Abstract
Introduction:
A majority of the fatalities due to COVID-19 have been observed in those over the age of 60. There is no approved and universally accepted treatment for geriatric patients. The aim of this review is to assess the current literature on efficacy of COVID-19 treatments in geriatric populations.
Methods:
A systematic review search was conducted in PubMed, MedRxiv, and JAMA databases with the keywords COVID-19, geriatric, hydroxychloroquine, dexamethasone, budesonide, remdesivir, favipiravir, ritonavir, molnupiravir, tocilizumab, bamlanivimab, baricitinib, sotrovimab, fluvoxamine, convalescent plasma, prone position, or anticoagulation. Articles published from January 2019 to January 2022 with a population greater than or equal to 60 years of age were included. Interventions examined included hydroxychloroquine, remdesivir, favipiravir, dexamethasone, budesonide, tocilizumab, bamlanivimab, baricitinib, sotrovimab, convalescent plasma, prone position, and anticoagulation therapy. Outcome measures included viral load, viral markers, ventilator-free days, or clinical improvement.
Results:
The search revealed 302 articles, 52 met inclusion criteria. Hydroxychloroquine, dexamethasone, and remdesivir revealed greater side effects or inefficiency in geriatric patients with COVID-19. Favipiravir, bamlanivimab, baricitinib, and supportive therapy showed a decrease in viral load and improvement of clinical symptoms. There is conflicting evidence with tocilizumab, convalescent plasma, and anticoagulant therapy in reducing mortality, ventilator-free days, and clinical improvements. In addition, there was limited evidence and lack of data due to ongoing trials for treatments with sotrovimab and budesonide.
Conclusion:
No agent is known to be effective for preventing COVID-19 after exposure to the virus. Further research is needed to ensure safety and efficacy of each of the reviewed interventions for older adults.
Keywords
Introduction
On 11 March 2020, the World Health Organization (WHO) declared the viral infection caused by COVID-19 outbreak a global pandemic. 1 Estimates of the case fatality rate vary during different times of the COVID-19 pandemic.2,3 Based on Canadian data from 22 April 2020, the crude mortality rate was reported at 4.9% which is noted to be variable between countries (Figure 1) depending on the availability of diagnostic testing and the capacity of national health care systems. 3 The majority of deaths were seen in adults greater than 60 years old.2,3 Estimated case fatality ratio for COVID-19 patients stratified by age illustrate the detrimental effect of the virus on this population. Case data from China demonstrated that the case fatality ratio for patients less than 60 years old was estimated at 0.3%, while the estimated fatality ratio in patients of 60 years and older was 6.4%, and in patients of 80 years and older, the ratio was 13.4%. 4 Increased risk of mortality in older patients has been seen in those who have symptoms of dyspnea, cardiovascular, cerebrovascular, and chronic obstructive pulmonary diseases. 5 Increased heart, respiratory rate; prothrombin time; and leukocytopenia have been shown to be indicators of poor outcomes for older patients infected with COVID-19. 5
Daily incidence of COVID-19 (bars) and associated deaths (black line) in Canada (a) and the United States (b), 2020. Crude fatality rate (dashed line) and adjusted case fatality rate estimates (red line) from 19 March to 22 April 2020 in Canada (C) and the United States (D). Shaded area around red line shows 95% credible interval for the adjusted cast fatality ratio.
Supportive care using antipyretics, opioids, antimicrobial agents, and oxygen are proposed in treatment protocols; however, the symptoms management between countries differ slightly. 6 Research into various treatment protocols, including hydrochloroquine (HCQ), tocilizumab (TCZ), chloroquine phosphate, remdesivir (RMD), ritonavir (RTV), favipiravir (FVP), corticosteroids, and ivermectin have been proposed. 6 In addition, passive immunization therapy with immunoglobulins has been suggested to reduce symptoms and mortality in patients with COVID-19 due to its effectiveness in previous epidemics and pandemics.7,8 Furthermore, supportive prone position (PP) or lateral position (LP) for patients with acute respiratory distress syndrome (ARDS) has shown to improve oxygenation and decrease mortality. 9 Given the continuously evolving context of the COVID-19 pandemic, this systematic review was launched. The objective of this review is to assess the current knowledge of the COVID-19 treatment modalities for the geriatric population.
Methods
A systematic review protocol was developed based on PRISMA guidelines. Articles for review were selected from electronic databases of PubMed, MedRxiv, and JAMA. Articles published between January 2019 and January 2022 that were in English or translated to English were included. Search terms included ‘COVID’ AND ‘geriatric’ AND (‘hydroxychloroquine’ OR ‘dexamethasone’ OR ‘budesonide’ OR ‘remdesivir’ OR ‘favipiravir’ OR ‘ritonavir’, ‘molnupiravir’ OR ‘tocilizumab’ OR ‘bamlanivimab’, ‘baricitinib’, ‘sotrovimab’, ‘fluvoxamine’ OR ‘convalescent plasma’ OR ‘prone position’ OR ‘anticoagulant’ OR ‘direct oral anticoagulant’ OR ‘heparin’ OR ‘antithrombotic’).
Geriatric population was defined as greater than or equal to 60 years of age. Observational cohort study (OCS) was defined as a clinically diagnosed group of infected patients who were treated with a specific treatment regimen (defined by exclusion criteria) and tested for viral markers at endpoint of treatment protocol. Distinct observational study (DOS) was defined as providing the same intervention to individual patients (distinct from OCS where articles reported results for the entire group) using an established and documented protocol and then, tested for viral markers at the end of the treatment. Randomized control trials (RCTs) were defined as studies that had two or more distinct groups of patients (treatment and control) and a clear treatment protocol. These patients were monitored at the end of the study for viral load, other viral markers, or clinical improvement.
