Association between salivary SARS-CoV-2 viral load and acute and late symptoms of COVID-19 in non- hospitalized patients: A cohort study

doi:10.21203/rs.3.rs-2949163/v1

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Association between salivary SARS-CoV-2 viral load and acute and late symptoms of COVID-19 in non- hospitalized patients: A cohort study

https://doi.org/10.21203/rs.3.rs-2949163/v1

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Background

The clinical course of COVID-19 can be divided into two phases: acute and late.

Aims

This study evaluated the association between salivary SARS-CoV-2 load and acute and late symptoms of COVID-19 in non-hospitalized patients.

Methods

This cohort study included 109 participants who tested positive for SARS-CoV-2 in a rapid antigen test (Ethics Committee, 4.434.828). Saliva samples were obtained and acute symptoms were recorded immediately after the diagnosis of COVID-19. Late symptoms were recorded 3 months later. The viral load was estimated based on real-time reverse transcription polymerase chain reaction (qRT-PCR) cycle threshold (Ct). The chi-square and Student t test were used to assess the association between salivary viral load and symptoms (p ≤ 0.05).

Results

A lower salivary viral load was associated with diarrhea (RR = 0.73, 95% CI = 0.55–0.97, p = 0.04), anosmia (RR = 0.63, 95% CI = 0.47–0.84, p = 0.002), and dysgeusia (RR = 0.69, 95% CI = 0.52–0.91, p = 0.01) in the acute phase of the infection. Regarding late symptoms, a lower viral load remained associated with anosmia (RR = 0.68, 95% CI = 0.51–0.90, p = 0.05) and dysgeusia (RR = 0.59, 95% CI = 0.50–0.70, p = 0.03).

Conclusion

Lower viral load is a known marker of mild COVID-19. The association of lower viral load with anosmia and dysgeusia in the acute and late phases of the disease and with diarrhea in the acute phase suggests that these symptoms are predictive of mild COVID-19.

Covid-19

pandemic

viral load

RT-PCR

anosmia

dysgeusia

Infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can cause asymptomatic, mild, or severe disease (COVID-19) [1]. Mild COVID-19 is the most frequent presentation of SARS-CoV-2 infection and symptoms include fever, cough, headache, anosmia, and dysgeusia. Recovery generally occurs within two weeks and the disease only requires outpatient care [2]. The severe form, characterized by rapid progression, affects 5–10% of infected people [3], requires hospital care, and can lead to respiratory failure and death [4].

The clinical course of COVID-19 can be divided into two phases: an acute, symptomatic phase that starts shortly after infection, with headache, cough, anosmia, and dysgeusia being the most common clinical manifestations [5]; the late phase is characterized by residual symptoms that last much longer than the usual course of infection and has been termed “long COVID” or “post-COVID-19 syndrome”. Long COVID is characterized by the persistence of one or more symptoms for several weeks or months [1, 6]. At this stage, the most commonly reported symptoms are anosmia, dysgeusia, fatigue, shortness of breath, and arthralgia [3].

Higher nasopharyngeal and plasma viral loads have been associated with disease severity and increased mortality in hospitalized patients [6–7]. Severe respiratory disease has been linked to a high viral load, while mild or absent symptoms are associated with low viral loads [8]. A study of 4,254 patients with COVID-19 found that viral load (estimated by Ct values) was associated with higher mortality among in- and outpatients [9]. A systematic literature review examined the correlation between SARS-COV-2 Ct values and patient-related outcomes. They concluded that lower Ct values (higher virus load) might be associated with worse outcomes and that Ct values may be useful in predicting the clinical course and prognosis of patients with COVID-19 [10].

To the best of our knowledge, no previous study has evaluated the association between salivary viral load and acute and persistent symptoms of COVID-19 in non-hospitalized patients with a mild form of the disease. Therefore, this study assessed the association between salivary SARS-CoV-2 load and acute and late symptoms of COVID-19 in non-hospitalized patients. The hypothesis is that salivary SARS-CoV-2 viral load is associated with early and persistent symptoms of COVID-19.

