As an increasing number of patients recover from COVID‐19, clinicians are increasingly caring for patients who fail to recover fully, even after microbiological resolution. Fatigue is often a significant complaint in these patients, often labeled as “post‐COVID” fatigue.^{1, 2} We studied patients with mild COVID‐19 with persistent fatigue to identify possible modifiable risk factors.

Patients who were diagnosed with mild COVID‐19 at least 30 days before presentation to our outpatient department (OPD) were asked the question: “Do you feel that you have returned to your usual state of health prior to the onset of COVID symptoms?” They were included if they endorsed fatigue as a prominent symptom, and their demographic, clinical, and disease course data were recorded. Blood investigations obtained during standard care included hemogram, liver and renal function tests, blood glucose, thyroid profile, and 25 hydroxy vitamin D levels. The treatment advised by the physician was noted, and patients followed up at least 60 days after onset of COVID‐19 symptoms.³ We also searched MEDLINE for the terms “COVID” AND (“post” OR “sequelae” OR “long” OR “symptoms AND recovery”) on September 30, 2020 to retrieve prevalence estimates of post‐COVID sequelae in various settings. Microsoft Excel was used to tabulate the data. Pooled prevalence estimates were measured using OpenMeta.

In the study period, 19 patients presented to our OPD with persistent symptoms of fatigue after suffering from mild COVID‐19 (median age 37 years [Q1–Q3, 30.5–41], M:F 10:9; Table S1). During the initial illness, most patients were symptomatic with fatigue, sore throat, fever, and cough. They were interviewed at a median of 47 days (Q1–Q3, 42.5–58) after the onset of COVID‐19 symptoms. Besides fatigue, patients also reported postexertional malaise, impairment in daily functioning, cognitive impairment, and disturbed sleep (Table S2). In 14 of 19 (74%) patients, laboratory investigations revealed a biochemical or hematological abnormality known to cause fatigue (Table 1). A single contributing factor was found in 11 patients, with vitamin D deficiency (n = 7), anemia (n = 2), hypothyroidism (n = 1), and polycythemia (n = 1). Three of these patients had two potential contributing factors for fatigue: one patient each with anemia plus vitamin D deficiency, anemia plus hypothyroidism, and polycythemia plus vitamin D deficiency. Three out of four patients with anemia had iron deficiency, and one patient had dimorphic anemia with iron and vitamin B12 deficiency. A second follow‐up after a median of 103 days (Q1–Q3, 93.7–107 days) after the onset of symptoms showed complete recovery from fatigue in 10 patients (53%) and at least partial recovery in the rest (n = 9).

We searched MEDLINE for available literature and found five published and one preprint article that detailed the long term outcomes of patients with COVID‐19 (Table S3).^{1, 2, 4-8} Pooled prevalence of fatigue among cohorts with predominantly mild COVID‐19 patients was 50% (95% confidence interval: 38%–‐63%; Figure 1).

The “post‐COVID” syndrome is the persistence of symptoms among survivors of COVID‐19 and included symptoms of fatigue, dyspnea, cough, myalgia, arthralgia, and cognitive disturbances, amongst others. The prevalence of post‐COVID symptoms hypothetically depends on many factors: the demographic profile, comorbidities, and the severity of acute COVID‐19 infection.^{2, 6} Furthermore, lung fibrosis, hypercoagulability leading to venous thrombosis and embolism, and kidney injury are well‐defined sequalae of severe COVID‐19. To differentiate these confounding factors from the true postviral syndrome, we included only mild COVID‐19 patients since they are unlikely to have chronic organ impairment.⁹

Fatigue, postexertional malaise, dyspnea, and cognitive dysfunction are common symptoms of anemia. Iron supplementation in iron deficiency states, even without anemia, improves subjective fatigue and quality of life. Alteration in iron metabolism have been widely reported in COVID‐19, and anemia has been linked to more severe disease.¹⁰ Thyroid function abnormalities during active nonmild COVID‐19 disease include lower TSH and fT3 levels than healthy controls and non‐COVID‐19 pneumonia, likely representing a sick euthyroid state.¹¹ Approximately half of our patients had vitamin D deficiency, comparable to the high population prevalence of 40%–80% in our region, for which they were started on supplementation.¹² The possibility of worsening of underlying vitamin D deficiency due to prolonged indoor‐stay during the nationwide lockdown cannot be denied.

Twelve patients (63%) described disturbances in cognition (frequent memory lapses, difficulty in concentration), sleep disturbances, and low mood. While the widespread social and economic upheaval may explain mood disturbances, further studies may shed light on depressive disorders in the post‐COVID state and their contribution to other symptoms such as fatigue and anorexia.