In vitro study, animal study, case-control study, or case reports of a single individual, or of individuals who did not receive the same treatment protocol, other systematic reviews, literature reviews, and meta-analysis studies that did not involve the use of HCQ, RMD, FVP, RTV, molnupiravir (MPV), dexamethasone (DMS), budesonide (BUD), TCZ, bamlanivimab (BMB), baricitinib (BNB), sotrovimab (SVB), fluvoxamine (FLV), convalescent plasma (CP), PP, anticoagulant therapy, or no age data provided were excluded.
Inclusion criteria consisted of established treatment protocols using HCQ, RMD, FVP, RTV, MPV, DMS, BUD, TCZ, BMB, BNB, SVB, FLV, CP, PP, or anticoagulant therapy in older patients with demographic information expressed in the form of at least one of the following: age, age range, mean age ± SD, or median age ± SD. Studies that included particpants aged ⩾ 60 years old ± 1 SD of the mean or median that were statistically significant were included. Study designs consisting of either; RCT, OCS, or DOS and primary outcomes of one of the following: the improvement of COVID-19 symptoms/clinical improvement, shortened duration of COVID-19 symptoms, decreased viral load, and inflammatory markers such as C-reactive protein (CRP) and interleukin-6 (IL-6) were included.
Article titles were assessed based on exclusion criteria. Articles that passed the first assessment based on title exclusion had their abstracts reviewed. Entire articles were assessed for the remaining studies that met inclusion criteria. Studies that were not statistically significant were excluded from the review. Only studies that did not include any exclusion criteria and met all inclusion criteria were used in the systematic review analysis. Duplicate articles were removed prior to systematic review analysis. The level of evidence for the included studies was assessed using the Level of Evidence for Therapeutic Studies grading system.
Patient and public involvement
Patients were not directly involved in this systematic review. All patient consent was given for the individual research articles examined.
Results
As of January 2022, the search identified 302 potentially relevant studies. After review of these studies based on inclusion and exclusion criteria, 52 studies were eligible and included in the systematic review (Figure 2).
PRISMA flowchart.
There were RCTs (n = 24), OCS (n = 21), and DOS (n = 7). Fourteen studies used HCQ (6 positive, 8 negative), 9 studies used CP (6 positive, 3 negative) as a treatment approach, 5 studies used RMD (2 positive, 3 negative), 1 study used BUD (1 positive), 2 studies of each used DMS (1 positive, 1 negative), 4 studies used TCZ (2 positive, 2 negative), 1 study used BMB (1 positive), 5 studies used BNB (4 positive, 1 negative), 1 study used SVB (1 positive), 3 studies used FVP (2 positive 1 negative), 3 studies used supportive PP (3 positive), and 5 studies used anticoagulation therapy (2 positive, 3 negative) (Table 1). The total number of patients reported in these studies were 30,265 (HCQ n = 9005; RMD n = 1749; BUD n = 4663; FVP n = 350; DMS n = 2062; TCZ n = 6764; BMB n = 1217; SVB = 583; CP n = 988; supportive PP n = 64; anticoagulation n = 2821). For the studies that listed patient demographic information as an age range, the widest age range was 22–97 years old. The narrowest age range was 67–71 years old.
Overview of available evidence of analyzed studies.
ACE, angiotensin converting enzymes; ARB, angiotensin II receptor blockers; ARDS, acute respiratory distress syndrome; AZT, azithromycin; BMB, bamlanivimab; BNB, baricitinib; BUD, budesonide; CAD, coronary heart disease; CHA2DS2-VASc, congestive heart failure, hypertension, age, diabetes, stroke/transient ischemic attack vascular score; CI, confidence interval; CP, convalescent plasma; CrI, credible interval; CRP, C-reactive protein; DMS, dexamethasone; DOAC, direct oral anticoagulants; DOS, distinct observational study; favipiravir; HCQ, hydrochloroquine; HR, hazard ratio; ICU, intensive care unit; IL-6, interleukin-6; IQR, interquartile range; LP, lateral position; n, number of individuals; OCS, observational cohort study; OR, odds radio; PP, prone position; RCT, randomized control trial; RMD, remdesivir; RTV, ritonavir; SD, standard deviation; SVB, sotrovimab; TCZ, tocilizumab; UC, usual care; WHO, World Health Organization; yo, years old; ABG, arterial blood gas; BCI, Bayesian credible interval; BLMB, baloxivir; CHF, chronic heart failure; CVA, cardiovascular accident; DM, diabetes mellitus; FVP, favipiravir; HTN, hypertension; LPV, lopinavir; LRTI, lower respiratory tract infection; LTC, long-term care; MV, mechanical ventilation; NG, nasogastric; NIV, non-invasive ventilation; NPS, national prescribing service; PE, pulmonary embolism; RR, respiratory rate; SBV, sotrovimab; SOB, shortness of breath; SOFA, sequential organ failure assessment; URTI, upper respiratory tract infection.
