Secondary Infection Risk in Patients With Severe COVID-19 Pneumonia Treated With Tocilizumab

Abstract

Background: 

Severe SARS-CoV-2 (COVID) pneumonia is characterized by marked inflammation. Current guidelines recommend the addition of the tocilizumab to dexamethasone in critically ill patients. In randomized trials, the use of tocilizumab was not associated with a statistically significant increased risk of secondary infections but concerns remain.

Study Question: 

Do patients with severe COVID pneumonia treated with tocilizumab experienced high rates of secondary infection.

Study Design: 

We performed a retrospective electronic chart review of patients with COVID pneumonia who received tocilizumab and dexamethasone (n = 62) from January 2021 to October 2021 and compared them with a cohort of patients (n = 49) who received only dexamethasone and admitted from July 2020 to December 2020 (before institutional use of tocilizumab). Patients received tocilizumab only if they had acute hypoxic respiratory failure and were felt to be clinically worsening. Patients were deemed to have a secondary infection only if a diagnosis of infection was confirmed via positive cultures.

Results: 

Sixty-six patients received tocilizumab; of which, 30 (45.5%) subsequently had culture-positive secondary infections compared with 24.5% of controls. Thirty-one patients (47.0%) who received tocilizumab died by the time of analysis, 14 (45.2%) of whom had a secondary infection. Gram-negative bacterial infections predominated, followed by fungal infections. Patients who received tocilizumab had over twice as many gram-negative pneumonias (30.3% vs. 14.3%).

Conclusions: 

Patients with severe COVID pneumonia treated with tocilizumab experienced high rates of secondary infection. Although the benefit of tocilizumab in reducing mortality is well-established and almost certainly outweighs secondary infection risks, we question if the “real-world” infection rates are much higher than those reported in trials or if the infection risk could be mitigated with dose reductions in tocilizumab without losing the mortality benefit. Further study into the infection risk, and risk–benefit analysis of dose adjustments, of tocilizumab in the critical care setting is warranted.

INTRODUCTION

Severe SARS-CoV-2 (COVID) pneumonia is characterized by marked inflammation and immune dysregulation. Current guidelines recommend the addition of the interleukin-6 inhibitor tocilizumab to dexamethasone in recently hospitalized, critically ill patients based on several large, published, randomized trials.^1,2 In these studies, the use of tocilizumab was not associated with a statistically significant increased risk of secondary infections³ but concerns of infection risk remain.⁴ Our goal was to assess the rate of secondary infection in patients with severe COVID pneumonia receiving tocilizumab in the real-world setting.

METHODS

We performed a retrospective electronic chart review of all patients with COVID pneumonia and who received tocilizumab (and dexamethasone) from January 2021 to October 2021. We compared them with a cohort of patients admitted in the preceding 6 months (July 2020 to December 2020) before institutional use of tocilizumab. All patients in the control group received dexamethasone as well. Our institution is a nonprofit, community-based hospital with 18 medical intensive care unit (ICU) beds. Patients were admitted to the ICU during the study period if they exceeded floor oxygen settings of nasal cannula oxygen combined with a nonrebreather mask, required organ support, or had other monitoring needs. Patients were determined to have COVID pneumonia if they had SARS-CoV-2 infection confirmed by nasal polymerase chain reaction, along with bilateral infiltrates on computed tomography or x-ray imaging. Patients received tocilizumab only if they had acute hypoxic respiratory failure requiring at least 15 L of nasal cannula oxygen and were felt to be clinically worsening. Patients with clinical suspicion for bacterial infection did not receive tocilizumab, as well as patients who had been intubated for greater than 24 hours. All patients that received tocilizumab received 8 mg/kg intravenously in addition to at least 6 mg of dexamethasone for at least 10 days.

Baseline data, including age, sex, and comorbidities, were collected. Patients were deemed to have a secondary infection only if a diagnosis of infection was confirmed via positive cultures (obtained after receiving tocilizumab). Secondary bacterial pneumonias were defined as clinical suspicion for pneumonia (ie, new fever, purulent tracheal secretions, new infiltrates, or worsening oxygenation) accompanied by positive cultures from tracheal aspirates or bronchoalveolar lavage. Bacteremias and fungemias were defined as positive blood cultures in patients with new signs and symptoms of sepsis, including new fevers, worsening shock, or organ dysfunction. Study outcomes were statistically analyzed using χ² testing and expressed as P values. The study was approved by our hospital's institutional review board.

RESULTS

Over the study period, 66 patients received tocilizumab for severe COVID pneumonia and were compared with 49 controls. Most patients in both groups were male (62.1% vs. 61.2%) and of similar age (Toci group mean age 68.2 ± 15.5 years; control group mean age 63.9 ± 14.4 years; P = 0.13). Requirement of mechanical ventilation or extracorporal membrane oxygenation and incidence of death were similar (Table 1).

Table 1. - Outcomes of tocilizumab and control groups.

