Background: Post-COVID-19 patients might be at higher risk of developing long-term depression.

Objectives: to determine risk factors associated with depression among COVID-19 long-haulers.

Methodology: This is a retrospective cohort study of 510 PCR-confirmed COVID-19 subjects. Integrative Classification for Defining Post-COVID-19 Symptoms was used in this study to define post COVID-19 syndrome. Depression severity was assessed for all patients during the long-term period of symptoms using PHQ-9 scale. Factors associated with depression were analyzed for all patients using SPSS V22. 

Results: This retrospective cohort study involved 510 PCR-confirmed COVID-19 patients. They were 73 % females. Average age of participants was 27.2±11.38 years old. Almost 92.5 % of subjects suffered from long-term COVID-19 symptoms. A hundred- fifteen patients (22.5 %) suffered from depression. There was a significant relationship between number of symptoms, gender, and depression at p value < 0.001 for each factor. There was a significant relationship between first symptom(s) patient suffered from, type of respiratory symptoms, both ageusia and anosmia, and depression, at p value < 0.001, for each factor. The odds of depression in females were 3 times more than males, p=0.012 and 1.15 in patients with increased number of symptoms, p=0.036. The odds of depression for patients with ageusia and anosmia, or who had a cluster of symptoms were 25 and 32, p=0.041, and 0.025, respectively. In contrast, headache and dizziness, anosmia alone, or GIT symptoms as first symptom (s), decreases risk of developing depression markedly, p=0.027, 0.033, and 0.014, respectively.

Conclusions: Depression among post-COVID-19 patients was associated with female gender, number of symptoms suffered during the acute phase, ageusia and anosmia, and cluster of symptoms. 

We have enough experience and long time in the pandemic to start studying the long-term effects of infection with coronavirus, SARS-CoV-2. Coronaviruses are crown shape peplomers, positive-sense single-strand ssRNA viruses, from the family of coronaviridae, which comes in different genotypic forms and can affect different body organs leading to mild to severe infections [1-3]. 

The coronavirus disease 2019 (COVID-19) is an ongoing viral pandemic that emerged from East Asia and quickly spread to the rest of the world [4]. The pathogen has been identified as a novel enveloped RNA β-coronavirus 2 and the genome size is one of the largest among RNA viruses, that has currently been named severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which has a phylogenetic similarity to SARS-CoV [5, 6]. COVID-19 spreads to a healthy person in the same way as other coronaviruses do, mainly through person-to-person contact, specifically through a droplet and splash from an infected person's mouth or nose. Human-to-human transmission is characterized by a troubling exponential rate, which has led to steep curves of onset in many areas [7].

Recent reports documented that most patients complained of impairment of both olfactory and gustatory perception, which was considered as early markers of COVID-19 infection [8]. COVID-19 is primarily a disease of the respiratory system, but in a number of patients also penetrates the CNS, and apparently could be responsible for fatal outcome in some cases. The entry of the virus into the brain can lead to neurological and psychiatric manifestations [9]. At the same time, the pandemic broadly imposes a high degree of psychosocial stress, a strong predictor of mental health disorders, on the general population. Similar coronaviruses, such as severe acute respiratory syndrome coronavirus 1 (SARS-CoV-1) and Middle East respiratory syndrome coronavirus (MERS-CoV) were recently associated with psychiatric and neurological disorders, with a prevalence of 0.09% for SARS-CoV-1 and 0.36% for MERS-CoV [10].

Female patients have a higher probability to develop a mild to moderate form of infection, as 90.7% of female patients had a mild to moderate form. Males are more likely to have the severe form, as 13.7% of male patients. Regarding the relationship between the infection likelihood and age, the same study showed that 95.6% of the patients were 18 to 65-year-old, which reflects a low infection rate among age extremities. However, when it comes to the disease severity, older patients aged 50-year-old and above counted for 81.3% of all severe cases while patients below 40 years of age are mostly predisposed to develop a moderate form of COVID-19[11].

Two meta-analysis studies showed that males have a higher risk of developing a severe infection and a higher mortality rate than females [12, 13].

Granted that no long-term data of substantial numbers of patients with various presenting symptoms exist and with comparison groups, and that it is still early in the COVID-19 pandemic, it is possible that large numbers of patients will experience long-term sequelae [14].

COVID-19 mainly in severe cases in addition to lungs involves different organs such as heart, liver, and kidney, as well as hematological and nervous system, and induces multi-organ failure. SARS-COV2 may directly invade the host cells of different organs through the ACE2 receptor due to the presence of this receptor in these organs [15]. Some follow-up studies for the patients rehabilitating from SARS indicated that impaired lung function could last for months or even years [16].

In this study, we try to find the relationship between different symptoms of COVID-19 and one of the most important long-term consequences of the infection, depression. Who are the patients with higher odds of developing long-term depression?

