Dear Editor:
It is estimated that about 10% of patients who have been infected with
SARS-CoV-2 worldwide suffer from Long-Covid, about 65 million people
[1]. Although we are beginning to know its pathophysiology, there is
still no evidence on its treatment. We present the case of a patient
with persistent prolonged symptoms who had an optimal response to
nirmatrelvir/ritonavir 2 years after acute infection.
A 38-year-old woman with a history of psoriasis (untreated and well
controlled) who, after receiving the first dose of Pfizer-BioNTech®
vaccine on January 13, 2021, presented with headache, fever of 38ºC and
myalgias. Given the persistence of symptoms after 48 hours, RT-PCR
against SARS-CoV-2 (ARGENE® SARS-COV-2 R-GENE®) was performed and was
positive. Anosmia, ageusia and dry cough were added to the referred
symptomatology. On February 8, serology was performed, detecting IgG
against protein S of SARS-CoV-2 by chemiluminescence technique (CLIA) in
automated equipment (Liaison ® SARS-CoV-2 S1/S2 IgG). Given the
persistence of symptoms, including hyperthermia, corticotherapy was
started at medium doses for 3 weeks. She presented better thermal and
other symptom control, but persisted with afternoon febrile fever. He
was referred to the Post-Covid-19 consultation of the Infectious
Diseases Unit.
In a first contact, physical examination was normal and complementary
tests were requested in which only elevated values of erythrocyte
sedimentation rate [ESR: 20 mm/h (0-10)] and D-dimer [900 ng/mL
(0-500)], with autoimmunity, hemogram, proteinogram, acute phase
reactants, immunoglobulins, lymphocyte populations, liver enzymes, ions,
hormone and vitamin studies were unremarkable. Serology was negative. A
second course of corticosteroids was started, with no response,
persisting with poorly tolerated afternoon febrile fever with headache,
asthenia, myalgia and atypical chest pain. A complete computed axial
tomography (CAT) scan was performed, showing adenopathies of
non-significant size at the cervical, retroperitoneal and mesenteric
levels. A positron emission tomography (PET) scan was requested, which
only reported diffuse inflammatory gastric hypermetabolism, so
gastroscopy was performed with biopsies that ruled out pathology
including infection by Tropheryma whipplei . The initial
analytical study was repeated 10 months after the onset of the clinical
picture, adding tumor markers and extraction of blood cultures, and
again the results were irrelevant.
One year after the onset of symptoms and due to the persistence of a
poorly tolerated daily afternoon fever, treatment with colchicine was
tried as an immunomodulator and a genetic study of autoinflammatory
syndrome was requested, which was negative. After starting colchicine,
the patient was afebrile and her general symptoms improved. The
treatment was maintained for 5 months with good control and after its
withdrawal she again presented febrile fever and worsening of the
previous symptoms. Colchicine was reintroduced at the same dose and
again she was asymptomatic.
A few weeks later, despite continuing with colchicine, the febrile fever
reappeared and she presented a significant clinical deterioration that
did not improve despite increasing the dose. Finally, two years after
the onset of symptoms and after the approval by a multidisciplinary
committee, we withdrew colchicine and started antiviral treatment
against SARS-CoV-2 (off-label) with nirmatrelvir/ritonavir for 5 days
with immediate resolution of symptoms. After 6 weeks of treatment, she
has not presented febrile fever or the symptoms previously mentioned.
Long-Covid has been more frequently associated with ages between 36-50
years, female sex and independently of the severity of the acute
infection [2]. Multiple hypotheses have been proposed, including the
persistence of viral activity from certain reservoirs [3, 4]. We
suggest that, in the present case, viral persistence would have
triggered a persistent inflammatory response, causing the
symptomatology. Colchicine would have modulated the inflammatory
response, thus explaining the good symptomatic control with its
administration and the worsening with withdrawal.
After a literature review, we found only 4 case reports describing a
clear improvement after the use of nirmatrelvir/ritonavir in patients
with persistent symptoms after acute infection [5]. However, in most
of them it was administered a few weeks later and after re-infection and
none of them had such a prolonged and disabling evolution as in the
referred patient. In addition, a recent preprint shows a decrease in the
incidence of Long-Covid with the use of nirmatrelvir/ritonavir in the
acute phase, supporting the practice [6].
In conclusion, the persistence of viral activity after acute infection
could be a cause of Long-Covid and in this sense, the use of
nirmatrelvir/ritonavir is a treatment option. However, the evidence is
scarce and there are probably other influencing factors such as immune
dysregulation, alteration of the microbiota or vascular microtombosis
and endothelial dysfunction [4].