Main findings
The geriatric population was a focus for this systematic review as it presents a unique perspective in addressing the treatment options for COVID-19. Despite the drastic impact that COVID-19 has had on this population with respect to morbidity and mortality rates, there is little research focusing on this population. 4 Studies focusing on FVP, BMB, and BNB in the treatment of COVID-19 was found to be useful in the geriatric population. In contrast, HCQ, DMS, RMD, and anticoagulant therapy have shown inefficacy in the geriatric population, as studies revealed no change or increased mortality and had minimal to no clinical benefits. There is conflicting evidence on the utility of TCZ, CP, supportive therapy, and anticoagulant therapy as there were mixed results in supporting the efficacy on mortality, ventilator-free days, and clinical improvements in the geriatric population in the reviewed data. In addition, there was limited evidence and lack of data due to ongoing trials for treatments with SBV and BUD. A significant decrease in viral load and improvement in clinical symptoms subsequent to these modalities was observed in some of the studies reviewed in the geriatric population. However, a large number of these studies utilized a wide patient demographic (e.g. age ranges) making it difficult to conclude the exact physiological effects various treatments are expected to have on older patients (e.g. shortened duration of COVID-19 symptoms, clinical improvement, decreased viral load, decreased inflammatory markers).10,13,17,22,24,27–29
HCQ treatment
Of the 14 studies focusing on HCQ, 6 studies showed positive changes in primary patient outcomes.10,11–14,20 Eight studies showed no statistically significant difference.15–19,39–41 Further to this, a large sample RCT noted that HCQ did not lower the incidence of death at 28 days compared with those that received usual care. 40 It should be noted that in addition to HCQ in some of the reviewed studies, azithromycin (AZT) was co-administered to some patients.11,13,17,18 In addition, cardiac arrest was more frequent in patients who received HCQ with AZT compared with patients who received neither drug. 1
Studies looking into the use of HCQ as a post-exposure prophylaxis have shown no significant prevention benefit in COVID-19. 20 Boulware et al. (2020) demonstrated that individuals with a severe to moderate risk of developing COVID-19 based on previous exposure who were treated prophylactically with HCQ were at greater risk for side effects compared with a placebo group (40.1% to 16.8%). 61
Corticosteroids
DMS treatment
Two of the analyzed studies supported the use of DMS in the treatment of COVID-19. One study noted a significant decrease in mortality seen in patients treated with steroids compared with controls (13.9% versus 23.9%).37,43 Among patients with COVID-19 and moderate or severe ARDS, use of intravenous DMS plus standard care compared with standard care alone resulted in a statistically significant increase in the number of ventilator-free days (days alive and free of mechanical ventilation) over 28 days. 37 In contrast, there was no significant change in mortality rate between steroid treated and control patients, and increased corticosteroid dosage was associated with significantly elevated mortality risk. 35 Studies that examined other corticosteroids other than DMS such as hydrocortisone and methylprednisolone, showed a significant increase in mortality rates observed in treatment groups compared with control groups.46,47
BUD treatment
There was one large open-labeled RCT conducted examining BUD. Yu et al. 55 examined 751 individuals aged > 65 who were randomized to receive 800 µg of inhaled BUD, twice daily for 14 days. It was found that inhaled BUD reduced self-reported time to recovery from 11 to 2 days (p = 0.017), hospital admission (p = 0.81) or death estimated outcomes, and serious adverse events compared with standard COVID-19 care. 55
Antiviral treatment (RMD and FVP)
RMD was not found to be effective in improving clinical symptoms in patients in most studies reviewed in this systematic review.43,62–64 The findings from the Grein et al. 22 study revealed that, in patients of 70 years of age and older, clinical improvement was observed less frequently than in patients less than 50 years of age [hazard ratio (HR) = 0.29 95% CI = 0.11–0.74]. The lack of a significant decrease in mortality with RMD treatment noted by Beigel et al. further supports the conclusion that RMD may not be as effective for COVID-19 treatment in the geriatric population. 21
FVP has been proposed as a treatment for patients with COVID-19 and is supported in two of the three studies reviewed in this systematic review.33,34 There was an observed statistically significant decrease in duration to patient viral clearance (p < 0.001) and increased rates to clinical recovery (p < 0.05) from COVID-19-related symptoms (fever, dyspnea, decrease in oxygen saturation, cough) with the use of FVP.33,34 Furthermore, in previously untreated patients, FVP had a higher clinical recovery rate (recovery of fever, respiratory rate abnormalities/instability, oxygen saturation, cough). 34
Monoclonal antibodies (TCZ, BMB, BNB, SVB)
TCZ treatment
The existing limited body of literature provides mixed evidence for its use, with only half of the identified RCTs suggesting benefit to clinical outcomes and overall survival benefit.44,49 One study found the risk of in-hospital mortality was lower in patients treated with TCZ in the first 2 days of intensive care unit (ICU) admission compared with those that received alternate treatment. Furthermore, the estimated 30-day mortality in the intervention group was 27.5% compared with 37.1% in the non-intervention group. 44 These findings were supported by a large-scale RCT comparing TCZ with standard of care (UC), where clinical benefit and survival outcome were observed more often in those treated with TCZ regardless of level of respiratory support and addition of systemic corticosteroids. 49 Two additional RCTs did not observe a benefit to COVID-19 disease progression compared with UC; however, both studies were limited by small sample size and narrow patient demographic.44,45
BMB treatment
An RCT conducted by Gottlieb et al. found that treatment with BMB and etesevimab compared with placebo was associated with a statistically significant (p = 0.01) viral load reduction at day 11; however, there was no significant viral load reduction using BMB monotherapy. Immediate hypersensitivity reactions were reported for 9 out of 613 patients with BMB monotherapy, and no deaths occurred during the treatment study. 48 An OCS examined the use of BMB in nursing facilities revealed a side-effect rate of 11.1% which included hospitalization and emergency department admissions with no deaths. 65 Gottlieb et al. who examined BMB in a combination dose concluded that, it is unclear whether monotherapy or different combinations have more clinical efficacy.
BNB treatment
There were five novel studies found examining BNB in older patients with COVID-19. Abizanda et al. 49 examined patients hospitalized with moderate-to-severe COVID with pneumonia; 328 patients were stratified to older or younger than 70 years old given 4 mg of BNB for 14 days. In the >70-year-old group, treatment with BNB significantly reduced death from any cause (48%) and 30-day absolute mortality (20.5%) compared with controls without BNB (p < 0.001).
