e.g., the risk of harm from a lung biopsy will usually outweigh any potential benefit). Thus, empiric use of steroids could be required to determine whether the lung injury is steroid-responsive. Of course, the use of steroids should ideally be based on direct clinical investigation (i.e., an RCT), rather than indirect histological evidence.
- The use of steroid in COVID was previously discussed here.
- 1.Kim J, Doo K, Jang H. Acute fibrinous and organizing pneumonia: Imaging features, pathologic correlation, and brief literature review✰. Radiol Case Rep. 2018;13(4):867-870. doi:10.1016/j.radcr.2018.04.028
- 2.Garcia B, Goede T, Mohammed T. Acute Fibrinous Organizing Pneumonia: A Case Report and Literature Review. Curr Probl Diagn Radiol. 2015;44(5):469-471. doi:10.1067/j.cpradiol.2015.02.006
- 3.Lu J, Yin Q, Zha Y, et al. Acute fibrinous and organizing pneumonia: two case reports and literature review. BMC Pulm Med. 2019;19(1):141. doi:10.1186/s12890-019-0861-3
- 4.Arnaud D, Surani Z, Vakil A, Varon J, Surani S. Acute Fibrinous and Organizing Pneumonia: A Case Report and Review of the Literature. Am J Case Rep. 2017;18:1242-1246. doi:10.12659/ajcr.905627
- 5.Dreyfuss D, Saumon G. Ventilator-induced lung injury: lessons from experimental studies. Am J Respir Crit Care Med. 1998;157(1):294-323. doi:10.1164/ajrccm.157.1.9604014
- 6.Copin M, Parmentier E, Duburcq T, Poissy J, Mathieu D, Lille COVID-19 ICU and Anatomopathology Group. Time to consider histologic pattern of lung injury to treat critically ill patients with COVID-19 infection. Intensive Care Med. April 2020. doi:10.1007/s00134-020-06057-8
- 7.Beasley M. The pathologist’s approach to acute lung injury. Arch Pathol Lab Med. 2010;134(5):719-727. doi:10.1043/1543-2165-134.5.719
- 8.Hwang D, Chamberlain D, Poutanen S, Low D, Asa S, Butany J. Pulmonary pathology of severe acute respiratory syndrome in Toronto. Mod Pathol. 2005;18(1):1-10. doi:10.1038/modpathol.3800247