Evaluation of patients at two time points has shown that most patients recover uneventfully by two and a half months. To conclude, patients presenting with persistent fatigue after the resolution of COVID‐19 should be evaluated for underlying abnormalities, the treatment of which may hasten recovery.

随着越来越多的患者从COVID-19中康复，临床医生越来越关注即使在微生物学解决后仍无法完全康复的患者。疲劳通常是这些患者的主要不适，通常被称为“ COVID后”疲劳。^1，2我们研究了轻度COVID-19伴持续性疲劳的患者，以确定可能的可改变危险因素。

在就诊前至少30天被诊断出患有轻度COVID-19的患者会被问到以下问题：“您觉得在COVID症状发作之前您已经恢复了正常的健康状态吗？” 如果他们认可疲劳为突出症状，则将其包括在内，并记录其人口统计学，临床和疾病过程数据。在标准护理期间进行的血液检查包括血常规，肝和肾功能检查，血糖，甲状腺状况和25个羟基维生素D水平。记录了医生建议的治疗方法，并且患者在COVID-19症状发作后至少60天进行了随访。³我们还于2020年9月30日在MEDLINE中搜索了术语“ COVID”和（“后”或“后遗症”或“长”或“症状与恢复”），以检索各种环境中COVID后后遗症的患病率估计值。使用Microsoft Excel将数据制成表格。使用OpenMeta测量汇总患病率估计值。

在研究期间，有19例患者在轻度COVID-19（中位年龄37岁[Q1-Q3，30.5-41]，M：F 10：9；表S1）之后出现了持续的疲劳症状。在初次生病期间，大多数患者都出现疲劳，喉咙痛，发烧和咳嗽的症状。他们在COVID-19症状发作后的中位数47天（Q1-Q3，42.5-58）接受了采访。除疲劳外，患者还报告了运动后不适，日常功能障碍，认知障碍和睡眠障碍（表S2）。在19名患者中的14名（74％）中，实验室研究表明，已知会引起疲劳的生化或血液学异常（表1）。在11位维生素D缺乏症（n  = 7），贫血（n = 2），甲状腺功能减退（n  = 1）和红细胞增多症（n  = 1）。其中三名患者有两个潜在的疲劳成因：一名贫血加维生素D缺乏症，贫血加甲状腺功能减退症和红细胞增多症加维生素D缺乏症。贫血患者中有四分之三患有铁缺乏症，铁质和维生素B12缺乏症有二型贫血。在症状发作后中位数103天（Q1-Q3，93.7-107天）后进行第二次随访，发现10例患者（53％）从疲劳中完全恢复，其余患者至少部分恢复（n  = 9 ）。

我们在MEDLINE中搜索了可用的文献，发现有五篇已发表的论文和一篇预印本文章详细介绍了COVID-19患者的长期预后（表S3）。^1，2，4-8具有主要温和COVID-19的患者群组中的疲劳汇集患病率为50％（95％置信区间：38％ - 63％;图1）。

“ COVID后”综合征是COVID-19幸存者中症状的持续存在，其中包括疲劳，呼吸困难，咳嗽，肌痛，关节痛和认知障碍等症状。假设COVID后症状的患病率取决于许多因素：人口统计学特征，合并症和急性COVID-19感染的严重程度。^[2，6]此外，肺纤维化，高凝性导致静脉血栓形成和栓塞以及肾脏损伤是严重COVID-19的明确特征。为了将这些混杂因素与真正的病毒后综合症区分开来，我们仅包括轻度COVID-19患者，因为他们不太可能患有慢性器官损伤。⁹

疲劳，劳累后不适，呼吸困难和认知功能障碍是贫血的常见症状。即使在没有贫血的情况下，缺铁状态下的补铁也会改善主观疲劳和生活质量。铁代谢的改变已在COVID-19中广泛报道，贫血与更严重的疾病有关。¹⁰活动性非轻度COVID-19疾病期间的甲状腺功能异常包括TSH和fT3水平低于健康对照组和非COVID-19肺炎，可能代表正常的甲状腺疾病。¹¹我们大约一半的患者维生素D缺乏症，与我们地区开始补充营养的40％–80％的高人群患病率相当。¹² 不能否认由于全国禁闭期延长的室内停留而导致潜在的维生素D缺乏症恶化的可能性。

十二名患者（63％）描述了认知障碍（频繁的记忆缺失，注意力不集中），睡眠障碍和情绪低落。尽管广泛的社会和经济动荡可以解释情绪障碍，但进一步的研究可以揭示COVID后状态下的抑郁症及其对其他症状（如疲劳和厌食）的影响。

在两个时间点对患者进行的评估显示，大多数患者在两个半月内恢复良好。总而言之，应评估在COVID-19消退后仍持续疲劳的患者的潜在异常，治疗可能会加快恢复。