Stebbing et al. 2021 conducted an observational chart review in 122 patients who were given high-dose BNB (8 mg), compared with low-dose BNB (4 mg) for 14 days in older patients. In the high-dose BNB group, blood oxygen saturation was stabilized earlier (p < 0.05) and had reduced intensive support (p < 0.05), reduced 30-day mortality (p < 0.05) and 60-day rehospitalization rate (p < 0.01) compared with the low-dose BNB group. 66
In Bronte et al., a longitudinal observational study, 20 patients with COVID were using 5 mg of BNB twice daily for 2 days, followed by 5 mg per day for 7 days. Patients treated with BNB had a reduction of serum IL-6, IL-1B, and TNF-alpha, rapid recovery of circulating T- and B-cell frequencies and increased antibody production to the spike protein. 51 In addition to the immunological findings, there was 1 death in the BNB group compared with 25 deaths in the group without BNB (p < 0.001), a decrease in ARDS (p = 0.37), with a similar duration of hospital stay for both groups. 51
In Rosas et al., a retrospective review on patients with confirmed COVID-19 comparing 23 patients who received BNB monotherapy (2–4 mg daily) and 31 patients who received TCZ (IV dose 400 mg). There was no significant mortality benefit or side effects noted with either treatment group; however, BNB monotherapy showed a significant reduction in temperature, CRP, D dimer, increase in oxygen saturation requirement, and decrease of respiratory rate compared with TCZ (p < 0.01), and less intensive care intubation (27% reduction). 52
In Izumo et al., 53 an observational study of 44 patients with severe COVID-19 received triple therapy of BNB (4 mg daily oral), RMD (IV 200 mg loading, 100 mg maintenance daily) and DMS (oral or IV 6 mg daily). It was found that patients who received BNB had a low mortality rate (2.3%) and decrease in mechanical ventilation requirement (90%) with approximately 34% adverse events observed. 53
SVB treatment
There was one multi-center RCT that had a geriatric cohort over 65 years of age, which randomized 93 patients into an SBV group (500 mg IV), and 93 who received placebo. 54 Three patients in the SVB group, compared with 21 patients in the placebo group had disease progression leading to hospitalization or death (p = 0.02). In addition, adverse events were reported in 17% of the SVB patients compared with 19% in the placebo group.
CP treatment
A decrease in viral load and an improvement in clinical symptoms of fever, dyspnea, cough, and chest pain was noted in reviewed studies in patients who received CP.24,23,26,27–29 Three RCTs that used CP as treatment did not report any significant difference in time to clinical improvement or overall mortality between patients who received CP therapy compared with the control group.38,42,67 Likewise, the RCT by Piechotta et al. supported the uncertainty of the use of CP in the effect on mortality and hospital discharge for COVID-19 patients. 68
Supportive therapy
Patients who were provided with a daily PP session in the reviewed studies showed decreased mean respiratory rate from 28.4 ± 3.5 breaths/min to 21.3 ± 1.3 breaths/min and an improvement in oxygen saturation during PP compared with baseline.30,32 However, Elharrar et al. reported that 42% of the patients who received this therapy experienced back pain due to the PP.31
Anticoagulant therapy
There were five studies that met the inclusion criteria treating geriatric patients with anticoagulant therapy. Fumagalli et al. (2022), retrospective observational study (ROS), on patients aged > 60 with atrial fibrillation who were on antiplatelet or oral anticoagulant therapy, found that oral anticoagulant use before (p < 0.001) and during hospitalization (p = 0.002) was higher among survivors. 56 In addition, higher self-sufficiency, less severe initial COVID-19 presentation, and the use of vitamin K antagonists or direct oral anticoagulants (DOACs) on admission, or the persistence of DOAC during hospitalization were associated with a lower chance of in-hospital death. 56
Rossi et al., retrospective OCS for patients aged >70 with COVID-19 and interstitial pneumonia with known coronary heart disease (CAD), who were on long-term anticoagulant or antiplatelet therapy including aspirin, P2Y12 inhibitors, dual antiplatelet therapy, DOACs, beta-blockers, statins, angiotensin converting enzymes (ACEs), angiotensin II receptor blockers (ARBs), or calcium-antagonists. 57 Long-term anticoagulant use in the survivor group was higher than non-survivor group (p < 0.001), specifically DOACs were associated with decreased mortality (p < 0.01) compared with other anticoagulation or cardiac therapies.
Olcott et al., a ROS on patients aged >70 who were admitted with a confirmed COVID-19 infection, where 22% of patients were on DOACs, 4% were on warfarin and 74% were the comparator group on no anticoagulant therapy, found no statistically significant improvement in all-cause mortality for patients who were anticoagulated preadmission (p > 0.05). 58
An RCT by Sadeghipour et al., randomized 562 patients to receive intermediate-dose (n = 274; enoxaparin, 1 mg/kg daily) versus standard prophylactic anticoagulation (n = 286; enoxaparin, 40 mg daily), found that intermediate-dose prophylactic anticoagulation, compared with standard-dose prophylactic anticoagulation did not result in a significant difference in venous or arterial thrombosis or morality within 30 days (p = 0.70). Interestingly enough, severe thrombocytopenia was noted in the intermediate-dose, and not in standard-dose anticoagulation cohort (p = 0.01). 59 Another RCT by Zarychanski et al. examined patients with severe COVID-19 on therapeutic anticoagulant therapy (unfractionated or low molecular weight heparin) versus thromboprophylaxis (DOAC), noted that therapeutic anticoagulation did not improve hospital survival (64.3% versus 65.3%) or days free of organ support (3 versus 5 days) compared with thromboprophylaxis. 60
Discussion
HCQ use in the geriatric population
In the studies analyzed in this review, the consensus on HCQ as an effective treatment is variable. The studies that concluded positive antiviral effects of HCQ had smaller sample sizes compared with studies that concluded no significant antiviral effects of HCQ. HCQ was proposed as an effective treatment for patients with COVID-19 due to its antiviral, anti-inflammatory, and antithrombotic effects. 25 However, potential side effects of HCQ need to be considered prior to starting geriatric patients on this drug. The therapeutic combination of HCQ with AZT may have influenced the primary outcomes in these studies. However, there was no agreed consensus between these studies that used combination HCQ/AZT therapy on an improvement or lack of improvement in terms of the primary outcomes.
