IMR Press / FBS / Volume 14 / Issue 4 / DOI: 10.31083/j.fbs1404026
Open Access Review
Nosocomial Infections in COVID-19 Patients Treated with Immunomodulators: A Narrative Review
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1 Department of Internal Medicine, Saint Vincent Hospital, Worcester, MA 01608, USA
2 Department of Cardiology, Saint Vincent Hospital, Worcester, MA 01608, USA
3 Department of Critical Care, Bangalore Baptist Hospital, 560032 Bangalore, Karnataka, India
4 Department of Medicine, Division of Pulmonary and Critical Care Medicine, Mayo Clinic, Rochester, MN 55905, USA
*Correspondence: Lal.Amos@mayo.edu; manavamos@gmail.com (Amos Lal)
Academic Editor: Anna Aiello
Front. Biosci. (Schol Ed) 2022, 14(4), 26; https://doi.org/10.31083/j.fbs1404026
Submitted: 29 June 2022 | Revised: 5 September 2022 | Accepted: 7 September 2022 | Published: 26 September 2022
Copyright: © 2022 The Author(s). Published by IMR Press.
This is an open access article under the CC BY 4.0 license.
Abstract

Nosocomial infections pose an imminent challenge to hospitalized Coronavirus disease-19 (COVID-19) patients due to complex interplay of dysregulated immune response combined with immunomodulator therapy. In the pre-pandemic era, immunomodulatory therapy has shown benefit in certain autoimmune conditions with untamed inflammatory response. Efforts to recapitulate these immunomodulatory effects in COVID-19 patients has gained impetus and were followed by NIH COVID-19 expert panel recommendations. The current NIH guideline recommends interleukin-6 inhibitors (tocilizumab and sarilumab) and Janus kinase inhibitors (baricitinib and tofacitinib). Several landmark research trials like COVAVTA, EMPACTA, REMDACTA, STOP-COVID and COV BARRIER have detailed the various effects associated with administration of immunomodulators. The historical evidence of increased infection among patients receiving immunomodulators for autoimmune conditions, raised concerns regarding administration of immunomodulators in COVID-19 patients. The aim of this review article is to provide a comprehensive update on the currently available literature surrounding this issue. We reviewed 40 studies out of which 37 investigated IL-6 inhibitors and 3 investigated JAK inhibitors. Among the studies reviewed, the reported rates of nosocomial infections among the COVID-19 patients treated with immunomodulators were similar to patients receiving standard of care for COVID-19. However, these studies were not powered to assess the side effect profile of these medications. Immunomodulators, by dampening the pyrogenic response and inflammatory markers may delay detection of infections among the patients. This underscores the importance of long-term surveillance which are necessary to discover the potential risks associated with these agents.

Keywords
immunomodulators
COVID-19
nosocomial infections
intensive care unit
critical care
outcomes
pandemic
inflammation
1. Introduction

The novel Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) was first identified in Wuhan, China, in December 2019. Since then, SARS-CoV-2has rapidly evolved into a global health threat and has been declared a pandemic by World Health Organization (WHO) [1, 2, 3]. The clinical presentation of Coronavirus Disease-2019 (COVID-19) is heterogeneous, ranging from asymptomatic infection to severe pneumonia involving respiratory failure that could progress to invasive mechanical ventilation or death. The disease is characterized by an initial phase of viral replication followed by a second phase driven by the host inflammatory response [4, 5, 6, 7, 8, 9]. Current evidence suggests that a subset of patients with COVID-19 develop severe inflammatory response resembling cytokine release syndrome (CRS) after chimeric antigen receptor (CAR) T-cell, macrophage activation syndrome (MAS)/hemophagocytic lymphohistiocytosis (HLH) [10]. This dysfunctional immune response contributes to the development of acute respiratory distress syndrome (ARDS) which is noted in up to 20% of patients [11, 12, 13, 14, 15, 16, 17, 18]. The cytokines orchestrating inflammatory damage to the lung include interleukin (IL)-1, IL -6, IL-12, IL-18, tumor necrosis factor α (TNF- α ), and interferon- γ (2).