The study was conducted following the Declaration of Helsinki and was approved by the Research Ethics Committee of the School of Dentistry, Federal University of Bahia (Protocol 4.434.828). The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guidelines were followed.

Study design

This was a prospective cohort study on acute and late symptoms of COVID-19. The exposure factor was the estimated SARS-CoV-2 load in saliva given by the cycle threshold (Ct) measured by real-time PCR (qRT-PCR). The Ct is the number of cycles required for the fluorescent signal to surpass the background level, with Ct levels being inversely proportional to the amount of target nucleic acid. The Ct value was used as a semi-quantitative viral load measure (CDC, 2020) [11].

Setting and participants

A convenience sample of 750 consecutive adult individuals with flu-like symptoms for 3 to 7 days, who attended Public Health Service Units in Salvador, Brazil, between December 18, 2020, and January 30, 2021, was submitted to rapid antigen testing. An immunochromatographic method (Vida Biotecnologia®, Belo Horizonte, MG, Brazil) using nasopharyngeal swab samples was employed. One hundred and ten individuals with positive results were invited to participate in the study and accepted. One individual had a negative salivary PCR test and was not included in the study. The eligibility criteria were age ≥ 18 years, both sexes and a positive COVID-19 test. Data were collected at two stages: during the acute phase of the disease, immediately after the positive COVID-19 result when symptoms were recorded and saliva was obtained, and 3 months later, when persistent symptoms were documented.

Variables and data measurement

A saliva sample was collected immediately after the rapid antigen test. The following data were recorded using a pre-tested questionnaire: sociodemographic data (age, sex, education, and income levels), health status (weight and height, and previous diagnosis of diabetes and hypertension), smoking, and COVID-19 symptoms (fever, cough, tiredness, anosmia or dysgeusia, sore throat, headache, body aches and pains, diarrhea, skin rash or discoloration of fingers or toes, red or irritated eyes, difficulty breathing or shortness of breath, chest pain, and others). Three months later, the volunteers had a virtual consultation and were asked about persistent symptoms or sequelae of COVID-19.

A single dentist performed the first data and sample collections in a private office of a Basic Health Unit, with the participant sitting in a standard chair. The second data collection was performed by the same dentist via virtual consultation, who recorded the symptoms using the same pre-tested questionnaire.

For the collection of saliva samples, the volunteers were asked to repeatedly spit into 80-mL collectors (J. Prolab®, São Paulo, SP, Brazil) until approximately 1.5 mL of saliva was collected, thus avoiding mucus secretion from the oropharynx or lower respiratory tract, i.e., sputum. The samples were identified and refrigerated in sterile 15-mL tubes. The samples were transported to the Infectious Diseases Research Laboratory, Federal University of Bahia, in a thermal box at 2-8^oC and kept at -80^oC until nucleic acid extraction.

Salivary specimens were homogenized and diluted 1:1 with 1x phosphate-buffered saline (PBS). Viral nucleic acid was extracted from 200 µL of diluted saliva and eluted to 55 µL with elution buffer according to the manufacturer’s instructions (High Pure Viral Nucleic Acid Kit, Roche, Mannheim, Germany). RNA templates were amplified by qRT-PCR (CDC, 2020), targeting nucleocapsid genes N1 and N2 and the RNAse P gene as an internal control (QuantStudio 3 Real-Time PCR System, Applied Biosystems, United States).

A convenience sample of 109 patients was included. After data collection and saliva analysis, a statistical power of 88.8% was calculated based on anosmia incidence and an alpha value of 0.05 (https://clincalc.com/Stats/Power.aspx).

The Ct value was the exposure variable, which was calculated as the arithmetic mean of Ct values obtained for the N1 and N2 genes. The cases were classified into two categories: low and moderate Ct (cases with Ct ≤ 30, indicating high and medium viral load) or high Ct (cases with Ct > 30, indicating low viral load (adapted from Magleby et al., 2021) [7].

Statistical methods

Missing data were excluded from the analysis. Descriptive analysis was performed by calculating the absolute and relative frequencies of the variables. The relative risk (RR), 95% lower and upper confidence interval (95% CI), and p-value were computed. Alpha was set to 0.05 (5%). Statistical analyses were performed using SPSS 15.0 (SPSS Inc., Chicago, IL, USA).

