In this study, the majority of cases were male, and the most predisposing factor was cardiovascular diseases. Weakness, myalgia, and fever were the most clinical presentation symptoms in each episode. Pneumonia was detected in nearly half of the patients in both episodes.
Except for significantly more dexamethasone consumption in the second episode; the clinical and laboratory characteristics were not significantly different between the two ones. Growing evidence in favor of dexamethasone usage could explain this finding. Severe disease was only observed in less than one-third of all episodes.
Ye et al. reported similar clinical characteristics in the patients with a second episode of COVID-19. Fatigue, fever, and cough were the most reported symptoms respectively, and none of them had dyspnea or severe pneumonia. In contrast, all elderly re-admitted COVID-19 patients, reported by Lafaie et al. died. They also remained asymptomatic between two episodes [3, 4]. Li et al. reported chest pain and cough as re-presenting symptoms, whereas fever and hypoxia reported in another patient who re-admitted because of COVID 19. Both of them survived although the latter referred to an inpatient rehabilitation facility [5, 6]. At least four case series reported lymphopenia and elevated concentrations of CRP in most re-admitted patients in [3, 4, 7, 8]. However, in line with our series, Wang and Li reported normal lymphocyte count and CRP level in majority of re-admitted patients [9, 10].
Among potential host risk factors for the second episode (gender, older age, and taking immunosuppressive agents) mentioned by Ye et al., our patients was mainly male and had cardiovascular diseases. Since six of 16 (38%) patients reported in the previous series [3, 7] and all older patients noted by Lafaie received corticosteroids in the first episode, older age and interleukins suppression mediated by steroids may play a significant role [3, 4]. However, our patients were relatively younger.
The mean 117 days between two episodes in our study is apparently longer than 4 to 17 days reported in previous studies [11, 10]. However, Lafaie et al., reported this period more than 30 days for a dead old patient [4].
Considering chest CT features of re-admitted patients, in contrast to our series, Li et al. showed a changing pattern from reticulation to Ground-glass opacity (GGO) indicating active infection, which occurred in 40% of patients [10]. However, most re-hospitalized patients in the Zheng series had improved CT abnormalities [12].
Several scenarios have been proposed to explain this phenomenon included persistent infection, reinfection, relapse or reactivation, and inflammatory rebound.
Persistent infection
The prolonged clinical course of COVID-19 disease for more than 2 months has been documented [13]. In addition, continuous viral shedding irrespective of clinical symptoms reported as long as 83 days by Li et al. [14]. The average range of viral shedding marked by positive RT-PCR was noted 20 to 22 days after symptoms onset [6]. On the other hand, the false-negative rate of RT‐PCR results was 12.5% in one study [15]. It could be due to low viral loads, collecting specimens by different methods, and laboratory errors [10]. Therefore, prolonged viral clearance or persistent infection rather “turning positive again” or “reoccurring” have been proposed [16]. Moreover, Wang et al., supported transmission of the whole or traces of the virus from the lower respiratory tract to the throat or nose as their patients had only slight coughs [9]. However, our patients as well as Ye, Lafaie, and Gousseff series remained asymptomatic between two episodes and presented again with notable symptoms such as fever and hypoxia, making this scenario in doubt [3, 4, 7]. Besides, re-emergence of GGOs in at least 40% re-admitted patients in Li et al. series provides another clue versus persistent infection [10]. Finally, culture the virus in the second episode and showing the cytopathic effect of SARS-CoV-2 as Gousseff et al. done for two patients [7], demonstrated the true; however, we could not perform it. Moreover, the RT-PCR cycle threshold (Ct) value below 24 may correlate to viable SARS-CoV-2, which was not available in our RT-PCR results [17].
Reinfection
As a rule, circulating antibodies, memory B cells, and memory T cells are three essential parts of the immune system to prevent viral reinfection. The presence of SARS-CoV-2-specific T cells documented in COVID-19, could quarantine the immunity of recovered patients even in the absence of specific antibodies; however, potential anamnestic B cell and T cell responses remains obscure [18].
Since no recurrent disease was observed after re-challenging the monkeys with the same strain of SARS-CoV-2, Duggan et al., concluded that different strains could responsible for reinfection [6]. Unfortunately, we could not perform the phylogenic sequencing in the returning patients to evaluate this conclusion.
Since four HCW of the Gousseff series had mild symptoms in both episodes along with persistent exposure could be expected, they suggested reinfection might occur [7]. In contrast, in view of the Ravioli et al., series, reinfection was less likely given the fact that the prevalence of COVID-19 was low in that region [8]. Most recently, To et al. documented reinfection in an immunocompetent patient by phylogenetic analysis of the virus in the two episodes, challenging herd immunity or even vaccination [19].
Relapse or reactivation
While a shorter duration between two episodes was in favor of reactivation [4], the mean time in our cases was more than 110 days. Suboptimal control of the SARS-CoV-2 infection or presence of sanctuaries was purposed as causes of relapse in these patients [7]. Host underlying conditions, SARS-CoV-2 viral load, and immunosuppression state in the first episode might predispose the patient to reactivation [3]. It seems old patients in Lafaie et al., series had a reactivation episode given the re-exposure was less likely and relatively short duration between two episodes; also, two patients had negative serology at re-admission [4]. Seven older patients with comorbidities with a median of 11 symptom-free days reported by Gousseff et al., appear to have a similar scenario [7].
In line with the Gousseff series, our patients had mainly mild disease and were healthcare personnel. In addition, the prevalence of COVID-19 was high in the period of study and the mean duration between two episodes was nearly four months. Therefore, reinfection is probably the best scenario to justify our case series.
An inflammatory rebound
Dysregulated immune reaction might be responsible for clinical deterioration, but the virus cultured successfully in re-admitted patients of pervious series making this hypothesis less likely [7]. All of our patients also had positive RT-PCR for SARS-CoV-2 in the second episode.
Another diagnosis:
Recurrence of clinical symptoms could be due to other bacteria and viruses causing pneumonia, or secondary complications such as pulmonary embolism; however, nearly all differential diagnosis of the COVID 19 infection in our and Lafaie et al., series had been ruled out [4].