Saturday, October 30, 2021

CANARD: Coronavirus Associated Nonpathogenic Aspergillus Respiratory Disease

Cavitary MSSA disease in COVID

One of the many challenges of pulmonary medicine is unexplained dyspnea which, after an extensive investigation, has no obvious cause excepting "overweight and out of shape" (OWOOS). It can occur in thin and fit people too, and can also have a psychological origin: psychogenic polydyspnea, if you will. This phenomenon has been observed for quite some time. Now, overlay a pandemic and the possibility of "long COVID". Inevitably, people who would have been considered to have unexplained dyspnea in previous eras will come to attention after being infected with (or thinking they may have been infected with) COVID. Without making any comment on long COVID, it is clear that some proportion of otherwise unexplained dyspnea that would have come to attention had there been no pandemic will now come after COVID and thus be blamed on it. (Post hoc non ergo propter hoc.) When something is widespread (e.g., COVID), we should be careful about drawing connections between it and other highly prevalent (and pre-existing) phenomena (e.g., unexplained dyspnea).

Since early in the pandemic, reports have emerged of a purported association between aspergillus pulmonary infection and COVID. There are several lines of biological reasoning being used to support the association, including an analogy with aspergillosis and influenza (an association itself open to debate - I don't believe I've seen a case in 20 years), and sundry arguments predicated upon the immune and epithelial disturbances wrought by COVID. Many of these reports include patients who have both COVID and traditional risk factors for invasive pulmonary aspergillosis (IPA), viz, immunosuppression. The association in these patients is between immunosuppression and aspergillus (already known), in the setting of a pandemic; whether or not COVID adds additional risk would require an epidemiological investigation in a cohort of immunosuppressed patients with and without COVID. To my knowledge, such as study has not been done. Instead, they are like this one, where there were allegedly 42 patients among 279 in the discovery cohort with CAPA (Coronavirus Associated Pulmonary Aspergillosis; see Figure 1) and of those 42, 23 of them were immunosuppressed (Table 1). In addition, 5 had rheumatological disease, 3 had solid organ malignancy. In the validation cohort, there were 21 suspected CAPA among 209 patients; among these 21, there were at least 6 and perhaps 9 who were immunosuppressed (Table 2).

There are other problems (many of which we outlined here: Aspergillosis in the ICU: Hidden Enemy or Bogeyman?). The strikingly high proportion of COVID patients with aspergillosis being reported - a whopping 15% - includes patients with three levels of diagnostic certainty: proven, probable, and possible. I understand the difficulties inherent in the diagnosis of this disease. I also understand that relying on nonspecific tests for diagnosis will result in many false positives, especially in low base rate populations. Therefore it is imperative that we carefully establish the base rate, and that is not what most of these studies are doing. Rather they are - apparently intentionally - comingling traditional risk factors and COVID leading to what is surely a gross overestimation of the incidence of true IPA in patients with COVID. Thus we warned:

We worry that if the immanent methodological limitations of this and similar studies are not adequately acknowledged—they are not listed among the possible explanations for the results enumerated by the editorialist (2)—an avalanche of testing for aspergillosis in ICUs may ensue, resulting in an epidemic of overdiagnosis and overtreatment. We caution readers of this report that it cannot establish the true prevalence of Aspergillus infection in patients with ventilator-associated pneumonia in the ICU, but it does underscore the fact that when tests with imperfect specificity are applied in low-prevalence cohorts, most positive results are false positives (10).

In the discovery cohort of the study linked above, Figure 1 shows that only 6 patients of 279 (2%) had "proven" disease, 4 with "tracheobronchitis" (it is not mentioned how this unusual manifestation of IPA was diagnosed; presumably via biopsy; if not, it should have counted as "probable" disease; see these guidelines), and 2 others meeting the proven definition. The remaining 36 patients had probable CAPA (32) and possible CAPA (4). In the validation cohort, there were 21 of 209 patients with alleged CAPA, all of them in the probable category (2 with probable tracheobronchitis, 19 with probable CAPA). Thus the prevalence (sic: incidence) of IPA in patients with COVID is a hodgepodge of a bunch of different diseases across a wide spectrum of diagnostic certainty.

Future studies should - indeed, must - exclude patients on chronic immunosuppression and those with immunodeficiency from these cohorts and also describe the specific details that form the basis of the diagnosis and diagnostic certainty category. Meanwhile, clinicians should recognize that the purported 15% incidence rate of CAPA/IPA in COVID comprises mostly immunosuppressed patients and patients with probable or possible - not proven - disease. Some proportion of alleged CAPA is actually a CANARD.

No comments:

Post a Comment

Note: Only a member of this blog may post a comment.