Our study profiled the different clinical manifestations in 300 patients who developed long COVID and were registered at our service between September 2020 and July 2021. Symptoms reported during the acute phase of the disease that persisted in the long term were fatigue, shortness of breath, myalgia, headache, change or loss of taste, and anosmia/hyposmia. New symptoms reported only during the post-COVID-19 phase were amnesia, anxiety, decreased visual and auditory acuity, dyslipidaemia, muscle weakness, facial paralysis, limb paraesthesia, and hair loss. To our knowledge, this is the first study to address the profile of persistent and new symptoms in patients with COVID-19. The number of symptoms in long COVID purportedly increased over time, and some symptoms appeared to be less tolerated than others because they were more prevalent among patients seeking assistance earlier than among those experiencing long COVID for longer durations.
The comparison of long COVID symptoms observed in our sample with those observed worldwide showed a trend toward lower symptom frequency among the participants in the present study. Notably, 14 of the 21 symptoms observed in our study had lower frequencies than those reported worldwide. Three symptoms exhibited extreme differences: memory and attention loss (16% in the present study and 78% worldwide), arthralgia (11% and 59%), and hair loss (10% and 71%, respectively)[19, 20].
Similar to our findings, some studies have shown that most patients have at least one symptom, such as fatigue, muscle weakness, insomnia, anxiety, or hair loss, up to 12 months after the onset of COVID-19 [10, 21]. Thus, COVID-19-related sequelae may be present for longer than 12 months in patients who develop COVID-19; however, it is not possible to define the extent to which these symptoms would persist. Our study indicated that sequelae may be present for at least 15 months after the initial onset of COVID-19 symptoms.
To date, we have not found studies on the progressive and cumulative increases in symptoms related to long periods of COVID-19, as suggested by our study. Thus, as the duration of COVID-19 increases, the number of symptoms also increase. In practice, this represents a gap in scientific knowledge that remains to be filled, as understanding the extent to which these sequelae and/or symptoms persist, appear, or disappear in patients who have developed long periods of COVID-19 is necessary for the correct clinical management of the disease[22, 23].
Our data indicated that women with mild acute COVID-19 reported experiencing symptoms for a longer period. Some studies have demonstrated that long COVID is more common in women than in men[13, 16, 24], although it is not yet fully established whether the risk of developing long-term effects of COVID-19 can be influenced by sex, age, ethnicity, underlying health conditions, viral load, or the progression of COVID-19[12, 22].
Regarding the need to differentiate between sequelae from ICU admission and symptoms of long COVID, we observed that only 7% (20/300) of patients were admitted to the ICU. Thus, the impact of ICU stay on the study population was very low and certainly did not influence the clinical profile of patients with long COVID in the study.
Despite the large number of symptoms described for long COVID worldwide, we compared their frequencies as well as the frequencies of underlying comorbidities between the Amazonian sample and studies conducted in southeastern Brazil[19, 20]. The most frequent comorbidities exhibited different patterns, with asthma being more prevalent in the Amazonian sample, and hypertension and diabetes being more prevalent in the southeastern region. Additionally, more frequent long COVID symptoms showed a tendency to be shared across all studies, but with statistical differences between the Amazonian and southeastern regions, such as higher frequencies of fatigue, myalgia, and memory/attention impairment, as well as a lower frequency of shortness of breath in the Amazonian sample.
The profile of long COVID in the Amazonian region exhibited similarities and dissimilarities with those described in the literature but was able to reveal new aspects of the disease. Future studies may confirm whether some of these aspects are specific or limited to the Amazonian region, which would not be surprising given its unique characteristics in terms of the environment, host genetics, and infectious agents (Fig. 2).
In the Amazon, deforestation and fires contribute to climate change, leading to the loss of biodiversity and alteration of the structure and function of the ecosystem[25]. These changes can affect the behaviour of disease-transmitting vectors and contribute to water, air, soil, and food contamination[26]. These environmental changes can induce stress in people living with endemic COVID-19 and long COVID. Furthermore, the Amazon region has a high burden of endemic and neglected tropical diseases [6]. The following questions arise: What will be the result of the interaction of COVID-19 and long COVID with other endemic infectious diseases in the region, such as malaria, dengue, Zika, chikungunya, and yellow fever, as well as the relationship between numerous potential emerging pathogens and hyperinflammatory diseases?
Additionally, the majority of the Amazonian population lacks adequate access to health services, nutrition, suitable housing, and sanitation conditions[7], which facilitate the spread and maintenance of infectious and parasitic diseases. Moreover, the genetic ancestry profile may be crucial in predisposing certain population groups to the development of diseases and their responses to treatments [8]. Thus, the extensive interethnic miscegenation of the Brazilian Amazonian population, comprising European, African, and Amerindian ancestries, may affect the distribution and frequency of polymorphisms[27]. For example, Amerindian populations exhibit different immune responses compared to non-Amerindian populations, with the Th2 immune response being the most prevalent, which is known for its inefficiency against intracellular pathogens, such as viruses[8].
To the best of our knowledge, this is the first study to address the profiles of new and persistent symptoms in patients with long COVID. However, we emphasise the need for further studies that monitor long COVID patients for longer periods (> 15 months) as well as cohort studies that can assess and reassess the signs and symptoms of long COVID to define long-term clinical findings, a topic that still represents a significant gap in scientific knowledge that needs to be addressed.
This study had some limitations, such as vaccine coverage, reinfection events, and variants of SARS-CoV-2. In Brazil, vaccination began in January 2021 and has progressed slowly to achieve high coverage. Therefore, we did not include vaccinated individuals in the sample because they were few in number, and it would be challenging to assess the potential impact of the vaccine on the clinical profile. However, this may be a strength as our study provides valuable data for comparison between these different epidemiological scenarios. Future ongoing studies conducted by our group are expected to provide data on the long COVID profile among vaccinated individuals, enabling this type of comparison within the same population.
The number of patients with suspected reinfections was very low (1%), and none of these cases were confirmed through diagnostic tests (RT-PCR or positive antigen detection test). Therefore, the present study did not address this issue. It was also impossible to genetically characterise the SARS-CoV-2 variants that affected the study population.