In this article, I review what we know about the symptoms of Long Covid as of April 25, 2021, based on the published academic literature. Long Covid represents a loosely defined collection of symptoms that occur after an incident of symptomatic or asymptomatic COVID-19 infection, and clear diagnostic criteria are still being developed (as of April 2021).(Alwan and Johnson 2021) The UK’s National Institute for Health and Care Excellence (NICE) published guidelines on Dec 18, 2020, that are currently used by clinicians and researchers to characterize Long Covid. These guidelines define 3 subtypes of Long Covid based on the timeframe of symptoms (Shah et al. 2021; Fernández-de-las-Peñas et al. 2021):
Nalbandian et al. recently reviewed the results from 9 separate observational studies reporting on symptoms experienced by COVID-19 patients months after symptom onset or discharge from a hospital. The 9 studies reviewed were based on patients in the UK, Spain, Italy, France, China, and the US. Nalbandian et al.’s review is significant because it represents the first attempt to consolidate the empirical observations from several published studies on Long Covid into a single, consolidated view. The drawback here is that, with such few studies to choose from, the authors could not control for typical variables that could confound their conclusions. For instance, how do we define the “start” of Long Covid? Is it the presentation of symptoms, a positive SARS-COV-2 test, or discharge from a hospital? Researchers have used all 3 definitions in an attempt to methodically identify Long Covid patients, yet the different definitions of the “start date” may end up biasing the type of patients included in a study. Thus, the results presented by Nalbandian et al., while comprehensive, are still subject to bias; they should be viewed as indicators of the direction in which the clinical science is pointing.
The prevalence of Long Covid symptoms in the 9 studies reviewed by Nalbandian et al. is presented below. These symptoms represent cross-sectional samples of patients followed up anywhere from 1-2 months post-discharge, to 6 months post-symptom onset. In other words, the list of symptoms and prevalence rates below reflect the full spectrum of Long Covid, regardless of the timeframe of symptoms.
From this review of 9 observational studies, our key takeaways are that (1) symptoms of Long Covid vary both in type and in prevalence, and (2) symptoms affect a broad range of physiologic systems. While the list of symptoms above appears small in comparison to symptoms in self-reported surveys, the symptoms reviewed by Nalbandian et al. were assessed by clinicians or other healthcare professionals (e.g. by a telephone call, or through a structured survey). As such, the “classes” of symptoms listed above reflect a clinical picture of Long Covid and will prove useful in helping clinicians better identify and classify the syndrome.
Other recently published papers have reported on diseases that are being diagnosed among Long Covid patients. Keep in mind that “diagnoses” represent a defined clinical entity, and a diagnosis can only be made by a licensed physician. A diagnosis is based upon a combination of symptoms, test results, and/or physical exam findings; both positive and negative findings factor into making a diagnosis. After discharge from a hospital, patients in the UK with Covid-19 were subsequently diagnosed with major adverse cardiovascular event, chronic liver disease, chronic kidney disease, and diabetes 3.0x, 2.8x, 1.9x, and 1.5x more frequently, respectively, than matched controls.(Ayoubkhani et al. 2021) In addition, Postural Orthostatic Tachycardia Syndrome (POTS), orthostatic intolerance, or vasovagal syncope are being increasingly diagnosed among Long Covid patients.(Johansson et al. 2021; Dani et al. 2021)
While symptoms identified and/or interrogated by healthcare professionals are useful in aiding clinicians, this approach is often at odds with the patient experience, especially in the case of chronic syndromes. In chronic syndromes, like Long Covid, irritable bowel syndrome, POTS, and many more, symptoms are myriad, and they wax and wane erratically. For patients, it is important to be able to distinguish when a somatic sensation – what we “feel” in our body – represents a true symptom that is part of a disease, versus a feeling that is not part of the disease, for we would handle each differently. In addition, as a patient, it is important to know what to expect: if I see one symptom, what else should I prepare for? To this end, the Patient-Led Research Collaborative distributed an online survey internationally to shed light on the subjective experience of individuals post-COVID-19. Their study was unique in that it assessed a broad range of symptoms – 205 in total – from respondents in 56 countries. They included 3,762 responses in their final analysis, 27% of which self-reported as having a positive test result confirming COVID-19.(Davis et al. 2021) In their results (first published in December 2020, and published on medRxiv in April 2021), they found that 51.7% of participants indicated that their symptoms improved over time, and 19.7% indicated their symptoms worsened over time. Only 6.8% of respondents had recovered after day 28 of illness, and 65.2% of respondents were experiencing symptoms for at least 6 months. Thus, their cross-sectional survey is more representative of the course of chronic post-Covid syndrome (defined as lasting longer than 12 weeks).