2. Immunomodulators and Raising Concerns for Infection

The optimal approach to the treatment of COVID-19 is continually evolving. In a single-center study from Wuhan, China, which included 15 patients with COVID-19 pneumonia at risk for CRS, treatment with tocilizumab (a recombinant humanized anti-human IL-6 receptor monoclonal antibody) appeared to have a clinical benefit [19, 20]. The accumulating evidence suggests medications targeting dysregulated inflammation comprises a promising therapeutic strategy among critically ill COVID-19 patients. Many immunomodulators have been studied in clinical trials for the treatment of COVID-19. Based on the NIH COVID-19 treatment guidelines, IL-6 inhibitors (Tocilizumab and Sarilumab), Janus Kinase inhibitors (Tofacitinib and Baricitinib), and Steroids (Dexamethasone) are currently approved, immunomodulatory agents [21]. This approach has been useful to reduce pulmonary inflammation in patients suffering from COVID-19 [22], but the historical evidence of increased infection among patients receiving immunomodulators for autoimmune conditions, raised concerns regarding concomitant administration of immunomodulators and corticosteroids in COVID-19 patients [23, 24].

3. Pathogenesis of Cytokine Release Syndrome and Mechanism of Action of IL-6 Inhibitors

COVID-19 primarily infects type II pneumocytes and cells expressing angiotensin-converting enzyme (ACE-2), which serves as a receptor and entry point for the virus [4, 25]. The viral replication and its cytopathic effects activate cells of innate immunity (monocytes and macrophages) by stimulating Toll-like receptors and leading to the synthesis of pro-inflammatory cytokine responsible for Cytokine Release Syndrome (CRS) [5, 6]. Among those cytokines, several studies suggest that IL-6 plays a central role in CRS pathogenesis in COVID-19. It works by binding to transmembrane IL-6 (mIL-6R) and IL-6 soluble receptor (sIL-6R). The complex then binds to signal transducer (gp130) and triggered gene expression leading to cellular proliferation, differentiation, and oxidative stress. CRS, marked by the uncontrolled release of the pro-inflammatory cytokine, may affect the alveolar gas exchange, reducing pulmonary tissue oxygenation [11, 26]. Tocilizumab and sarilumab are the monoclonal antibodies that prevent IL-6 from binding to its receptors (both membrane-bound and soluble receptors) and inhibit its interaction with gp130, thus hindering the downstream activation of the inflammatory cascade. On the other side, suppression of IL-6 may also impair B-cell proliferation, T-cell differentiation, and cytotoxicity, which are essential for immune clearance of bacterial and fungal pathogens [27]. This is supported by the reduced ability of interleukin-6 deficient mice to clear systemic candida infection when compared with IL-6 positive controls [28, 29].

4. JAK Inhibitors: Mechanism of Action and Current Evidence in COVID-19 Treatment

Baricitinib is an inhibitor of JAK 1 and 2 receptors with high oral bioavailability. Similarly, Tofacitinib inhibits JAK 1 and 3 receptors. JAK inhibitors affect multiple cytokines orchestrating CRS such as IL-2, IL-6, IL-10, and interferon-gamma, unlike other biological drugs which are predominantly inhibitors of one cytokine. Data suggests that in addition to immunomodulatory effect, Baricitinib, may have antiviral action by interfering with viral entry into the cell. It binds to ACE2 receptors (angiotensin-converting enzyme) thereby inhibiting the entry of the virus into the cell and its intracellular coupling by binding to GAK (cyclin G-associated kinase), which regulates endocytosis and acts on AAK1 (Associated protein kinase 1), consequently interfering with viral replication [30]. These observations pivoted attention towards the JAK inhibitors as a promising strategy in the treatment of COVID-19.

5. Materials and Methods

In this narrative review, we aimed to summarize the information from seminal articles on the presentation of nosocomial infections among the COVID-19 patients treated with immunomodulators. We have focused our discussion pertinent to NIH-approved IL-6 inhibitors and Janus kinase inhibitors. We searched the PubMed and Medline databases for “COVID-19”, “tocilizumab”, “sarilumab”, “tofacitinib”, and “baricitinib”. Additionally, we examined the bibliography of the selected articles for further potential studies. Studies published in English, including adults with COVID-19 who received either IL-6 inhibitors or Janus Kinase inhibitors (JAK), were eligible to be included in this narrative review. We included only studies that reported details of nosocomial infection and the pertinent microbiological data. Additional information regarding the prevalence of nosocomial infection including ventilator-associated pneumonia (VAP), central line-associated bloodstream infections (CLABSI), catheter-associated urinary tract infections (CAUTI), length of hospital stay, intensive care admission rates, and mortality rates was collected. All the studies published before January 2022 were included. Articles that did not have patient details, conference papers, expert opinions, letters, articles not published in English, and studies not reporting nosocomial infections were excluded. All the articles were reviewed by 2 independent clinicians (CR and GN) and findings were confirmed by AL.

