Which trial do we need? Management of elderly, fragile, fully vaccinated patients hospitalized for SARS-CoV-2 infection

The clinical question

An 81-year-old man is admitted to the hospital because of progressive confusion. The family cannot precisely tell when symptoms started, possibly 1 week ago or a few days before. The patient has early Alzheimer's disease but has been independent in activities of daily living until 2 days ago, when the family reports increased confusion. The patient received four doses of the SARS-CoV-2 mRNA vaccine BNT162b2, with the last dose administered 2 months ago. He is afebrile. The room air oxygen saturation is 93%. Following the hospital screening policy before admitting patients, a nasopharyngeal swab is performed, and the result is positive for SARS-CoV-2. The level of C-reactive protein is 19.7 mg/dL. The level of ferritin is 58 ng/mL, and that of lactate dehydrogenase is 186 UI/L. A chest radiograph does not show pulmonary infiltrates. A head computed tomography scan shows no remarkable findings.

Diagnostic and therapeutic questions

In our opinion, this SARS-CoV-2 breakthrough infection raises three diagnostic and therapeutic questions:

• 1)Is this incidental or primary COVID-19? In other words, is SARS-CoV-2 contributing to the decompensation of our patient's clinical status or not?
• 2)Would this patient benefit from treatment with a SARS-CoV-2 anti-viral agent, or is the window of opportunity for anti-virals closed?
• 3)Does the patient need dexamethasone for COVID-19?

This clinical and therapeutic conundrum is frequent in countries where a successful SARS-CoV-2 vaccination campaign has achieved the fact that most of the population has immunity against SARS-CoV-2. In these countries, vaccinated, elderly persons with decompensation of chronic co-morbidities associated with a SARS-CoV-2 breakthrough infection represent most patients admitted to hospitals with a positive SARS-CoV-2 PCR result [1]. Recent figures from the United States have shown that people aged ≥65 years account for 90% of new COVID-19-related deaths, and vaccinated elderly adults now make up a larger share of COVID-19-related deaths than the unvaccinated do [2]. In addition to immunosuppressed patients [3], elderly, fragile patients with COVID-19 have been neglected in COVID-19 clinical trials, and consequently, there are limited high-quality evidence data to support the optimal therapeutic approach for these important sub-groups of patients with COVID-19. Of note, even if COVID-19 becomes an endemic disease, it is plausible that the clinical problem which we want to address will become a relevant and persistent medical issue.

Distinguishing incidental from primary COVID-19 is problematic, and there is no consensus about these definitions. If the patient does not have any or has only mild COVID-19 symptoms and does not receive any medical treatment for these symptoms, we can label this hospital admission as incidental COVID-19 [4]. However, if SARS-CoV-2 infection is a contributing factor to the decompensation of a co-morbidity, then it would be difficult to dismiss the importance of SARS-CoV-2 infection as a contributing factor for hospital admission. This distinction is even more blurred in elderly patients with multiple co-morbidities.

Therapeutic decisions about the use of SARS-CoV-2 anti-virals in this patient population are further complicated because for patients with co-morbidities such as neurocognitive impairment of chronic dyspnoea due to pulmonary or heart disease, it is often difficult to establish with precision when symptoms possibly related to COVID-19 started. Hence, we do not know whether the window of opportunity for anti-virals is still open.

The decision about the use of dexamethasone in breakthrough infections is also difficult. The survival benefit of dexamethasone was established in clinical trials such as Recovery, which only included unvaccinated participants [5]. Our patient has no increased levels of inflammatory biomarkers. In contrast with the plethora of information about the clinical course and the evolution of inflammatory biomarkers of unvaccinated, hospitalized patients with COVID-19 which was published at the beginning of the pandemic [[6], [7], [8]], there is a paucity of information about the natural history of hospitalized patients with SARS-CoV-2 infection who are fully vaccinated.

In a recent study, authors prospectively compared the clinical and laboratory data of 29 unvaccinated and 36 vaccinated hospitalized patients with COVID-19. The vaccinated patients displayed more risk factors for the development of severe COVID-19 than the unvaccinated patients, including older age and more co-morbidities. The unvaccinated patients showed significantly higher levels of ferritin and lactate dehydrogenase. The two groups displayed similar viral loads. The unvaccinated patients had a higher frequency of pneumonia and had more alterations in the composition of circulating leukocytes. Importantly, the mortality was higher in the unvaccinated group [9]. These data suggest that cellular immunity induced by vaccination can protect from lower-respiratory-tract infection and the development of a hyper-inflammatory response. However, since the advent of the omicron variant, we know that vaccine-induced humoral immunity cannot protect from symptomatic disease and SARS-CoV-2 replication in the upper respiratory tract. Of note, for elderly, fragile, fully vaccinated patients with co-morbidities, an upper-respiratory-tract infection can be enough to decompensate such co-morbidities.