They found that the most common physiologic symptoms reported were: fatigue (98%),post-exertional malaise (89%), sore throat (60%), palpitations (67%), tachycardia (61%), shortness of breath (77%), tightness of chest (75%), and diarrhea (60%). Among neuropsychiatric symptoms, they found the most commonly reported symptoms were: anxiety (58%), short-term memory loss (65%), dizziness or vertigo (67%), loss of smell (36%), insomnia (60%), difficulty finding the right words (46%), and brain fog (85%). Importantly, of those who experienced memory and/or cognitive dysfunction symptoms and had a brain MRI, 87% of the brain MRIs (n=345, of 397 who were tested) came back without abnormalities. Sensorimotor symptoms - tremors, “vibrating sensation”, numbness, coldness in a body part, tingling/pins and needles, “electric zap,” facial paralysis, facial pressure/numbness, and weakness – were reported by 81% of respondents.
From the COVID Symptom Study, Sudre et al. analyzed the self-reported symptoms of 4,182 individuals who had a positive test for COVID, tracking their symptoms over time.(Sudre et al. 2020) They found that 13.3% of participants reported symptoms lasting longer than 4 weeks (28 days, referred to as LC28), 4.5% had symptoms lasting ≥8 weeks, and 2.3% had symptoms lasting more than ≥12 weeks; these proportions were similar across patients from the US, the UK, and Sweden.
Based on patients’ self-reported symptoms, Sudre et al. found that individuals with LC28 reported fatigue (97.7%) and intermittent headaches (91.2%) most frequently, followed by anosmia (loss of smell) and lower respiratory symptoms. Importantly, LC28 individuals also reported new symptoms, i.e. symptoms that were not observed in the first 3-4 weeks. These symptoms were self-reported through the free-text box in the app nearly twice as frequently by LC28 compared to short COVID (81% in LC28 compared to 45% in short COVID), with short COVID defined as illness lasting <10 days. The main distinguishing symptoms reported by LC28 were:
• Cardiac symptoms – palpitations and tachycardia (LC28 6.1% vs short COVID 0.5%; P<0.0005)
• Concentration or memory issues (LC28 4.1% versus short COVID 0.2%; P<0.0005)
• Tinnitus and earache (LC28 3.6% versus short COVID 0.2%; P<0.0005)
• Peripheral neuropathy symptoms (pins and needles and numbness; LC28 2% versus short COVID 0.5%; P=0.004)
Another characteristic of LC28 individuals was that they reported relapses (i.e. ≥2 days of symptoms after 1 asymptomatic week) twice as frequently as Short Covid individuals (16.0% vs 8.4%, p<0.0005).
Mandal et al. assessed 384 COVID-19 patients after discharge from three hospitals in London (Mandal et al. 2020), with a median follow-time of 54 days – nearly 8 weeks. Among patients who had abnormal lab results at discharge, 7.3% of 247 patients had persisting lymphopenia, 30.1% of 229 patients had elevated d-dimer, and 9.5% of 190 patients had elevated C reactive protein (CRP) at follow-up. Of the 244/384 (66%) patients that had follow-up chest X-rays, 151 (62%) were normal, 66 (27%) improvement, 4 (2%) were unchanged, and 23 (9%) showed deterioration. It is unknown whether the prevalence of these results differs between Long Covid at 4 weeks or Long Covid at 12 weeks.
On March 5, 2021, Huang et al. used electronic health records (EHR) to analyze symptoms of Long Covid.(Huang et al. 2021) Although the symptoms in an EHR are narrower than those found via self-reporting, the symptoms recorded in an EHR represent the data entered by a physician or nurse and may represent a more objective point of view. Huang et al. analyzed the EHRs of 1,407 individuals never hospitalized for an initial COVID-19 infection, but who had tested positive for COVID-19. Importantly, they found that 32% of Long Haulers (LC≥61, or 8 weeks) were initially asymptomatic at the time of their positive SARS-COV-2 test. Among Long Haulers (LC≥61, or 8 weeks), they found that chest pain, dyspnea, anxiety, abdominal pain, cough, low back pain, and fatigue were the most prevalent symptoms.
