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Characteristics of 100 consecutive patients with COVID-19 referred to consultation-liaison psychiatry services in Qatar: A comparison of patients with delirium versus other psychiatric diagnoses

Introduction: Coronavirus disease 2019 (COVID-19) can present with various neuropsychiatric manifestations. This study reports on patients with COVID-19 who were referred to the consultation–liaison (CL) psychiatry services in Qatar and compares the clinical and sociodemographic characteristics of those diagnosed with delirium versus other psychiatric diagnoses. Methods: This is a retrospective review of the first 100 consecutive patients with COVID-19 who were referred to the CL services. Results: Within the total cohort (n=100), most patients (92%) were male, and the mean age was 46 years. About 27% of patients had asymptomatic COVID-19, 35% had a past psychiatric history, and 48% reported pandemic related psychosocial stress. Delirium was the most common psychiatric diagnosis (n=29), followed by acute stress reaction/adjustment disorder, depression, mania, anxiety, non-affective psychosis, and dementia. Among patients with delirium, agitation was the most common symptom (76%), 86% were treated with psychotropic medications, and 17% died. Higher age, longer hospital stays, lower oxygen saturation, lower lymphocytic count, and higher C-reactive protein (CRP) values were significantly associated with delirium versus other psychiatric diagnoses. Higher age and lower oxygen saturations predicted delirium.Conclusion: Delirium was associated with a range of clinical variables and had significant mortality, despite the relatively young age of the patients. COVID-19 should be considered in patients presenting with delirium. Finally, early identification and management of delirium should be integral to COVID-19 protocols.


INTRODUCTION
Patients with Coronavirus disease 2019 (COVID- 19) can present with a range of neuropsychiatric disorders, including delirium 1 -6 . Delirium in COVID-19 can reflect multiple factors, including inflammation, endothelial damage, increased oxidative stress, hypoxemia, iatrogenic factors, and potentially direct infection of the central nervous system by SARS-CoV-2 7,8 . In fact, delirium has been reported as the presenting and only feature of COVID-19 7,9 . A recent systematic review and meta-analysis of delirium in COVID-19 patients identified its prevalence and incidence rates as 24.3% and 32.4%, respectively 10 . Other studies have also demonstrated that delirium associated with COVID-19 is more prevalent in the elderly, who are also more prone to developing severe COVID-19 11 . Delirium in COVID-19 patients has been associated with in-hospital death, increased length of hospital stay, intensive care admission, and ventilator utilization; it has also been reported to be a predictive factor of inhospital death and adverse outcomes in hospitals 12 . In this study, we conducted a retrospective review of the electronic patient records for the first 100 consecutive patients with COVID-19 referred to the consultation -liaison (CL) psychiatry service in Doha after Qatar recorded its first COVID-19 case (February 2020) 13 . The aim was to better understand the psychiatric morbidity associated with acute COVID-19 among patients referred to a CL service.

METHODOLOGY
We have previously reported on the first 50 patients seen in this cohort 14 . In the current report, we describe the full cohort of 100 patients and compare the characteristics of those diagnosed with delirium versus other psychiatric diagnoses. During the pandemic, the Qatar CL service operated across three hospitals in Doha managed by the Hamad Medical Corporation (HMC). The inclusion criteria for the study were individuals aged 18 years and over and a positive real-time polymerase chain reaction test for Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) during the index admission. The 100 cases presented between February 28 th and August 3 rd , 2020. Psychiatric diagnoses were those recorded by the CL team in the patient records and reflected the team's clinical judgment. The study was approved by the HMC Institutional Review Board (MRC-05-072). Table 1 shows the characteristics of the 100 patients. Most (92%) were male, mean age was 46 years, 27% had asymptomatic COVID-19 (i.e., no characteristic physical symptoms of COVID- 19), and 35% had a past psychiatric history. Significant recent psychosocial stress, which is largely related to the pandemic, was recorded in the notes of 48 patients. A psychiatric diagnosis was made by the CL team in all but one case. Delirium was the most common psychiatric diagnosis (n ¼ 29), followed by acute stress reaction or adjustment disorder (n ¼ 25), depression (n ¼ 16), mania (n ¼ 15), anxiety (n ¼ 14), non-affective psychosis (n ¼ 13), and dementia (n ¼ 6). Nearly half of the delirium cases (n ¼ 12/29) had a medical comorbidity (i.e., a current medical condition other than COVID-19). Moreover, sleep disturbance was the most common psychiatric symptom (n ¼ 65, 65%), followed by anxiety (n ¼ 52, 52%) among all 100 patients. Recent selfharm thoughts or attempts were present in 24 (24%) of all patients with COVID-19 referred to the CL team. The most common psychiatric symptoms in the delirium cohort were agitation (n 22, 76%), impaired memory (n ¼ 19, 66%), disorientation (n ¼ 18, 62%), sleep-wake disturbance (n ¼ 11, 38%), and confusion (n ¼ 11, 38%). Recent self-harm thoughts or attempts were present in 2 patients in the delirium cohort. Psychotropic medications were prescribed to 25 out of the 29 (86%) patients with delirium during their admission. The most common medications were haloperidol (n ¼ 17), benzodiazepines (n ¼ 10), and quetiapine (n ¼ 9), and low doses were used in all cases. All patients with delirium were offered nonpharmacological management strategies including advice to the general medical team to assist with orientation, reassurance, and effective communication. A univariate comparison of the characteristics of patients with and without delirium showed older age, a prolonged hospital stay, lower oxygen saturation, higher C-reactive protein (CRP) value, lower lymphocyte count, and a range of treatment variables (use of steroids, antivirals/antibiotics and chloroquine/hydroxychloroquine) as factors that were significantly associated with a diagnosis of delirium (Table 2). Binary logistic regression using a stepwise method, which was employed to control for significant variables in the univariate analysis, revealed higher age and lower oxygen saturations that had statistically significant links with a delirium diagnosis (Table 3).