One hundred and ten individuals with positive results were invited to participate in the study and accepted. One individual had a negative salivary PCR test and was not included in the study. Loss to follow-up occurred in 9 cases due to wrong contact information or the lack of telephone contact. An e-mail was sent to these cases. However, there was no reply, and these cases were excluded only from the late symptoms analysis.

The general characteristics of the sample are presented in Table 1. Tables 2 and 3 show the Ct values (mean ± standard deviation) for early and late symptoms. The most frequent acute symptoms were myalgia, headache, cough, fever, and rhinorrhea, while the most common late symptoms were fatigue, anosmia, memory deficit, myalgia, and dysgeusia (Table 1).

Table 1

General characteristics of participants (n = 109).
Variables	N (%)
Age
18–37 years	51 (46.8)
≥ 38 years	58 (53.2)
Sex
Men	54 (49.5)
Women	55 (50.5)
Color
White	26 (23.9)
Brown/Black	83 (76.1)
Income
< US$ 237.00	82 (75.2)
≥ US$ 237.00	27 (24.8)
Education
< 9 years of schooling	89 (81.7)
≥ 9 years of schooling	20 (18.3)
Obesity
BMI ≥ 30.00 kg/m²	27 (24.8)
BMI < 30.00 kg/m²	82 (75.2)
Smoking
No	106 (97.2)
Yes	3 (2.8)
Chronic Diseases
No	83 (76.1)
Yes	26 (23.9)
Hypertension
No	90 (82.6)
Yes	19 (17.4)
Diabetes mellitus
No	103 (94.5)
Yes	6 (5.5)
Asthma
No	108 (99.1)
Yes	1 (0.9)
Hepatitis B
No	108 (99.1)
Yes	1 (0.9)
HIV
No	108 (99.1)
Yes	1 (0.9)
Sickle cell anemia
No	108 (99.1)
Yes	1 (0.9)
Hypothyroidism
No	108 (99.1)
Yes	1 (0.9)
Leukopenia
No	108 (99.1)
Yes	1 (0.9)

Table 2

Association between SARS-CoV-2 salivary viral load and COVID-19 acute symptoms (N = 109).
		Viral load
Acute symptoms	N	High	Low	RR	95% CI	P
		N (%)
Anosmia
No	63	32 (76.2)	31 (46.3)	0.63	0.47–0.84	0.002
Yes	46	10 (23.8)	36 (53.7)	0.63	0.47–0.84	0.002
Cough
No	29	10 (23.8)	19 (28.4)	1.09	0.79–1.50	0.60
Yes	80	32 (76.2)	48 (71.6)	1.09	0.79–1.50	0.60
Diarrhea
No	73	33 (78.6)	40 (59.7)	0.73	0.55– 0.97	0.04
Yes	36	9 (21.4)	27 (40.3)	0.73	0.55– 0.97	0.04
Dysgeusia
No	67	32 (76.2)	35 (52.2)	0.69	0.52–0.91	0.01
Yes	42	10 (23.8)	32 (47.8)	0.69	0.52–0.91	0.01
Dyspnea
No	108	42 (100)	66 (98.5)	0.61	0.53–0.71	0.42
Yes	1	0 (0)	1 (1.5)	0.61	0.53–0.71	0.42
Eye pain
No	107	40 (95.2)	67 (100)	0.37	0.29–0.48	0.07
Yes	2	2 (4.8)	0 (0)	0.37	0.29–0.48	0.07
Fatigue
No	100	38 (90.5)	62 (92.5)	1.12	0.61–2.04	0.70
Yes	9	4 (9.5)	5 (7.5)	1.12	0.61–2.04	0.70
Fever
No	50	19 (45.2)	31 (46.3)	1.02	0.75– 1.37	0.92
Yes	59	23 (54.8)	36 (53.7)	1.02	0.75– 1.37	0.92
Headache
No	28	9 (21.4)	19 (28.4)	1.15	0.84–1.57	0.42
Yes	81	33 (78.6)	48 (71.6)	1.15	0.84–1.57	0.42
Myalgia
No	26	11 (26.2)	15 (22.4)	0.92	0.64–1.33	0.65
Yes	83	31 (73.8)	52 (77.6)	0.92	0.64–1.33	0.65
Odynophagia
No	62	22 (52.4)	40 (59.7)	1.12	0.83–1.53	0.45
Yes	47	20 (47.6)	27 (40.3)	1.12	0.83–1.53	0.45
Otalgia
No	102	39 (92.9)	63 (94)	1.08	0.56–2.09	0.81
Yes	7	3 (7.1)	4 (6)	1.08	0.56–2.09	0.81
Rash on skin
No	108	41 (97.6)	67 (100)	0.38	0.30–0.48	0.20
Yes	1	1 (2.4)	0 (0)	0.38	0.30–0.48	0.20
Rhinorrhea
No	51	22 (52.4)	29 (43.3)	0.87	0.64–1.18	0.35
Yes	58	20 (47.6)	38 (56.7)	0.87	0.64–1.18	0.35
Sneeze
No	53	19 (45.2)	34 (50.7)	1.09	0.81– 1.47	0.58
Yes	56	23 (54.8)	33 (50.3)	1.09	0.81– 1.47	0.58

