Discussion
Among symptomatic hospitalised and outpatient COVID-19 cases at the
beginning of the pandemic in Italy, we observed that disease severity,
death, 6-month sequelae and the number of signs and symptoms at
diagnosis distributed according to the amount of nasal-pharyngeal
SARS-CoV-2 detected within the first week from disease onset,
independently from other known determinants of COVID-19 severity.
While for other viral illnesses initial viral load has been associated
with disease severity 17,18,25, a consensus has not
been reached in COVID-19. To the best of our knowledge, 11 studies have
shown that nasal-pharyngeal SARS-CoV-2 Ct are not associated to nor
predict COVID-19 severity 13–15,19,26–32. However,
only six of them analysed samples with >100 cases, the
majority included only hospitalised patients, and the follow-up was
relatively short 13–15,19,26–32. Significantly, only
a minority took into account the time between COVID-19 onset and the
time of swab collection. As example, an inverse correlation between
viral load and pulmonary lesions at CT scan has been described: the
higher the viral load in nasopharynx, the milder was the pneumonia32. Considering viral kinetics and immune-pathology
dynamics 5,27,29,33, the lower viral load could have
been associated with worse imaging as in this group SARS-CoV-2 may have
had longer time to replicate and diffuse in the lower respiratory
airways, stimulating the noxious inflammatory response. Patients with
the highest viral load in the upper respiratory airways may have been
detected at an earlier stage, when lung involvement had not yet had time
to reach its zenith 32.
If it is not a matter of snapshot issues, it could be a matter of grey
scale. Some of the studies supporting no difference in disease severity
according to viral load did not include the whole spectrum of COVID-19
and compared either asymptomatic with very mildly symptomatic patients
or not hospitalized with hospitalized patients, with the latter ranging
from mild to critical symptoms 14,15.
On the opposite, studies where a positive association between
nasal-pharyngeal SARS-CoV-2 Ct values and COVID-19 severity and/or
outcomes was detailed are flourishing 6,7,9–12. Most
of them included samples of more than 100 individuals with the reference
swab represented by the diagnostic one, despite only one reported the
time between disease onset and swab collection 7. As
compared to previous studies, the one here described has the longest
follow-up and included non-hospitalized patients. Furthermore, our
retrospective design at 6 months from COVID-19 onset and the
availability of data on time between disease onset and swab collection
allowed us to adjust for this factor as well as to analyse outcomes and
parameters of the infection at a time when its evolution was surely
over.
Lower Ct values were associated with more signs and symptoms at
diagnosis and a more frequent pattern of respiratory and systemic
complaints. Our findings are in line with those recently published by
others 8,12,34. As for the latter34, we did observe higher viral load in febrile
patients compared to afebrile ones: a greater burden of virus could
induce higher inflammatory response primarily manifesting as fatigue,
malaise, fever and headache. In accordance with this, plasma and
nasopharyngeal SARS-CoV-2 RNA has been correlated with pro-inflammatory
cytokines and inflammation biomarkers levels, such as IL-6 and CRP/serum
amyloid A ratio 19,20.
On the contrary, we did not observed any association between
nasal-pharyngeal viral load and prevalence of olfactory/taste disorder
as described by others and plausibly explained by higher local amount of
virus and related inflammation 34. Nevertheless, we
did not quantify the dysfunction with an objective scale and even others
failed in finding such an association 35. Olfactory
and gustatory dysfunction represented the second most common sequelae
(7.7%) still present at 6 months from the infection, after dyspnoea and
just before chronic cough. Other studies reported persistent olfactory
and gustatory dysfunction at 6 weeks and at 3 months in the 28.2-16.7%
(smell-taste loss) and 10.3% of individuals 35,36. Up
to 6 months, the dysfunction may persist in a small proportion and,
together with other sequelae was more common in patients with lower Ct
values regardless of age, gender, comorbidities and infection severity.
Our study relied on data collected by surveys and electronic medical
records of hospital admitted patients but also outpatient cases; thus,
it could be less controlled compared to studies focusing on inpatient
cases only, lacks of data on treatments, and did not differentiate
further the category of patients requiring from low-flow oxygen to
reservoir mask. However, in March, most of the potentially impactful
treatments were not available, while recall bias may have affected signs
and symptoms reliability, but less likely that of the other outcomes. A
classification of COVID-19 severity based on the worst oxygen support
during hospitalisation should be carefully used as single parameter,
since biological variables depending on disease severity such as the
ratio of arterial oxygen partial pressure to fractional inspired oxygen
may not directly correlate with the provided oxygen support, especially
in case of intubation and CPAP in elderly or comorbid patients. Lastly,
we faced a 13% of non-responder to the survey that partially unbalanced
the representativeness of our sample compared to the Ct distribution of
the sampling frame.
The currently emerging evidence is that early Ct values from
nasal-pharyngeal swab correlate with disease susceptibility (age and
comorbidities, such as smoking and hypertension, both associate with
potential differential expression of ACE2 37,38) and
clinical presentations and predict disease severity, survival and
sequelae.
Whether a better definition of these patterns could help at triaging
newly diagnosed cases is pending, as well as potential application of
SARS-CoV-2 viral load in routine clinical practice. Reporting predictive
virological parameters, as already done for other infections, could
inform clinicians management and strategies for monitoring and
allocating resources; this may be especially useful during the climax of
SARS-CoV-2 waves when hospital beds and resources are limited and
require programmed and evidence-based selections and timely risk
stratifications.
The interpretation of a single Ct value should still be performed
cautiously as it may be affected by sample collection, analysed gene,
adopted assay, and analytic limits 39. Longitudinal
studies should evaluate further viral dynamics to better interpret Ct
values in accordance with the moment of swab collection along COVID-19
course. Indeed, quantitative assays based on RT-PCR and other techniques
are under development to exactly quantify SARS-CoV-2 RNA and may be soon
introduced in routine clinical management, integrating qualitative tests
by overcoming many of these limitations.