This is a retrospective cohort study of 550 COVID-19 patients in Palestine. Out of that, 510 subjects matched our inclusion criteria and were included in the study. Patients had a first positive reverse transcription–polymerase chain reaction (RT-PCR) test for SARS-CoV-2 in West Bank. We designed a google form questionnaire and posted on line from February 17 to March 20, 2021. The questionnaire consisted of 40 questions in two parts; part I: socio-demographic and clinical data, part II: include questions correlate COVID-19 to health status of patient. In addition to that, we used The Patient Health Questionnaire (PHQ-9) which is a 9-question instrument was used to determine the severity of depression for each patient. Integrative Classification for Defining Post-COVID Symptoms was used in this study to define post COVID-19 syndrome (long haulers, Long COVID). We adopted the definition for COVID-19 symptoms as follows: transition phase (1- 4 weeks), phase 1(4th -12th week), phase two (12th -40th week), & phase three (˃ 40 week). Symptoms lasted more than 14 days were considered persisting symptoms. We divided patients into three groups according to period of lasting symtoms: 14-28 days (46%), 29-90 days (42%), & 91-284 days (12%). Unfortunately, not all patients who had long-term symptoms knew for how long they had it. As such, we included in analysis all patients with persisting symptoms after the usual recovery period of 14 days, i.e., 471 patients.

Depression severity was assessed for all patients during the long-term period of symptoms using PHQ-9 scale.

Statistical analysis: We used SPSS version 22 for data analysis and logistic regression models. Fisher exact test and Chi square test were used to find relationships between symptoms of COVID-19 and different levels of depression among patients.

This retrospective cohort study involved 510 subjects, 73

Scientists used many terms to describe it; PASC, post-acute consequences of SARS-CoV2, long COVID or post-COVID syndrome, but all describe what some patients might suffer from after recovering from the acute phase of COVID-19. It was found that most people who have coronavirus disease 2019 (COVID-19) recovered completely within a few weeks. On the other hand, a significant number of COVID-19 patients continue to have symptoms related to COVID-19 after the acute phase of illness [17].  These long term symptoms include; fatigue, shortness of breath, joint pain, chest pain, memory disturbances, sleep problems, muscle pain, loss of smell and/or taste, fever, headache, depression or anxiety [18].

In our study, we found that 92.5 % (471) of patients have symptoms after recovery from COVID-19 infection. Our result comes along with other studies that found anywhere from 87.4 % to 96 % of patients suffered from at least one long-lasting COVID-19 symptom [19-23]. 

A thorough look at table 1 and 2 showed that, 148 patients out of 170 patients who suffered from shortness of breath, suffered from different levels of depression, and 114 of the 148 have moderate to severe depression. Breathing problem is a life-threatening symptom that has long-lasting consequences on patients, so it might leave the patient with a very bad medical experience.   There is longstanding evidence that human coronaviruses, such as SARS-CoV-2, can spread to the brain from the respiratory tract. 

On the other hand, 114 patients out of 128 patients who had muscle weakness as first symptom, suffered of different levels of depression. Free mobility, on contrary to bed-ridden state, affects patient`s ability to move, get food, and do other basic needs for life. Free mobility, on contrary to bed-ridden state of a patient, affects his/her ability to move, get food, and do other basic needs for life. This is taken by the human brain as a life-threatening situation in which human feels and reacts as helpless and hopeless case.

Subjects in our study are mostly young people, so they didn`t suffer of fulminant fatigue rather muscle weakness where 128 patients suffered from any kind of muscle weakness and 50 patients suffered from joint pain. These results came in harmony with a study that predicted fatigue as a natural part of the reaction of the body to the fight against a viral infection like COVID-19. It is possible that weakness will persist for some time after the infection has cleared up. For this to happen, the symptoms would have to have lasted over a period of at least 6 months [25]. The same study concluded that even if patients recover physically they could be at particular risk of suffering from long-term mental health problems or perceive a reduced quality of life. This is valid in our study where 22.5% (115 patients) suffered of different degrees of depression for long-time after recovery. 

SARS-CoV-2 virus is a neurotropic virus that stays dormant in nerve endings and /or ganglionic and nerve roots for unpredictable periods. We harbor chicken box virus, varicella zoster virus, and herpes simplex virus for example in our bodies since we were kids. Infection with these viruses can cause encephalitis or brain-targeted autoimmune responses in susceptible individuals, in the short-term. In animal models, it leads to behavioral and cognitive function impairment at the long-term [8]. SARS-CoV-1, Middle East respiratory syndrome coronavirus [MERS], and influenza have involved neuropsychiatric sequelae that could linger for months in “recovered” patients [14].  However, we can`t ignore the importance of other theories in explaining neurologic symptoms of COVID-19 including depression. One of these theories is the microbiota-gut brain axis theory that indicated the importance of tryptophan availability and loss of its synthesis due to death of microbiota or hijacking the ACE2 receptors in the gut by the virus that prevents its absorption, which leads to serotonin deficiency and depression. 

On the other hand, anxiety and depression were reported in a Spanish study (28.5% of women and 16.7% of men) and in another study in Hong Kong (39.5 %), [27, 28]. In our study prevalence rate of depression was 22.5 %. Our results match the results of the Spanish study that found a higher proportion of anxiety and depression levels in the younger population (18–35 years), especially in women. Our sample is 73

Ethics approval and consent to participate: the IRB board at Hebron University approved this research. An on-line consent form was assigned for all forms where the form will open only after the participant agree to conditions of the study and his rights (voluntarily participate in this study with the right to withdraw at any time or at any stage of the study). We guaranteed information confidentiality.

Consent for publication: not applicable

Competing interest: we declare no competing interest for this work.

Funding: we did not receive any fund for this research.

Availability of data and materials: The datasets during and/or analyzed during the current study available from the corresponding author on reasonable request.

Author’s contributions: MS: project idea and design, field supervision, monitoring progress and time schedule, writing the manuscript, MJ: idea, data analysis. Other 4 co-authors: literature-review, data collection, field work, Google form preparation, participated in data analysis.