	Tocilizumab group (n = 66)	Control group (n = 49)	P
Mechanical ventilation (%)	51 (77.3)	34 (69.4)	0.34
Extracorporal membrane oxygenation (%)	6 (9.1)	1 (2.0)	0.12
Secondary infection (%)	30 (45.5)	12 (24.5)	0.02
Death (%)	31 (47.0)	25 (51.0)	0.67

Thirty patients in the tocilizumab group (45.5%) had culture-positive secondary infections, compared with 24.5% of patients in the control group [odds ratio 2.6, 95% confidence interval 1.1–5.8]. Mortality was similar between the 2 groups (Table 1). Gram-negative infections predominated, followed by fungus (Table 2). Patients who received tocilizumab had over twice as many gram-negative pneumonias (30.3% vs. 14.3%), with higher rates of organisms such as Serratia, Enterobacter, and Stenotrophomonas, which were not seen in the control group.

Table 2. - Incidence of Secondary infections in tocilizumab and control groups.

	Tocilizumab group (n = 66)	Control group (n = 49)
Gram-positive pneumonia	4 (6.1%) Staphylococcus aureus (4)	4 (8.2%) S. aureus (4)
Gram-negative pneumonia	20 (30.3%) Stenotrophomonas (4) Serratia (4) Pseudomonas (3) Enterobacter (3) Klebsiella (2) Escherichia coli (2) Haemophilus influenzae (2)	7 (14.3%) Pseudomonas (4) Escherichia coli (2) Acinetobacter (1)
Fungal pneumonia	5 (7.6%) Candida (4) Aspergillus (1)	2 (4.1%) Candida (2)
Gram-positive bacteremia	4 (6.1%) S. aureus (2) Enterococcus (1) Streptococcus pneumoniae (1)	2 (4.1%) Staphylococcus epidermidis (1) Micrococcus (1)
Gram-negative bacteremia	5 (7.6%) Enterobacter (3) Pseudomonas (2)	1 (2.0%) Pseudomonas (1)
Fungemia	2 (3.0%) Candida (2)	0 (0%)

Of the 30 patients in the tocilizumab group, 9 patients had polymicrobial infections (S. aureus PNA + Escherichia coli PNA; Strep pneumoniae bacteremia + Stenotrophomonas PNA; S. aureus PNA + bacteremia; Klebsiella PNA + Escherichia coli PNA + Candida PNA; Pseudomonas PNA + Stenotrophomonas PNA; Stenotrophomonas PNA + Candida PNA; Klebsiella PNA + Enterococcus bacteremia; Pseudomonas bacteremia + Candida Fungemia; S. aureus and Candida PNA). Of the 12 patients in the control group, 3 patients had polymicrobial infections (Pseudomonas PNA and bacteremia; Escherichia coli + Pseudomonas PNA + Staphylococcus epidermidis bacteremia; Pseudomonas PNA + Escherichia coli PNA).

PNA, pneumonia.

DISCUSSION

Secondary infections in critically ill patients are associated with increased morbidity and mortality. Such infections present diagnostic and management challenges in the intensive care setting, especially before culture data are available. This difficulty is compounded by the signs and symptoms that may be attributed to severe viral infection itself. Clinical suspicion and laboratory analysis can be misleading because inflammatory markers may be elevated as part of the systemic inflammatory response syndrome, and elevated procalcitonin has been associated with severe COVID pneumonia alone.⁵ Conversely, traditional inflammatory markers can remain low due to immunosuppression even in the presence of infection.⁶

Initial reports suggested that secondary infection rates were not dramatically elevated in patients with COVID pneumonia.⁷ However, treatment has evolved to include escalating levels of immune suppression, including the interleukin-6 inhibitor tocilizumab, which has been historically associated with an increased risk of severe infection and has a “black box” warning for the same.⁸ Meta-analyses of high-quality trials have reported the secondary infection rate as 21.9% at 28 days,³ which was similar to that seen in our control group before tocilizumab use. However, following the widespread use of tocilizumab, our institution experienced much higher rates of secondary infections—at least 45.5%—not including culture-negative infections. Furthermore, although postviral pneumonias are typically due to gram-positive bacteria,⁹ we identified high rates of secondary infections due to gram-negative bacteria and fungal infections, possibly related to the intense immunosuppression. Others have raised similar concerns.⁴ A meta-analysis by Peng et al identified an increased risk of fungal infections (odds ratio, 2.02),¹⁰ and a large retrospective study is underway to further describe infection risks associated with tocilizumab (https://clinicaltrials.gov/ct2/show/NCT05017441).

There are several possible explanations for our findings. It may be that our institution is a significant outlier, we are overreporting infection rates through our retrospective review or that survivor bias has resulted in more opportunity for critically ill patients to acquire secondary infections. Indeed, our patients seem to be more critically ill than those in major trials, with over double the requirement for invasive mechanical ventilation (73.9% vs. 31%).³ Additionally, all our patients received corticosteroids, whereas only 35% of patients did in large trials.³ These factors may be predisposing such patients to increased infection risk and morbidity. Our study may also be limited because we were only able to use a historical cohort before widespread tocilizumab use and therefore confounded by the rapidly evolving changes in the population admitted to our ICU (changes in outpatient and inpatient therapies offered).

CONCLUSION

Patients with severe COVID pneumonia treated with tocilizumab experienced high rates of secondary infection, with notably different microbiology, including higher rates of gram-negative infections. Although the benefit of tocilizumab in reducing mortality is well-established and almost certainly outweighs secondary infection risks, we question if the “real-world” infection rates are much higher than those reported in trials, or if the infection risk could be mitigated with dose reductions in tocilizumab¹¹ without losing the mortality benefit. Further study into the infection risk, and risk–benefit analysis of dose adjustments, of tocilizumab in the critical care setting is warranted.