Letter: Response to Comment on “Association of Inhaled Corticosteroid Use With COVID-19 Severity and Hospitalization in Patients With and Without Respiratory Disease”

To the Editor:

I enclose our responses to the comments from Dr. Hinpetch Daungsupawong and Dr. Viroj Wiwanitkit.

• 1.

Inhalers purchases as a selection bias:

In the Discussion, we wrote as a limitation: “Second, the information regarding ICS was the purchase data and not the actual use information, which are not necessarily the same.” Nevertheless, since patients pay for their medications, it is reasonable to assume that most patients use the drugs and that the large study population (44,866 patients) may overcome small biases.

2.

Frequency of use or combinations:

Calculations of ICS dosage and combination therapy are too complicated and would create small groups of patients, which would not enable analysis. Since most inhalers that we use are dual or triple therapy, it is common in most trials to evaluate the exposure for each drug separately. Furthermore, we estimated that ICS did not alter the disease, as we wrote, “This might be explained by the fact that ICS treatments are markers for more severe illness or exacerbations, rather than the impact of the ICS inhaler itself on COVID-19 outcomes.”

3.

Multivariate analysis:

See Methods, statistical analysis: “All multivariate analyses adjusted for age, gender, SES, smoking (current and past vs. never), CCI, and at least one vaccination (at least two weeks before a COVID-19 diagnosis).” Since this study did not aim to develop a predictive model, the OR and 95% CI were chosen to be reported, which is in line with most studies in this field.

4.

ICS usage: See in Methods:

“ICS could only be purchased as a prescribed drug.”

And in the Discussion: “ICS can be prescribed based on clinical suspicion without any known diagnoses of respiratory disease, often due to acute illness such as acute bronchitis or URTI, during or for post-infectious/viral cough (which is not coded). Although these diagnoses were analyzed in our study, in many cases they are not well recorded in the diagnoses lists in the patient’s file.”

And “Our hypothesis is that these patients might be at higher risk for more severe COVID-19 due to their prior lung injury or due to a personal higher lung susceptibility to respiratory infections. ICS prescription may also signal a general deterioration in the health of patients who were not well diagnosed with lung disease and should have been better investigated by their general practitioners.”

5.

Socioeconomic status:

Since it was a retrospective study, we could not inquire about the motivation for hospitalization and correlate it with the SES.

We speculated in the discussion; demographic, and clinical parameters, that “Therefore, it is possible that patients from the lower SES used the public healthcare systems from the early stages of their COVID-19 symptoms, while patients from the higher SES were more aware of hospitalization risks and chose to rely on different medical sources, such as private doctors.”

6.

As in every retrospective study, further studies, especially prospective randomized trials, are needed to explore complex relationships. However, this is hard to do in a pandemic situation.

Regards,

Dekel Shlomi