As of January 2022, a total of 828 papers were identified by literature search (Fig. 1). Among these, 40 fulfilled the eligibility criteria for our study. Out of these, 37 studies investigated IL-6 inhibitors and 3 studies analyzed the role of JAK inhibitors as a potential therapy in COVID-19 patients. There were significant differences in the study design, data collection, and measured outcomes among the studies which made the comparison of the data difficult.

Fig. 1.

Schema for literature review.

6. Nosocomial Infections in COVID-19 Patients Receiving IL-6 Inhibitors
6.1 Study Characteristics

Among the 37 studies that reported nosocomial infections in hospitalized COVID-19 patients treated with IL-6 inhibitors, 18 studies were prospective in design, 18 were retrospective and 1 was a phase II trial evaluating tocilizumab dosage (Table 1, Ref. [26, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66]). Out of 18 prospective studies, 11 were randomized control trials, 5 were prospective studies with a control arm, and the remaining 3 studies were without a control arm. 16 out of 18 retrospective studies had a control arm. Studies were published from all over the world with the majority from North American and European nations. Most of the included studies were from the United States with 13 studies followed by Italy with 8 studies, Spain with 2 studies, India with 2 studies, France with 2 studies, Sweden with 1 study, Brazil with 1 study, Egypt with 1 study, Belgium with 1 study, and the Netherlands with 1 study, respectively. There were 5 multinational studies. EMPACTA and COVACTA study groups reported the highest recruitment of ethnic minority groups at 40% and 29%, respectively [31, 32]. The diagnosis of COVID-19 was uniformly established with a reverse transcription-polymerase chain reaction. Of the 38 studies that reported the use of IL-6 inhibitor, 34 studies investigated Tocilizumab, and 4 studies evaluated Sarilumab. A single dose of 400 mg or 8 mg/kg intravenous was the most reported regimen of Tocilizumab. 20 out of 34 studies suggested that the second dose of Tocilizumab may be administered based on clinical judgment. In terms of Sarilumab, two dosing regimens 200 mg and 400 mg were investigated. The patients with active bacterial, tuberculosis, fungal and viral infections were uniformly excluded across all the studies. Hydroxychloroquine, antivirals, azithromycin, steroids, or anticoagulants were the most reported regimen in the standard of care treatment. A total of 8325 patients were reported in the 38 studies, including 4560 patients in the tocilizumab group, 360 patients in the sarilumab group, and 3405 in the control group. All the subjects in the intervention group also received standard treatment for COVID-19 in addition to IL-6 inhibitors. The mean age of patients who received IL-6 inhibitors was 61.1 years with male preponderance reported in all the 38 studies. The most common comorbidities reported across all the studies were arterial hypertension (21% to 72%), diabetes mellitus (11% to 36%), and obesity with BMI greater than 30 (21% to 52%) which varied according to the country of study.