The elephant in the room is that COVID-19 in elderly, vaccinated, hospitalized patients with breakthrough infections is a different disease from COVID-19 in unvaccinated, hospitalized patients. If we follow the advice of guidelines, such as those of the National Institutes of Health [10], our patient could be classified into two categories.

• 1)If we think that this is incidental COVID-19: ‘hospitalized for reasons other than COVID-19’.
• 2)If we think that this is primary COVID-19: ‘hospitalized and requires conventional oxygen’.

Category 1 would imply considering anti-viral treatment because this patient is at a high risk of progressing to severe COVID-19 based on his age and co-morbidities. However, because we do not have precise estimation of when symptoms started, there is uncertainty about the possible benefits of anti-virals, such as ritonavir-boosted nirmatrelvir or remdesivir, which have shown benefit in out-patients when started during the first 5 or 7 days of symptoms, respectively [11,12]. Because the patient has a low oxygen saturation but no infiltrates, as determined on the chest radiograph, further work-up, such as a chest computed tomography scan, would be necessary to rule out other diagnostic possibilities.

Category 2 would imply considering treatment with remdesivir and dexamethasone. As the guidelines state, remdesivir is most effective against COVID-19 in patients who are earlier in the course of the disease, and again, we do not know when the disease started in our patient. Regarding dexamethasone treatment, we do not know its risk-to-benefit ratio in vaccinated patients with breakthrough infections, without radiological evidence of pneumonia, and without increased levels of inflammatory biomarkers. Of note, we recently observed a possible safety signal in hospitalized, vaccinated patients with COVID-19 treated with baricitinib, another anti-inflammatory drug, which raises the issue of the potential adverse effect of anti-inflammatory drugs in vaccinated patients [13]. Although the use of dexamethasone has been reported to increase the risk of bacterial infections [14], the potential excess risk of infections related to dexamethasone has not been established in elderly, fragile populations [15].

We believe that new clinical trials of anti-virals and anti-inflammatory drugs are needed to guide therapeutic decisions for SARS-CoV-2 infection in vaccinated, elderly patients with co-morbidities. We do not know whether our current recommendations based on clinical trials which mainly included unvaccinated participants with pneumonia apply to this new disease phenotype. This trial would help to clarify the relevance of a positive SARS-CoV-2 PCR result in our target population. If interfering directly with viral replication and inflammation does not improve outcomes, the relevance of a positive PCR test result would be more questionable.

We propose a large, randomized, pragmatic clinical trial of hospitalized, fully vaccinated, elderly patients with confirmed SARS-CoV-2 infection. The trial questions would be as follows:

• 1)Is remdesivir beneficial?
• 2)For patients who need oxygen, is dexamethasone beneficial?

The clinical trial would include hospitalized patients with confirmed SARS-CoV-2 infection, aged >65 years, who have received the primary SARS-CoV-2 vaccine series plus at least one booster, without typical/clear radiological evidence of pulmonary COVID-19, and with any duration of symptoms.

There would be two randomizations in the trial.

• 1)Remdesivir vs. no remdesivir. We choose remdesivir because it has shown efficacy when used early during the course of the disease [12], is the only anti-viral recommended for hospitalized patients with COVID-19 given the circulating variants, has a good interaction profile in our target population in which poly-pharmacy is frequently occurring, and is easy to administer intravenously in the hospital setting.
• 2)For patients who need oxygen to maintain a saturation of >94%: dexamethasone vs. no dexamethasone.

All randomized participants would be followed up until death or discharge from the hospital. The primary objective would be to estimate the effect of treatments on all-cause mortality within 60 days. The secondary objectives would be to estimate the effect of treatments on the duration of hospital stay and the composite end point of death or need for mechanical ventilation.

We would perform a sub-group analysis based on baseline viral loads to identify which patients, if any, are more likely to benefit from anti-viral therapy. We would also perform a sub-group analysis in the most prevalent co-morbidity groups. In addition, we would estimate the rate of serious adverse events, including thromboembolic events, as adverse events of special interest. Finally, for dexamethasone evaluation, the occurrence of bacterial and fungal co-infections would be monitored as adverse events of special interest.

Author contributions

The authors contributed equally to this work.

Transparency declaration

The authors declare that they have no conflicts of interest.

Editor: L. Leibovici