Tubulointerstitial nephritis and uveitis syndrome post-COVID-19:
a paediatric case and literature review
To the Editor.
The angiotensin-converting-enzyme-2 receptor is expressed in many
extrapulmonary organs: eyes (conjunctival, corneal and limbal epithelial
cell, retina), nerves, vessels, enterocytes of the small intestine, the
kidney proximal tubules, with possible involvement of these districts by
SARS-CoV-2 infection. Positive conjunctival swab tests are documented,
as well (1). Furthermore, a transmembrane serine protease (TMPRSS2)
cleaves the S protein into S1 and S2 domains upon virus binding to ACE2
and consequently allows the fusion of the viral membrane with the host
cellular membranes permitting the viral entry. The cornea is a potential
site for SARS-CoV-2 infection: the co-expression of ACE2 and TMPRSS2 are
documented in corneal epithelium and endothelium. However, the
expression of both ACE2 and TMPRSS2 in superficial conjunctival
epithelium is much lower than in lung and kidney tissues, as only 6.6%
of cells of the superficial conjunctival epithelium express both entry
proteins TMPRSS2 and ACE2 . Recently, some cases of uveitis
and optic neuritis as an uncommon presentation of ocular involvement in
COVID-19 were described (2). Furthermore, the phlogistic involvement of
renal interstitium and uveal tissue characterizes the two components of
tubulointerstitial nephritis and uveitis (TINU) syndrome. Eyes and
kidneys involvement can persist as asymptomatic and can have an
independent outcome. TINU usually shows bilateral anterior uveitis and
may evolve into a chronic disease. TINU syndrome accounts for
approximately 1%-2% of uveitis in tertiary referral centres (3). Renal
and ocular manifestations in some patients do not occur simultaneously,
making the diagnosis challenging. Treatment includes topical and oral
corticosteroids. Renal disease shows as acute kidney injury and resolves
spontaneously with full recovery of kidney function or evolves into
permanent renal insufficiency. However, uveitis can persist, or it
recurs years after its first presentation (4).
A 7-years-old girl was admitted in our Children Hospital for persistent
fever and bilateral red eyes, photophobia, eye pain, during the COVID-19
pandemic. The nasopharyngeal swab for SARS-CoV-2, diagnosed by a reverse
transcription-polymerase chain reaction - RT-PCR diagnostic on 2
molecular targets (E, N2) (Xpert Xpress SARS-CoV-2, Cepheid,
Maurens-Scopont, France), was positive in two different swabs,
confirming SARS-CoV-2 infection. The swab for other respiratory viruses
was negative. The ophthalmologist diagnosed bilateral, anterior uveitis
and she started a course of eye drops 0.1% dexamethasone (to both eyes
at an initial schedule of once every 2 h for 3 days), and a 1-week
course of eye drops to both eyes twice daily. Treatment was tapered over
a 2-week period and the patient’s symptoms resolved. Furthermore, she
showed nocturia, polyuria and polydipsia.
14 days after the end of steroids’ treatment and a negative swab, she
showed a relapse of uveitis, with a reduction of visual acuity in the
right eye (4/10), ipsilateral conjunctival hyperaemia, bilateral
irido-capsular synechiae, papilledema and macular edema. The optical
computerized tomography (OCT) confirmed the diagnosis. The encephalic
computerized axial tomography was negative, and the magnetic resonance
showed a bilateral slight distension of the perioptic sheath in the
retrobulbar area. Cerebrospinal fluid (CSF) analysis showed normal
chemical-physical examination and cell count, with concordance between
the CSF and serum bands, excluding an intrathecal production of IgG.
Specific PCR analysis for viruses and microbic agents was conducted on
CSF and was negative. Furthermore, autoimmune tests, the anti-NMDA,
anti-MOG and anti-aquaporin 4 antibodies were negative. Blood tests
revealed: C-reactive protein (CRP) 1.79 mg/dl (n.v. < 0.5),
erythrocyte sedimentation rate (ESR) 56 mm/h, serum amyloid A (SAA) 30
ng/dl (< 6.4), fibrinogen 460.3 mg/dl, ferritin, IL-6,
lymphocyte subpopulation analysis in the normal range, creatinine 0.83
mg/dl; hyponatremia: 134 mmol/L; mild increase of C3: 150 mg/dl (n.v.