Table 1.Study demographics and rates of nosocomial infection in COVID-19 patients receiving IL-6 inhibitors.
Reference study Country Study type No. of patients (Treatment arm /Control) Age (mean ± SD) Gender Common comorbidities Study drug Concomitant use of systemic steroids Rates of any infections (Treatment arm vs Control) Rates of Bacterial pneumonia Mortality
1 Rosas et al. (COVACTA) [32] Multinational RCT 294/144 60.9 ± 14.6 M: 205 (70%) DM: 105 (36%) Tocilizumab 54.1% 38.3% vs 40.6% 5.4% vs 7% 19.7% vs 19.4%, p = 0.94
F: 91 (30%) HTN: 178 (61%)
2 Salama et al. (EMPACTA) [31] Multinational RCT 249/128 56.0 ± 14.3 M: 150 (60%) NR Tocilizumab 80.3% 10.0% vs 12.6% NR 10.4% vs 8.6%
F: 99 (40%)
3 Hermine et al. (CORIMUNO-TOCI-1) [33] France RCT-Open label 63/67 64 (IQR: 57–74) M: 44 (70%) DM: 20 (33%) Tocilizumab 33% 3.1% vs 16.4% NR 11% vs 11.9%
F: 19 (30%) Cardiac disease 20 (33%)
4 Salvarani et al. (RCT-TCZ-COVID-19) [34] Italy RCT-Open label 60/66 60 (IQR: 53–73.2) M: 40 (67%) DM: 10 (16.7% Tocilizumab NR 1.7% vs 6.3% NR 3.3% vs 1.6%
F: 20 (33%) Obesity: 16 (28%)
HTN: 27 (45%)
5 Stone et al. (BACC BAY Tocilizumab) [35] USA RCT 161/81 61.6 (IQR: 46.4–69.7) M: 96 (60%) HTN: 80 (50%) Tocilizumab 11% 8.1% vs 17.1, p = 0.03 NR 3.7% vs 2.4%
F: 65 (40%) Obesity: 80 (50%)
6 Soin et al. COVINTOC [36] India RCT open label 91/88 56 (IQR: 47–63) M: 76 (84%) HTN: 36 (40%) Tocilizumab 91% 7% vs 6% NR 12% vs 17%, p = 0.35
F: 15 (16%) DM: 31 (34%)
7 Alaa Rashad et al. [37] Egypt RCT 46/63 60.5 (IQR: 49–67) M: 26 (56%) HTN: 26 (56%) Tocilizumab vs Dexamethasone NR 30.4% vs 25.4%, p = 0.356 NR 69.6% vs 52.4%, p = 0.05
F: 20 (44%) DM: 16 (35%)
8 Rosas et al. (REMDACTA) [38] Multinational RCT double blind 430/210 60.1 ± 13.3 M: 266 (62%) HTN: 267 (62.1%) Tocilizumab 83.2% 30.5% vs 33.3% NR 22.6% vs 25.7%, p = 0.39
F: 164 (38%) DM: 172 (40%)
9 Farias et al. (TOCIBRAS) [39] Brazil RCT open label 65/64 57.4 ± 15.7 M: 44 (68%) HTN: 30 (46%) Tocilizumab 25% 15% vs 16%, p = 0.98 7.6% vs 10.9%
F: 21 (32%) DM: 22 (34%)
Obesity: 15 (23%)
10 Declercq et al. (COV-AID) [40] Belgium 2X2 Factorial design RCT-Open label 227/115 65 (IQR: 54–73) M: 175 (77%) HTN: 115 (51%) Ant interleukin vs Usual care 62% 9% vs 8% NR 17.6% vs 12%
F: 52 (23%) DM: 59 (26%)
11 Lescure et al. [41] Multinational RCT Double blinded 332/84 58 (IQR: 51–67) M: 206 (62%) HTN: 138 (42%) Sarilumab NR 12% vs 12% NR 9% vs 8%, p = 0.85
F: 126 (38%) DM: 92 (28%)
12 Monica Mehta et al. [42] USA Single center, Retrospective 33/74 54.6 M: 25 (76%) Pulmonary disease 22% Tocilizumab NR 30% vs 23%, p = 0.193 30% vs 14%, p = 0.69 NR
F: 8 (24%)
13 Ramiro et al. [43] Netherlands Prospective control study 86/86 67 ± 12 M: 68 (79%) HTN: 19 (22%) Tocilizumab 100% 9% vs 8%, p = 0.780 NR 16% vs 47.6%, p = 0.0004
F: 18 (21%) DM: 9 (11%)
COPD: 10 (12%)
14 Amer et al. [44] Multinational Prospective multicenter 121/406 60.6 ± 13.8 M: 87 (72%) NR Tocilizumab vs Dexamethasone NR 29.7% vs 23.9%, p = 0.46 29.7% vs 23.9%, p = 0.46 NR
F: 44 (28%)
15 Della-Torre et al. [45] Italy Prospective single center 28/28 56 (IQR: 49–60) M: 24 (85%) DM: 3 (11%) Sarilumab NR 21% vs 18%, p = 0.99 NR 7% vs 18%, p = 0.42
F: 4 (15%) HTN: 6 (21%)
16 Campochiaro et al. [46] Italy Retrospective single center 32/33 64 (IQR: 53–75) M: 29 (91%) DM: 4 (12%) Tocilizumab NR 13% vs 12%, p = 0.99 NR 16% vs 33%, p = 0.15
F: 3 (9%) HTN: 12 (37)
17 Sinha et al. [47] USA Prospective, Single center 255 59 (IQR: 47–70) M: 161 (63%) DM: 79 (31%) Sarilumab or Tocilizumab NR 13.3% NR 10.9%
F: 94 (37%) HTN: 125 (49)
Obesity: 135 (52)