As of 24 April 2020, the Food and Drug Administration has cautioned the use of HCQ outside of hospital due to the ill side effects of the drug-based RCT. 25 In addition, clinical guidelines are not recommended HCQ due to lack of benefit, potential harm, and system implications of overuse. 69 The use of adjunctive therapy seen in the studies in which AZT was co-administered with HCQ, may have didanosine (DDI), which could lead to a synergistic effect and impact the efficacy and outcomes of the primary treatment assessed in the studies.
The most commonly reported side effects of HCQ post-exposure prophylaxis included nausea, loose stools, and abdominal discomfort. 36 QT prolongation to > 500 ms has also been observed with the use of HCQ and is a known marker for malignant arrhythmia and sudden cardiac death.15,16 HCQ and AZT combined have higher incidence of torsade de pointes, ventricular tachycardia, or cardiac arrest if taken (>4 days) and can result in cardiac-related mortality, which can be detrimental in older individuals with pre-existing heart conditions.70,71 When aggregating the results of HCQ, six studies showed positive effects and eight studies had negative side effects.
There was a high risk of bias in the HCQ studies (Table 2). High attrition bias was noted in some of the analyzed studies, particularly evident in the HCQ studies, due to early cessation of the treatment, death of patients, or lack of patient follow-up.10,14,17,20,22
Risk of bias of analyzed studies.
AZT, azithromycin; BNB, baricitinib; DMS, dexamethasone; HCQ, hydrochloroquine; LP, lateral position; PP, prone position; RMD, remdesivir; TCZ, tocilizumab.
Corticosteroid use in the geriatric population
DMS
Corticosteroids, including DMS and BUD are immunomodulators that may act to suppress the inflammatory storm, reduce inflammatory exudation, and prevent multiple organ injuries in the context of COVID-19 ARDS. 72 Studies that examined hydrocortisone and methylprednisolone compared with DMS showed a significant increase in mortality rates observed in treatment groups compared with control groups possibly due to suppression of the immune response that allows for virus replication.62,72 The immunosuppressant nature of systemic corticosteroids leads to reduced lymphocyte count which may lead to higher risk of superinfections. 72 Clinical guidelines recommend DMS only for moderately and critically ill patients requiring low-flow supplemental oxygen and ventilatory support; however, it is not recommended for mildly ill patients. 69
The risk of bias in the studies for DMS was high due to the lack of standardization of the treatment doses (i.e. 6 mg, 10 mg, 20 mg, or not reported route of administration; for example, oral compared with intravenous), and duration of treatment (e.g. 5 days, 10 days, or until ICU discharge) which varied between patients within the same study, and between all the analyzed studies (Table 2).35,37
BUD
RCT that examined BUD in the geriatric population revealed positive outcomes in recovery time, hospital admission, and death estimated outcomes. 55 This is consistent with current clinical guidelines, and inhaled BUD may be considered especially for symptomatic high-risk immunocompromised patients who are mildly ill and not requiring supplemental oxygen. 69
Even though there was only one large multi-center RCT examining BUD, the risk of bias was low as the treatment dose was standardized and it was as a large multi-center RCT (Table 2). 55
Antiviral (FVP and RMD) in the geriatric population
FVP
As of 22 October 2020, the US Food and Drug Administration granted approval for RMD as treatment of COVID-19 among patients requiring hospitalization. 36 Similarly on 28 July 2020, the Health Canada authorized RMD as a treatment of patients with severe COVID-19. 21 Current clinical guidelines recommend RMD for moderately ill patients who are newly requiring low-flow supplemental oxygen; however, it is not recommended for critical ill patients receiving mechanical ventilation. 69 However, despite the proposed antiviral mechanism of action of RMD of impairing viral RNA production by obscuring viral RNA polymerase and inhibiting viral exonuclease, RMD was not found to be effective in improving clinical symptoms in patients in most studies reviewed in this systematic review.
FVP is a nucleoside analogue antiviral drug with a similar mechanism of action to RMD but is taken orally. FVP has been used in the treatment for many types of influenza virus strains, Ebola, arenavirus, bunyavirus, filovirus, West Nile virus, yellow fever virus, Coxsackievirus, and Lassa virus. 18 Furthermore, the control treatments that FVP was compared against when drawing conclusions on its antiviral activity were different between the studies. Of particular consideration is the variability in dosing between patients of the same treatment group which may have largely affected the conclusions drawn by this study, which was the only study to conclude that FVP did not provide any further benefit over the control treatment. 35
The exact dosing of FVP and duration of treatment varied largely between the analyzed studies, notably dosing of 600 mg twice daily to 1600 mg twice daily and duration of 10–14 days. An advantage of FVP in patient treatment for COVID-19 is its oral administration, thus allowing it to be easier utilized in an outpatient setting to symptomatic patients. 35
The risk of bias in these studies was low due to well-constructed design and statistical significance of the reported data.62–64,43 It should be noted that blinding was not performed in any of the analyzed studies focusing on FVP which may have given a possible source for performance and detection bias.33,48
RMD
RMD was not found to be effective in improving clinical symptoms in patients in most studies reviewed in this systematic review.62–64,43 Despite that the current clinical guidelines recommend RMD for moderately ill patients requiring low-flow supplemental oxygen, it is not recommended for critically ill patients requiring ventilatory support or mildly ill patients. 69 This suggests that RMD should not be used as firstline in geriatric patients and can be considered only in moderately ill population requiring minimal supplemental oxygen.