Table 3

Association between SARS-CoV-2 salivary viral load and COVID-19 late symptoms(N = 109).
		Viral load
Late symptoms	N	High	Low	RR	95% CI	P
		N(%)
Anosmia
No	86	36 (94.7)	50 (80.6)	0.68	0.51–0.90	0.05
Yes	14	2 (5.3)	12 (19.4)	0.68	0.51–0.90	0.05
Arrhythmia
No	99	38 (100)	61 (98.4)	0.62	0.53–0.72	0.43
Yes	1	0 (0)	1 (1.6)	0.62	0.53–0.72	0.43
Arthralgia
No	94	36 (94.7)	58 (93.5)	0.93	0.51– 1.67	0.81
Yes	6	2 (5.3)	4 (6.5)	0.93	0.51– 1.67	0.81
Dysgeusia
No	93	38 (100)	55 (88.7)	0.59	0.50–0.70	0.03
Yes	7	0 (0)	7 (11.3)	0.59	0.50–0.70	0.03
Fatigue
No	82	32 (84.2)	50 (80.6)	0.92	0.63–1.32	0.65
Yes	18	6 (15.8)	12 (19.4)	0.92	0.63–1.32	0.65
Headache
No	96	37 (97.4)	59 (95.2)	0.82	0.46–1.48	0.59
Yes	4	1 (2.6)	3 (4.8)	0.82	0.46–1.48	0.59
Loss of hair
No	94	34 (89.5	60 (96.8)	1.92	0.61–6.00	0.14
Yes	6	4 (10.5)	2 (3.2)	1.92	0.61–6.00	0.14
Memory deficit
No	89	31 (81.6)	58 (93.5)	1.79	0.81–3.97	0.06
Yes	11	7 (18.4)	4 (6.5)	1.79	0.81–3.97	0.06
Myalgia
No	93	36 (94.7	57 (92.9)	0.86	0.52–1.41	0.59
Yes	7	2 (5.3)	5 (8.1)	0.86	0.52–1.41	0.59

A higher Ct value (lower viral load) was significantly associated with anosmia (RR = 0.63, 95% CI = 0.47–0.84, p = 0.002), dysgeusia (RR = 0.69, 95% CI = 0.52–0.91, p = 0.01), and diarrhea (RR = 0.73, 95% CI = 0.55–0.97, p = 0.04) (Table 2). Regarding late symptoms, a lower viral load remained associated with anosmia (RR = 0.68, 95% CI = 0.51–0.90, p = 0.05) and dysgeusia (RR = 0.59, 95% CI = 0.50–0.70, p = 0.03). The other clinical symptoms were not associated with salivary viral load (p ≥ 0.06) (Tables 2 and 3).

This 3-month prospective cohort study evaluated the association of salivary SARS-CoV-2 viral load with early and persistent symptoms of COVID-19. We found an association of lower viral load with anosmia and dysgeusia in the acute and late phases of the disease and with diarrhea in the early stage of COVID-19.