18 Lewis et al. [48] USA Retrospective, Multi center 497/497 60.2 M: 352 (70.8%) NR Tocilizumab 51.7% 34.4% vs 10.7%, p < 0.001 25.9% vs 5.8% 29.2% vs 42.4%, p = 0.001
F: 145 (29.2%)
19 Morena et al. [26] Italy Prospective, Single centre 51 60 (IQR: 50–70) M: 40 (79%) DM: 6 (12) Tocilizumab NR 27% NR 27%
F: 11 (21%) HTN: 15 (30)
20 Nasa et al. [49] India Multicentre, Reterospective 22/63 51 M: 22 (100%) DM: 13 (59%) Tocilizumab NR 9% NR 9%
HTN: 16 (72%)
21 Rosas et al. [50] Spain Reterospective study 43/17 67 ± 14 M: 32 (74%) Charleson comorbidity index: 3.41 Tocilizumab and Baricitinib 82% 21% vs 25.9% NR 20%
F: 11 (26%)
22 Roumier et al. [51] France Prospective, Single centre 49/47 57.8 ± 11.5 M: 40 (82%) DM: 12 (24%) Tocilizumab NR 22% vs. 38%, p = 0.089 8% vs 26%, p = 0.022 10.2% vs 12.8%, p = 0.69
F: 9 (18%) HTN: 9 (18%)
23 Strohbehn et al. [52] USA Phase II open label 32/41 69 (IQR: 41–73) M: 16 (50%) NR Tocilizumab NR 15.6% 16% NR
F: 16 (50%)
24 Toniati et al. [53] Italy Prospective, single center 100 62 M: 88 (88%) DM: 17 (17%) Tocilizumab 100% 2% NR 20%
F: 12 (12%) HTN: 46 (46%)
25 Biran et al. [54] USA Retrospective, Multicenter 210 62 (IQR: 53–71) M: 155 (74%) DM: 77 (37%) Tocilizumab 46% 17% vs 13% 12% vs 7% 49%
F: 55 (26%) HTN: 122 (58%)
26 Canziani et al. [55] Italy Retrospective, Multicenter 64/64 63 ± 12 M: 47 (73%) HTN: 33 (52%) Tocilizumab 48% 27% vs 38%, p = 0.185 NR 27% vs 38%
F: 16 (27%)
27 Eimer et al. [56] Sweden Retrospective single center 22/22 56 (IQR: 49–64) M: 21 (96%) DM: 4 (18.2%) Tocilizumab 13% 18.2% vs 27.3%, p = 0.72 23% vs 36.4%, p = 0.51 23% vs 32%, p = 0.73
F: 1 (4%) HTN: 8 (37%)
28 Fisher et al. [57] USA Reterospective Single center 45/70 56.2 M: 29 (65%) NR Tocilizumab 73% 29% vs 26%, p = 0.71 NR 29% vs 40%, p = 0.23
F: 16 (35%)
29 Guaraldi et al. [58] Italy Reterospective, Multicenter 179/365 64 (IQR: 54–72) M: 127 (71%) NR Tocilizumab NR 13% vs 4%, p < 0.0001 NR 20% vs 7%, p < 0.0001
F: 52 (29%)
30 Gupta et al. [59] USA Retrospective Multicenter 433 58 (IQR: 48–65) M: 299 (69%) DM: 165 (38.1%) Tocilizumab 19% 32.3% vs 31.1% 26% vs 21% 29% vs 41%
F: 134 (31%) HT: 234 (54%)
31 Hill et al. [60] USA Retrospective, single cener 43/45 57.2 ± 13.5 M: 30 (70%) DM: 16 (36%) Tocilizumab NR 21% vs 16% 21% vs 11% 20.9% vs 33.3%
F: 13 (30%)
32 Kewan et al. [61] USA Reteropsective single center 28/23 62 (IQR: 53–71) M: 20 (71%) DM: 11 (39%) Tocilizumab 71% 18% vs 22%, p = 0.74 NR 11% vs 9%
F: 8 (29%) HTN: 19 (68%)
33 Kimmig et al. [62] USA Reterospective single center 54/57 64.5 ± 13.6 M: 37 (68%) Charleson comorbidity index: 3.59 ± 3.82 Tocilizumab 24% 48.1% vs 28.1%, p = 0.029 33.3% vs 15.8% 35.2% vs 19.3%, p = 0.020
F: 17 (32%)
34 Pettit et al. [63] USA Reterospective single center 74/74 66 ± 13.7 M: 43 (58%) DM: 24 (32%) Tocilizumab NR 23% vs 8%, p = 0.013 9.5% vs 6.8%, p = 0.76 39% vs 23%, p = 0.03
F: 31 (42%) HTN: 41 (55%)
35 Rodriguez-Bano et al. [64] Spain Retrospective Multicenter 88/344 66 (IQR: 56–72) M: 40 (73%) DM: 15 (17%) Tocilizumab 18% 12.5% vs 10.3%, p = 0.57 NR 2.3% vs 11.9%, p = 0.004
F: 24 (27%) HTN: 30 (34.1)
36 Rossotti et al. [65] Italy Reterospective single center 74/148 59 (IQR: 51–70) M: 61 (82%) NR Tocilizumab NR 32.4% NR NR
F: 13 (18%)
37 Somers et al. [66] USA Singlecenter 78/76 55 ± 14.9 M: 53 (68%) HTN: 50 (64%) Tocilizumab 30% 54% vs 26%, p < 0.001 45% vs 20%, p < 0.001 22% vs 15%, p = 0.42
F: 25 (32%) Solid organ transplant 7 (9%)
SD, Standard Deviation; RCT, Randomized Control Trial; DM, Diabetes Mellitus; HTN, Hypertension; M, Male; F, Female; NR, Not Reported.
6.2 IL-6 Inhibition and Infection