The risk of bias was low in half of the RMD RCT studies that were blinded.5,21,43 However, two OCS studies had a small sample size, and no control group or blinding performed, which may lead to a possible performance and detection bias.27,53
TCZ
TCZ is a recombinant humanized anti-IL-6 receptor monoclonal antibody that inhibits the binding of IL-6 and soluble IL-6 receptors to membrane, blocking IL-6 signaling and thereby reducing inflammation. 44 It is commonly used in the treatment of rheumatoid arthritis, and most recently considered for use in adult patients, with an age range of 52–71, hospitalized with severe COVID-19.44,49
There were conflicting outcomes for TCZ in the review. In critically ill patents >60 years old, TCZ has shown benefit for lowering the risk of death and faster hospital discharge.44,49 In other studies, it showed no benefit on disease progression.45,51 In addition, compared with other monoclonal antibodies such as BNB, TCZ had worsened improvement in respiratory rate and in oxygen saturation. 67 Despite this conflicting evidence, TCZ is currently recommended for moderately and critically ill patients with serum CRP of 75 mg/l or higher and evidence of disease progression based on respiratory or ventilatory parameters. 69
The risk of bias of the TCZ studies were high in one of the observation studies, with limited blinding of participants, outcomes, and selective reporting results from younger patients (<60). 65 The three other RCTs had an adequate blinding and randomization which minimized the performance and detection bias.49,51,66
BMB
Novel treatments for COVID-19 have been geared toward biologics, specifically monoclonal antibodies. BMB is a neutralizing IgG1 monoclonal antibody that works against the SARS-CoV-2 spike protein.48,65 BMB has been used both as a monotherapy and a combination therapy with etesevimab or casirivimab-imedevimab, which have the same antibody properties as BMB. It was concluded that BNB monoclonal therapy was generally well tolerated and beneficial for the geriatric population. 65
Early data on monoclonal antibody treatment suggest that high-risk patients including those older than 65 years may benefit from BMB and other approved biologics. 73 The National Institutes of Health (NIH) has only approved BMB for mild-moderate symptoms of COVID-19 in older adults. 74 It is unclear whether BMB can be beneficial for the geriatric population with severe symptoms. Currently, BMB is not recommended based on the clinical guidelines. 69
It should be noted that blinding was not performed on the single BMB study, which may have resulted in performance and detection bias. 48 Furthermore, patient population was small, limiting generalizability. 48
BNB
BNB, a Janus kinase (JAK) inhibitor, originally approved for rheumatoid arthritis, has been approved for emergency use authorization by the Food and Drug Administration. 75 JAK inhibitors can prevent proinflammatory cytokines and have shown clinical usefulness in inflammatory diseases, and thus has been evaluated for treatment of COVID-19. 76 Current clinical guidelines recommend the consideration of BNB for moderately ill patients on low-flow supplemental oxygen and for critically ill patients requiring ventilatory support who are also on DMS or have contraindications to corticosteroid therapy. 69
Although there is increasing evidence for the use of BNB in the older population, all of the studies reviewed were observational. These studies have the high selection and performance bias, as there was no blinding of participants, personnel or outcome assessment. Furthermore, known and unknown confounding variables could have affected the reported results as well. In addition, three of the five reviewed studies had small sample sizes limiting overall statistical power.51–53 The study by Bronte et al. has missing data for outcomes of immunological parameters which may have skewed the results and did not allow statistical power calculations for the flow cytometry results. The last study conducted by Izumo et al. was conducted at the Red Cross, which had an environment that differed from traditional hospital resources and could have other factors contributing to the reported results. 53
SVB
The WHO group has made a conditional recommendation for the use of SVB in patients with non-severe-COVID but at high risk of hospitalization. 77 Current clinical guidelines only recommend SVB for patients who are mildly ill, presenting within 7 days of symptom onset, which may include residents of long-term care facilities, inpatients with nosocomial infection, and high-risk patients >70 years of age with comorbidities such as diabetes, cerebral palsy, sickle cell disease, or immunocompromised.