DISCUSSION
Our data revealed that delirium was the most common psychiatric diagnosis seen by the CL team in COVID-19 patients in the early months of the pandemic. Our cohort of patients with delirium is younger than that reported in other studies of delirium related to COVID-19 11,15,16 . This is consistent with Qatar's relatively young population (median age of 33.7 years) 17 .The most prevalent symptoms of delirium in our case series included sleep -wake disturbances and agitation. Hyperactive delirium has been reported to be more common in younger adults with COVID-19, whereas the hypoactive form appears more common in elderly patients 18 . Furthermore, patients with hyperactive delirium may be more likely to be referred to psychiatric services than those with hypoactive delirium. In our study, over a quarter of COVID-19 patients who were referred to the CL team were physically asymptomatic (i.e., they had no characteristic physical symptoms of COVID-19). These included patients who were transferred from quarantine centers, from psychiatric hospitals, or were admitted following screenings at emergency departments where they first presented with psychiatric symptoms. Nearly one quarter of the patients in the full cohort of 100 patients reported self-harm thoughts or attempts. The diverse psychiatric symptoms seen in the full cohort could reflect the effects of psychosocial stressors, such as quarantine, social distancing, and financial difficulties, the physical effects of SARS-coV2 including potential direct neurotoxic effects and iatrogenic factors 19 .
Our finding of an association between delirium and raised CRP level suggests that inflammation may be involved in the pathophysiology of COVID-19associated delirium. Furthermore, raised CRP level has also been found to be independently associated with acute renal failure in COVID-19 patients 20 . Higher age and lowest oxygen saturation were significantly associated with delirium, as previously reported 11,21 .
In the non-delirium group, patients presented with a range of psychiatric diagnoses, including acute stress reaction/adjustment disorder, depression, anxiety disorders, non-affective psychosis, and first onset mania. Sleep disturbance was the most common psychiatric symptom among all patients with COVID-19 referred to the CL service, and other studies have also highlighted its high prevalence 22 . This underscores the importance of recognition and the management of sleep disturbances in clinical practice. Furthermore, nearly two-thirds of patients in the non-delirium group had no past psychiatric history, thus supporting the view that COVID-19 was likely to be a significant etiological factor in the appearance of these disorders.
The first limitation of this study is that it only assessed patients referred to the HMC CL services. There are likely to be COVID-19 patients who had delirium, especially during intensive care unit (ICU) admissions, who were not referred to CL services because their psychiatric symptoms may not have posed significant management issues. Second, this was an observational study that utilized secondary data. Thus, it is dependent on the quality of the information recorded in the notes. An important finding from our study is that delirium can occur in relatively young and otherwise healthy patients with COVID-19. Moreover, delirium is not invariably associated with severe COVID-19 illness but can present in people who are physically asymptomatic or have mild physical symptoms of COVID-19. Therefore, it is important to consider a diagnosis of COVID-19 in patients presenting with delirium. In our results, we recorded a 17% (n ¼ 5/29) mortality in the delirium cohort despite the relatively young mean age of these patients (59.4 years).
Characteristics of 100 consecutive patients with COVID-19 referred to consultationliaison psychiatry services in Qatar Iqbal et al.

CONCLUSION
Delirium was the most common psychiatric disorder seen in patients with acute COVID-19 who were referred to CL services in Qatar-a country with a young, predominantly migrant population. Furthermore, the data showed that delirium was not invariably associated with severe COVID-19 illness but can also present in people with COVID-19 who were physically asymptomatic or had mild physical symptoms of COVID-19. In our population, delirium was associated with a range of variables, including hypoxia, older age, elevated CRP, and a prolonged hospital length of stay compared to patients with other psychiatric diagnoses. In addition, delirium was associated with significant mortality (17%). This is consistent with the findings of other studies, which show that delirium is associated with poor outcomes, including mortality, in COVID-19 patients 23 Table 3. Binary logistic regression using a stepwise method to look for independent factors associated with delirium (variables that were significant in the univariate analysis were entered into the analysis). Only significant predictors are shown in the Characteristics of 100 consecutive patients with COVID-19 referred to consultationliaison psychiatry services in Qatar Iqbal et al.