The rates of nosocomial infection reported among the patients who received IL-6 inhibitors range from 1.7% to 54% depending on the severity of COVID-19 in study patients [34, 66]. Most infections were bacterial with pneumonia being the most common manifestation followed by bloodstream infections [48, 56, 58, 59, 62, 66]. Four retrospective studies reported a statistically significant higher rate of infections in the tocilizumab group compared to the control group [48, 58, 62, 66]. Out of 11 randomized control trials, 9 trials reported similar rates of nosocomial infections among the tocilizumab-treated group and control group [31, 32, 33, 34, 36, 37, 38, 40, 41]. Interestingly, one double blinded randomized trial showed statistically significant higher infection rates in the control arm than the tocilizumab arm [35].

Lewis et al. [48] reported a higher prevalence of nosocomial infections in the tocilizumab group compared with propensity-matched controls in the retrospective analysis of 497 patients with an odds ratio of 4.18 (95% CI = 2.72–6.52, p < 0.001) [48]. A higher prevalence of bloodstream infections, pneumonia, and urinary tract infections was noted in the tocilizumab group. In comparison with matched controls, infections occurred later during the course among the tocilizumab group (median 10d; IQR, 5–15 vs 4d; IQR, 1–8). Of note, a higher proportion of tocilizumab-treated patients received steroids compared with matched controls (51.7% vs 25.2%) and the cumulative dose of corticosteroids was higher in the tocilizumab group (median methylprednisolone equivalents, 350 mg vs 125 mg). Despite a higher prevalence of nosocomial infections, the tocilizumab-treated group was associated with improved survival (HR = 0.24, 95% CI = 0.18–0.33, p < 0.001). Similar conclusions were drawn by Somers et al. [66] based on a single-center retrospective analysis of critically ill patients receiving tocilizumab within 24 hours of endotracheal intubation, wherein tocilizumab-treated patients developed higher rates of nosocomial infections than controls (54% vs 26%, p < 0.001). The results were driven primarily by an increase in ventilator-associated pneumonia (45% vs 20%, p < 0.001). This did not impact the patient mortality as the case fatality rates were similar between infected and uninfected tocilizumab-treated patients (22% vs 15%, p = 0.42). Staphylococcus aureus was identified as the predominant pathogen responsible for pneumonia in both groups [66].

Five studies reported the prevalence of fungal infection among tocilizumab-treated patients, which ranges from 1.35% to 6.9% [35, 38, 41, 63, 67]. The commonly reported invasive fungal infection was candidemia followed by pneumonia and sinusitis. Antinori et al. [67] reported 6.9% of candidemia in a retrospective analysis of 43 patients treated with tocilizumab wherein all the patients with candidemia received parenteral nutrition during hospitalization.

7. Discussion
7.1 IL-6 Inhibitors: Current Evidence in Treatment of COVID-19

The EMPACTA trial reported fewer patients on IL-6 blockade progressed to mechanical ventilation, but it did not translate to increased survival [31]. The RECOVERY trial showed an increased survival rate in tocilizumab-treated patients with respiratory failure and elevated C-Reactive Protein (CRP) levels above 75 mg/L [68, 69]. The REMAP-CAP trial concluded an increased number of organ support-free days at day 21 with tocilizumab or sarilumab in patients who were ventilated or received cardiovascular organ support [70]. On July 6, 2021, based on a meta-analysis of 27 RCTs, the World Health Organization (WHO) rapid evidence appraisal for COVID-19 therapies (REACT) working group showed an association between administration of IL-6 inhibitors and reduced 28-day all-cause mortality, compared with the standard of care, in hospitalized patients with COVID-19 (pooled odds ratio = 0.86; 95% confidence interval 0.79–0.95) [71]. Based on the above evidence, the National Institutes of Health conditionally recommend tocilizumab or sarilumab in combination with steroids for intensive care unit (ICU) patients with rapidly progressing respiratory failure or high inflammatory markers.