As the single SVB study was a large multi-center double-blinded RCT and the dose was standardized to 500 mg of SVB for each patient, there was minimal risk of bias, but there were only three patients in the SVB group who were hospitalized after treatment, which led to difficulties in determining which patient characteristics were associated with treatment failure. 54 A major limitation of this study was lack of reporting of secondary outcomes such as the percentage of patients with emergency visits and the need for supplemental oxygen, as the trial is still ongoing. A recent study has shown benefit of SVB treatment in patients without immunity to COVID-19 (vaccine or disease-induced) within early onset of symptoms (<7 days). 54 This early use of SVB is reflected in current clinical guidelines which recommend against SVB in moderately ill patients requiring supplemental oxygen and critically ill patients requiring ventilatory support; however, SVB may be considered in mildly ill patients who do not require new or additional supplemental oxygen from their baseline. 69
CP in the geriatric population
Immunomodulation through the passive transfusion of CP to patients acts to add neutralizing antibodies, anti-inflammatory cytokines, clotting factors, and defensins to the patient’s blood to enhance the immune system’s ability to clear the virus. This may be effective treatment for COVID-19, as it is associated with prevention of the over-activation of the immune system, and as a result, the ‘cytokine storm’ which may perpetuate pulmonary damage seen in infected patients. 78 However, current clinical guidelines do not recommend CP for COVID-19. 69
There is a high risk of bias in CP studies. All the studies included in the review lack significance of the results and as a result, it is difficult to draw conclusions.10,23,24,27–30
Supportive therapy in the geriatric population
When considering supportive therapies for older individuals, it is important to consider the possible harms that therapy may have; PP was reviewed in the assessed studies, and while PP may have a supportive role in COVID-19 patients, it may exacerbate or contribute to back pain. The physical pain experienced by these patients may have affected the duration that they could undergo PP and subsequently the efficacy of this therapy.30–32
PP and LP studies have high risk of bias, as all studies were observation and were not standardized by patient’s position. The mean age of the included population was 54.4 years with no comorbidities. The treatment was administered concurrently with other interventions such as antibiotics, anticoagulants, and antiviral medications. 30 In addition, the sample size was small in multiple studies, with lack of a control group, which led to increased risk of selection bias.31,32
Other supportive interventions that did not meet the inclusion criteria of this review may be helpful for COVID-19 patients, and balance should be found between the potential benefits and adverse effects. Lorazepam has been used in the management of anxiety in patients with COVID-19. 79 However, benzodiazepines may exacerbate mental status changes, cause increased sedation, and lead to the development of delirium in this population. 80 Opioids and oral hydration have been used to alleviate pain, dyspnea, and keep patients comfortable in palliative care settings. 79 Oxygen functional materials (OFM) used to deliver oxygen therapy to palliative geriatric patients may impair the interaction and communication between the patient and their family, lead to xerostomia, and need for intravenous hydration, which may have a negative impact on quality of life, increase pulmonary secretions and generalized edema. 81 Studies have illustrated the potential for traditional Chinese medicine as an effective treatment for COVID-19 and improvement of clinical symptoms.82,83 Additional supportive strategies, in addition to PP, should be considered if the benefits of treatment outweigh the adverse effects to the older patient and should be based on patient goals of care. Furthermore, these supportive strategies may be used synergistically to any upcoming accepted treatment for COVID-19.
Anticoagulant therapy in the geriatric population
Prophylactic dose of anticoagulation is recommended in moderately ill patients requiring low-flow supplemental oxygen, whereas therapeutic dose anticoagulation may be considered for those who are at low risk for bleeding. 71 However, a therapeutic dose of anticoagulant therapy is not recommended for critically ill patients, instead a prophylactic dose specifically of low molecular or unfractionated heparin is recommended. 69 These clinical guidelines are for adults, and not necessarily tailored toward patients >65 years of age with comorbidities that put them at a higher baseline of bleeding.
Of the five studies that met inclusion criteria, three had negative or negligible effects in the geriatric population with severe COVID-19 requiring hospitalization, two of which were large RCTs that revealed that neither prophylactic nor therapeutic anticoagulation protect against venous or arterial thrombosis, mortality, or days free of organ support in severe cases of COVID-19.59,60 This does not support the current clinical guidelines, as both therapeutic and prophylactic anticoagulation therapy can even lead to severe thrombocytopenia 79 and major bleeding in COVID-19 patients. 60 Two of the studies supporting anticoagulant therapy were observational studies assessing moderate COVID-19 cases and had cohort with specific cardiac comorbidities such as atrial fibrillation or CAD.56,57
Overall, the risk of bias for the anticoagulant studies was high. Three of the observational studies were lacking blinding and randomization which may have led to performance and detection bias.56–58 A major bias in these retrospective reviews was incomplete outcome data from participants, as drug history was taken from pervious discharge letters and as a result, some patients may have commenced anticoagulation therapy out of hospital, in primary or secondary care which was not documented. In addition, both RCTs were open-label, without a double blinding for anticoagulant cohort allocation, and as such a drawn conclusion could be questioned.
Additional COVID-19 treatments
Despite current clinical guidelines recommend FLV for moderately and critically ill patients, this treatment was not found in the reviewed data for the geriatric population based on the inclusion criteria. FLV is a selective-serotonin receptor inhibitor which may be considered for mildly ill patients with COVID, based on low certainty evidence of reduction in hospitalization, but the reviewed studies were lacking efficacy and safety against the new COVID-19 Omicron variant. 69 As a result, FLV therapy should be used with caution in this cohort as there is a lack of evidence. Current guidelines for the NIH and the Centers for Disease Control and Prevention (CDC) assert that no agent is known to be effective for preventing COVID-19 after exposure to the virus. 74
Limitations
A lack of statistical reporting, single-centered studies, lack of blinding, selective reporting, and attrition bias due to voluntary withdrawal or death led to challenges in assessment of the reported outcome and the validity of the reviewed studies (Table 2). Further to this, some studies changed primary outcome measure after initiation of study protocol, leading to possibility of outcome bias.
The short follow-up and small sample size of some of these studies presents a challenge in determining the accuracy of the statistical significance of the results and its impact on the population of interest.
A major problem of these studies includes early cessation of treatment, death of patients, and lack of patient follow-up, as seen in HCQ studies.10,12,14,15,22 In addition, most of the HCQ studies were observational, which increased the risk of confounding factors that may have affected clinical outcomes. Furthermore, positive clinical outcomes for HCQ studies came from the observational studies, with small sample sizes.