Anosmia and dysgeusia were significantly associated with a lower viral load in the present study, indicating a possible reduction in viral load in saliva samples collected 3–7 days after the onset of symptoms or a baseline low viral load in these patients with mild disease. However, the viral load has been shown to peak at the onset of symptoms and to drop after 10 days in mild disease [12, 13]. Previous studies analyzing the association between SARS-CoV-2 viral load and symptoms in hospitalized patients with severe COVID-19 revealed an association between higher viral load and invasive mechanical ventilation and death [4, 7, 12, 14].

In the present sample, the rates of taste and smell disorders were about 40% in the acute phase, similar to the findings of previous studies [5, 15]. Critically ill hospitalized patients are less likely to develop anosmia and dysgeusia [6]. Anosmia and dysgeusia persisted for more than 90 days since COVID-19 onset in 14% and 7% of our patients, respectively. The persistence of these symptoms for at least 60 days has been reported in patients who developed the mild form of the disease [16]. This finding suggests that anosmia and dysgeusia are predictors of a lower risk of developing the severe form of COVID-19. In the present sample, only one volunteer was hospitalized and required intubation and mechanical ventilation.

In the present study, lower viral load and diarrhea were significantly associated in the early stage of COVID-19. Diarrhea during the acute phase has been associated with a higher risk of developing long COVID-19 [3], probably because of the presence of SARS-CoV-2 in the small intestine [17]. However, this association was not found in the present sample (p ≥ 0.09, data not shown).

One limitation of the present study is that the semi-quantitative RT-PCR assay measures relative mRNA template abundance and not viral viability. However, given the limitations in culturing SARS-CoV-2, viral RNA level has been considered a reliable surrogate marker of viral load [18]. Further limitations include the small sample size and the use of a questionnaire for anosmia and ageusia diagnosis instead of a validated olfactory or taste test. Other studies involving a larger sample are necessary.

Future studies should assess the association between SARS-CoV-2 viral load in saliva or other samples and COVID-19 worsening to determine whether the initial viral load can assist in risk stratification and in predicting clinical outcomes of COVID-19 [12]. The type of sample (nasopharynx, sputum, and saliva) and optimal collection time for this purpose need to be defined.

In conclusion, the association of lower salivary viral load with anosmia and dysgeusia in the acute and late phases of COVID-19 and with diarrhea in the early stage indicates that these symptoms can predict a mild form of COVID-19.

Ethics approval, guidelines and consent to participate

This study was performed in line with the principles of the Declaration of Helsinki. Approval was granted by the Ethics Committee of University of the School of Dentistry, Federal University of Bahia (Date: 10/10/2020, Protocol 4.434.828). All participants received guidance and written informed consent was obtained from all individual participants included in the study.

Consent to publish

The authors affirm that there is no images of human participants.

Availability of data and materials

The datasets generated during and analysed during the current study are available upon request to Dr. Patricia Ramos Cury (e-mail: [email protected]).

Competing Interests

The authors have no relevant financial or non-financial interests to disclose.

Funding

This study received no funding.

Author Contributions

Denis Damião Costa, Carlos Brites, Patricia Ramos Cury contributed to the study's conception and design. Material preparation, data collection and analysis were performed by Denis Damião Costa, Jean Nunes dos Santos, Patricia Ramos Cury, Daniele Souza de Santana and Sara Nunes Vaz. The first draft of the manuscript was written by Denis Damião Costa and Patricia Ramos Cury and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

Acknowledgments

We thank the Public Health Department of the City of Salvador-Bahia, Brazil, for making its health units available for this study.

Author information (optional)

Not applicable.

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No competing interests reported.

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Association between salivary SARS-CoV-2 viral load and acute and late symptoms of COVID-19 in non- hospitalized patients: A cohort study

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Abstract

INTRODUCTION

MATERIALS AND METHODS

Study design

Setting and participants

Variables and data measurement

Statistical methods

RESULTS

DISCUSSION

Declarations

References

Additional Declarations

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