7.2 Nosocomial Infections in COVID-19 Patients Receiving Janus Kinase (JAK) Inhibitors

Three double-blinded randomized control trials reported nosocomial infection in hospitalized COVID-19 patients treated with JAK inhibitors (baricitinib and tofacitinib) [39, 72, 73]. Of the 3 studies that reported the use of JAK inhibitor, 2 multinational studies investigated baricitinib, and 1 study from Brazil evaluated tofacitinib (Table 2, Ref. [71, 72, 73]). A total of 2847 patients were reported in the 3 trials, including 1279 patients in the baricitinib group, 144 patients in the tofacitinib group, and 1424 patients in the control group. All the subjects in the intervention group received standard treatment for COVID-19 in addition to JAK inhibitors. The mean age of patients who received JAK inhibitors was 55.9 years with male preponderance reported in all the 3 studies ranging from 61.9% to 65% of the study population. The investigated dose of baricitinib was 4 mg daily and tofacitinib was 10 mg daily for 14 days or until hospital discharge in patients with estimated glomerular filtration 60 mL/min/1.73 m 2 .

Table 2.Study demographics and rates of nosocomial infection in COVID-19 patients receiving JAK inhibitors.
Reference study Country Study type Study drug No. of patients (Tx/Control) Age (mean ± SD) Gender Common comorbidities Rates of nosocomial infections (Tx vs Control) Concomitant use of systemic steroids Mortality
1 COV-BARRIER Vincent Marconi et al. [74] Asia, Europe, North America, South America Double blinded RCT Baricitinib vs Placebo 764/761 57.8 ( ± 14.3) M: 490 (64%) F: 274 (36%) HTN: 48% Obesity 33% DM: 29% Chronic Respiratory disease 4% 16% Treatment emergent infections in baricitinib vs 16 % placebo Details of infection, Serious infections (9%) vs 10%, Herpes simplex ( < 1%) vs 1%, Tuberculosis ( < 1%) vs 0, Opportunistic infections Candida Infection ( < 1%) vs 1%, Eye infection fundal, Fungal retinitis( < 1%) Herpes Zoster ( < 1%) Listerosis 0, Oropharyngeal candidiasis 0, Pulmonary TB ( < 1%), Systemic candida ( < 1%) 80% vs 78% 8% vs 13%
2 ACCT-2 AC Kalil et al. [72] United States, Singapore, South Korea, Mexico, Japan, Spain, the United Kingdom, and Denmark Double blinded RCT Baricitinib and remdesivir vs placebo and remdesivir 515/518 55 ( ± 15.4) M: 319 (61.9 %) F: 196 (38.1%) Obesity: 295 (58%), HTN: 258 (51%) DM: 200 (40%) 6.6% vs 8.9% Details of infection Septic shock: 4 (0.8%) vs 8 (1.6%) Pneumonia: 12 (2.4%) vs 21 (4.1%) UTI: 5 (1%) vs 2 (0.4%) Bacteraemia: 2 (0.4%) vs 5 (1%) Fungaemia: 1 (0.2%) vs 0 21.2% vs 22% 4.6% vs 7.1%
3 STOP-COVID Guimaraes et al. [73] Brazil Double blinded RCT Tofacitinib 144/145 55 ± 14 M: 94 (65%) F: 50 (35%) HTN: 67 (46.5%) DM: 34 (23.6%) 3.5% vs 4.2% risk ratio 0.83 (95% CI 0.25 to 2.58), Pneumonia: 0.7% vs 1.4% , UTI: 0.7% VS 0% 79.2% vs 77.9% 2.8% vs 5.5%
SD, Standard Deviation; RCT, Randomized Control Trial; DM, Diabetes Mellitus; HTN, Hypertension; M, Male; F, Female; NR, Not Reported.

The reported rates of nosocomial infections among the patients who received JAK inhibitors ranges from 3.5% to 16% [73, 74]. Pneumonia was the most common reported infection in JAK inhibitors group [72, 73]. Viral mediated respiratory epithelial cell damage and defective mucociliary clearance may have a role in the observation of pneumonia being commonly reported as a nosocomial infection regardless of the class of immunomodulators (IL-6 inhibitors or JAK inhibitors). These three trials with high quality evidence, reported similar rates of nosocomial infections between the patients treated with JAK inhibitors and the control group. Pertinent microbiological data including the pathogen and its susceptibility were not reported.