Overall, there was minimal research conducted for corticosteroid use in the geriatric population. Out of the two DMS studies and one BUD study, there were a lack of standardized dosing (ranged from 6–20 mg, inhaled BUS and intravenously administrated DMS) and duration of treatment (ranged from 5 days to discharge) varying between all participants.35,37,55
There were unique limitations to both types of antiviral therapy. Two of the three FVP studies were RCTs; however, they were limited by small sample size 55 and measured by viral clearance and imaging 33 instead of clinical improvements. This limits the generalizability of FVP to the entire geriatric population. For RMD, the only clinically positive study was an observational study, 22 the other RCTs found no significant decrease in mortality and no significant clinical benefits.5,21 This conflicting evidence limits the conclusion that RMD is safe and effective for the geriatric population.
Monoclonal antibodies also had a variety of limitations. Many patients in the TCZ groups had severe COVID and were in the ICU.49,51,65,66 The efficacy of TCZ on mild or moderate COVID severity in the geriatric population is unclear. There was only one large RCT for BMB; however, it was not blinded, and all patients were not > 60 years old, limiting the generalizability of the reported outcome to the geriatric population. Similarly, there was only a single RCT for SVB with lack of reported secondary outcomes, as the follow-up trial is still ongoing. 26 BNB studies had small sample sizes limiting their statistical power.51–53 In addition, all these studies were observational which may have had additional confounding factors.
Many of the analyzed studies for CP had less than 50 patients, which resulted in being under powered.14,17,23,24,26,28,29,30,32 Four of the seven studies were DOS without drawn conclusions and based only on individual patient observations.23,28,29,81,68 The study designs, reported outcome, and lack of statistical significance of the analyzed studies makes it difficult to assess the true effectiveness of CP in treatment for COVID-19 in the geriatric cohort. Each of the reviewed studies focusing on PP were statistically under powered as had less than 50 patients receiving the intervention. As a result, the reliability of these studies was questioned in this specific population.
The only supportive therapies found in this review included PP and LP, but these studies were observational, with small sample sizes (<25 patients) and were lacking standardized approach to positioning.30–32 In addition, the true efficacy of PP and LP is unknown, as other treatments such as antibiotics, anticoagulants, and antiviral medications were used at the same time.30–32 The efficacy of other supportive therapies such as antipyretics, opioids, antimicrobial agents, and oxygen are unknown.
Many anticoagulant studies were ROS with the exception of the two RCTs, which were not blinded.56–60 In addition, the retrospective analyses only had inpatient data, and not previous drug history outside of the hospital, which may have skewed the results. 58
There is a lack of reported impact of age to outcome on the treatment. It is possible that the older patients did not respond well to the treatment, and therefore the effects of the treatment on non-geriatric patients may have impacted the studies’ conclusions on effectiveness of treatment. In addition, the studies that provided age demographic information as mean ± SD and median ± SD were lacking the exact age of the participants and therefore did not solely include individuals >60 years old.
There was no standardized approach to the treatment in reviewed studies, and exact dosing and duration of treatments varied within each of the reviewed treatment modality. These differences may have influenced the outcome of the treatments and confounded the results. In some of these studies, adjuvants were administered to patients in addition to the specified main treatment modality, which may lead to bias in the reported outcome. The design in some of these studies (e.g. DOS and OCS) led to low levels of evidence and reduced power from which conclusions were drawn on the effectiveness of each of the reviewed treatments for geriatric patients infected with COVID-19. In addition, many of these trials are still ongoing, and data were not fully disclosed, awaiting peer review and future publication.15,51,64
Future directions
The limitations of the analyzed studies may spark the need for further testing each of the reviewed treatments to determine the true accuracy in clearing the viral load and impact to clinical symptoms of COVID-19. Attention to studies employing isolated single treatment modality would be pertinent to reduce the confounding effect of DDI, particularly seen in studies exploring concomitant use of HCQ and AZT. Large multi-centered, double-blinded RCT specifically looked at older, age 60 and above, with standardized control group, and longer follow-up should be conducted to assess the most effective treatment for COVID-19 and to determine the effects each of the above treatment on mortality rates in COVID-19 patients as well as assess its efficacy, in order to minimize bias. There is a need for standardized reporting of the inclusion criteria, administered treatment, and minimum effective dose used to yield patient recovery, as well as outcome endpoints, in order to compare results in the geriatric population which will most likely differ from adults.
Further stratification of this population could be analyzed by comorbidities such as cardiovascular disease, DM1, HTN, chronic respiratory disease, cancer, and other immunocompromised conditions which are shown to increase mortality in this group age. From a health prevention standpoint, future RCTs should investigate the use of pre- and post-exposure prophylaxis for high-risk older patients.
Specifically, anticoagulant therapy studies suggest that there may be clinical efficacy in geriatric patients with heart disease and severe cases of COVID-19, not necessarily in patients with mild cases or other comorbidities which should be further explored and applied to COVID-19 severity.59,60 The role of FLV should be further investigated, as there is a lack of up-to-date evidence, and the existing challenges with drug-drug interactions poses a barrier for its utility in the geriatric population.
COVID-19 is a rapidly developing area; there is no known agent that is effective for preventing COVID-19 after exposure to the virus at this time; as a result, the gold standard of pharmacological treatment is constantly changing. Future consideration into biologics such as antibody treatment is warranted in the older adults.
Conclusion
This review revealed that no agent is known to be effective for preventing COVID-19 after exposure to the virus and such, further research is needed to focus on older patients to ensure safety and efficacy of any of the reviewed above treatment protocols, in both pre- and post-exposure settings.
Footnotes
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The research conforms to the ICMJE recommendations for the conduct, reporting, editing, and publication of scholarly work in medical journals. Ethics/governance/data protection approval was not required due to the systematic review nature of the manuscript.
Author contribution(s)
Funding
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Conflict of interest statement
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