< 140); blood urea and C4 were in the normal range. The kidney
involvement was confirmed by the creatinine values above the normal
range (0.83 mg/dl), with a glomerular filtration rate of 60 ml/min/1.73
m2, according to Scwartz’s formula. The chemical-physical examination of
the urine shows glycosuria (172 mg/dl), albuminuria (101 mg/l),
proteinuria (130 mg/dl). The diagnosis of tubulointerstitial nephritis
was done and confirmed by the increased serum and urinary levels of
tubular enzymes beta2 microglobulin, alpha1 microglobulin, alpha2
macroglobulin. The Human Leukocyte Antigens (HLA) -B27, -B51, -B57 were
not expressed in the patient. Specific anti-SARS-CoV-2 IgG were
significantly increased: 8080.7 UA/ml (n.v. < 50). She was
treated with prednisone (1 mg/kg/day) for 1 month, with a gradual
tapering of the steroid dose.
She started a second course of topic 0.1% dexamethasone and mydriatics.
During the follow-up, creatinine and glomerular filtration rate
normalized, with the resolution of uveitis, as well.
However, 3 months after the stop of steroids, she showed a relapse of
bilateral uveitis, treated again with steroids (prednisone: 0.75
mg/kg/day) for 1 month, with a gradual tapering. A new relapse occurred
2 months later, and the patient started anti-TNF-alfa treatment
(adalimumab) (40 mg/every 14 days), with the complete resolution of the
eye involvement. The diagnosis of TINU syndrome was done, in conformity
of the clinical outcome of the patient.
TINU syndrome is a rare disease with kidney and eyes inflammatory
involvement. The prevalence of TINU syndrome between patients attending
specialist uveitis centres, is < 0.1- 2% in the general
populations and 1.1-2.3% in paediatric populations (5), with variation
reflecting many factors including level of diagnostic certainty
necessary to recognize the disease, otherwise underdiagnosed. The
epidemiological and etiological data do not permit the real definition
of genetic, epigenetic and environmental factors implicated in the
pathogenesis of the disease (5).
The limited number of patients and studies do not support the
identification of a HLA haplotype and a genetic pattern that predispose
to TINU syndrome. Some studies propose infectious triggers or drugs as
the principal acquired risk factors for the syndrome. Furthermore, there
is an evident different approach between studies on renal diseases,
highlighting the role of a drug-induced hypersensitivity reaction in
most of the cases, and ophthalmic studies, with no clear supported
triggers (5). The most frequent drugs correlated to TINU syndrome are
antibiotics and non-steroidal anti-inflammatory drugs. It is essential
to exclude systemic diseases proven to trigger an overlap of ocular and
renal inflammation, especially Behçet disease, systemic lupus
erythematosus (SLE), Sjogren’s syndrome, sarcoidosis and tuberculosis
(TB), atypical Kawasaki disease (6-9). COVID-19 and MIS-C can show eyes
involvement. Ocular symptoms in adults with COVID-19 are polymorphous:
conjunctival hyperaemia, epiphora, chemosis, anterior uveitis, visual
impairment, abducens nerve palsy. Most of children with MIS-C or with
Kawasaki disease, show conjunctivitis, less frequently anterior uveitis
or corneal punctate epitheliopathy (10). COVID-19-related uveitis show
multifactorial pathogenetic mechanisms, including: 1) direct cytopathic
effect of the virus: the ACE-2 and TMPRSS2 are in the cornea and limbus;
2) the eyes thrombotic vasculopathy; 3) the antigen mimicry between
virus and self-antigens of the eyes, especially in patients with
HLA-B27; 4) activation of the cytokine secretion, especially of
TNF-alfa, IL-1, IL-18.
The clinical course of our patient showed a recurrence of uveitis, with
full recovery of kidney function after a course of steroids therapy.
However, uveitis recurred several times, after its initial presentation,
and resolved with adalimumab.
The prompt diagnosis and treatment of uveitis is of great consequence,
due to the unfavourable ocular complications, as band keratopathy,
posterior synechiae, cataract, increased intraocular pressure with
secondary glaucoma, cystoid macular oedema, visual impairment. To our
knowledge, this is the first paediatric case with TINU syndrome and
SARS-CoV-2 in the international literature.
Keywords: tubulointerstitial nephritis and uveitis (TINU) Syndrome;
SARS-CoV-2; adalimumab; COVID-19.
References
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manifestations in COVID-19 patients: A systematic review and
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Authors:
Maria Cristina Maggio Professor 1; Filippo Collura M.D. 1; Maria Michela
D’Alessandro M.D. 2; Barbara Gramaglia, M.D. 1; Giovanni Corsello Full
Professor 1.
1) University Department PROMISE “G. D’Alessandro, University of
Palermo - Children Hospital “G. Di Cristina”, A.R.N.A.S. Palermo,
Italy
2) U.O.C. of Paediatric Nephrology, Children Hospital “G. Di
Cristina”, A.R.N.A.S. Palermo, Italy