The COV-BARRIER trial showed a 38.2% relative reduction in 28-day all-cause mortality in the baricitinib group among hospitalized COVID-19 patients with 1 elevated inflammatory marker [39]. The ACCT-2 trial demonstrated that baricitinib used in combination with remdesivir accelerates the recovery time in COVID-19 patients especially in adults who were receiving high-flow oxygen or non-invasive ventilation [72]. Based on the above evidence, the NIH expert panel recommends baricitinib can be used in hospitalized COVID-19 patients with rapidly increasing oxygen requirements and systemic inflammation. Tofacitinib can be used in a scenario where baricitinib treatment is unavailable or not feasible [21]. There are no studies directly comparing JAK inhibitors and IL-6 inhibitors, leading to insufficient evidence to recommend either a drug or a class of drug over the other.

In this review, we summarized the nosocomial infections among the COVID-19 patients receiving immunomodulators (IL-6 inhibitors and JAK-2 inhibitors). Our review of the literature revealed many interesting findings. The reported rates of nosocomial infections among the COVID-19 patients treated with immunomodulators were similar to patients receiving standard of care for COVID-19 based on the randomized control trials with high quality of evidence. However, none of these studies were powered to assess the side effect profile of these medications. Phase IV studies to assess the long-term outcomes and population-based data is necessary to comment on the potential risks associated with these agents. Most infections were bacterial with pneumonia being the most common manifestation followed by bloodstream infections. Out of the reported pathogens, staphylococcus aureus was identified as the predominant pathogen responsible (cause) for pneumonia. Nosocomial bacterial infections occurred later during the course of treatment among the patients receiving tocilizumab when compared to the control group, necessitating longer surveillance. Whether this is related to the long half-life of the tocilizumab (11 days) causing prolonged immunomodulation is a question worth asking. As most of the inflammatory response to infection and diagnostic clues (i.e., fever, high C-reactive protein) can be blunted following immunomodulatory treatment, a high index of suspicion with proactive surveillance should be necessitated for these patients. While similar rates of infection were observed between the treated patients and the control, larger randomized control with longer follow up are needed in this field to confirm this finding.

Implementation of strict infection control measures during the COVID-19 pandemic like hand washing, widespread use of personal protective equipment and limiting visitors is important to reduce nosocomial transmission of infection. The evolving evidence suggests that these infection control measures might have contributed to reduction in nosocomial transmission of Clostridium difficile, infections with multidrug resistant organisms and surgical site infections during COVID-19 pandemic [64, 75, 76, 77, 78, 79, 80]. König et al. [81] in their retrospective analysis of multicentric inpatient data from Germany reported that strict hygiene measures during the pandemic might have contributed to decreased rates of in-hospital mortality when compared to pre-pandemic era, after excluding COVID-19 cases.

8. Limitations

Our review provides comprehensive, up-to-date information in a timely manner about nosocomial infections among COVID-19 patients treated with immunomodulators by analyzing studies from different countries across the globe. However, this review also has important limitations. The nosocomial infections were possibly under- or over-represented, as there was a lack of consistent microbiological diagnostic methods. A specific testing method was not reported in half of all the studies. Further, distinguishing bacterial colonization from infection presents a challenge, particularly in the context of critically ill or rapidly progressing COVID-19 infection who may have clinical deterioration for various reasons [82, 83, 84]. With the evolving standard of care for COVID-19 infections, varying proportions of patients received steroids and antibiotics across all the studies which may skew our conclusions.

9. Conclusions

We conclude that the reported rate of nosocomial infections among the COVID-19 patients treated with immunomodulators were similar to patients who received standard of care for COVID-19 based on the 40 studies reviewed. As most of the inflammatory response to infection (i.e., fever, high C-reactive protein) can be blunted following immunomodulatory treatment, a high index of suspicion with proactive surveillance should be the standard of care for these patients. Implementation of strict inflection control measures is necessary to reduce the nosocomial transmission of infections.

Author Contributions

Manuscript draft—CR, GN, AKM, KJJ, AL; Conception of idea—CR, GN, AL; Data Accrual—CR, GN, AKM; Figures and Tables—CR, GN, KJJ; Critical review and revision of manuscript—CR, GN, AKM, KJJ, AL. All authors reviewer and approved the final version of the manuscript.

Ethics Approval and Consent to Participate

Not applicable.

Acknowledgment

Not applicable.

Funding

This research received no external funding.

Conflict of Interest

The authors declare no conflict of interest.

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