Paradoxically, fatigue – the central feature of Long Covid in other studies – was found to be weakly correlated with other symptoms among LC≥61 patients. This salient feature strongly suggests a flaw in their data: from patient experiences, we have learned that there may be a cognitive bias on the part of healthcare providers leading to the under-recording (different from under-reporting) of fatigue. As such, symptoms important to patients may be under-reported in the study by Huang et al. In addition, they only focused on symptoms attributable to SARS-COV-2, and we know that, at the time of their analysis (Feb 4, 2021), our understanding of these set of symptoms was limited.
On March 27, 2021, Ziauddeen et al. published the results from a social media survey of individuals (n=2550, 80% from the UK) living with Long Covid.(Ziauddeen et al. 2021) The average duration of illness at the time of their survey was 7.2 months (~28 weeks). They found that the most common symptoms were exhaustion (72.6%), cognitive dysfunction (brain fog, poor concentration, memory problems, confusion) (69.2%), chest pressure and/or tightness (52.6%), shortness of breath (54.2%), headache (46.0%), muscle aches (44.6%) and palpitations (42.0%).
The key takeaways from this review of the literature are the following:
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Davis, Hannah E., Gina S. Assaf, Lisa McCorkell, Hannah Wei, Ryan J. Low, Yochai Re’em, Signe Redfield, Jared P. Austin, and Athena Akrami. 2021. “Characterizing Long COVID in an International Cohort: 7 Months of Symptoms and Their Impact.” MedRxiv, April, 2020.12.24.20248802. https://doi.org/10.1101/2020.12.24.20248802.
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Huang, Yong, Melissa D. Pinto, Jessica L. Borelli, Milad Asgari Mehrabadi, Heather Abrihim, Nikil Dutt, Natalie Lambert, et al. 2021. “COVID Symptoms, Symptom Clusters, and Predictors for Becoming a Long-Hauler: Looking for Clarity in the Haze of the Pandemic.” MedRxiv, March, 2021.03.03.21252086. https://doi.org/10.1101/2021.03.03.21252086.
Johansson, Madeleine, Marcus Ståhlberg, Michael Runold, Malin Nygren-Bonnier, Jan Nilsson, Brian Olshansky, Judith Bruchfeld, and Artur Fedorowski. 2021. “Long-Haul Post–COVID-19 Symptoms Presenting as a Variant of Postural Orthostatic Tachycardia Syndrome: The Swedish Experience.” JACC: Case Reports 3 (4): 573–80. https://doi.org/10.1016/j.jaccas.2021.01.009.
Mandal, Swapna, Joseph Barnett, Simon E. Brill, Jeremy S. Brown, Emma K. Denneny, Samanjit S. Hare, Melissa Heightman, et al. 2020. “‘Long-COVID’: A Cross-Sectional Study of Persisting Symptoms, Biomarker and Imaging Abnormalities Following Hospitalisation for COVID-19.” Thorax 76 (4): 396–98. https://doi.org/10.1136/thoraxjnl-2020-215818.
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Sudre, Carole H., Benjamin Murray, Thomas Varsavsky, Mark S. Graham, Rose S. Penfold, Ruth C. Bowyer, Joan Capdevila Pujol, et al. 2020. “Attributes and Predictors of Long-COVID: Analysis of COVID Cases and Their Symptoms Collected by the Covid Symptoms Study App.” MedRxiv, October, 2020.10.19.20214494. https://doi.org/10.1101/2020.10.19.20214494.
Ziauddeen, Nida, Deepti Gurdasani, Margaret E. O’Hara, Claire Hastie, Paul Roderick, Guiqing Yao, and Nisreen A. Alwan. 2021. “Characteristics of Long Covid: Findings from a Social Media Survey.” MedRxiv, March, 2021.03.21.21253968. https://doi.org/10.1101/2021.03.21.21253968