Autor :Bisero, Elsa D.1, Inwentarz, Sandra J.2, Luque, Graciela F.1, Giusti, Silvana A.1, Melillo, Karina C.1, Zatko, Edgar Samuel1, Zapata, Alejandra E.1
1 Hospital Nacional Prof. A. Posadas. Department of Pediatric and Maternity Nursing. Pediatric Service
.
2Instituto Dr. Raul Vaccarezza.
https://doi.org/10.56538/ramr.PUUC3010
Correspondencia : Dra. Elsa Delia Bisero - Soler 1077- Ituzaingó. Zip code: 1714 Province of Buenos Aires. T.E: (011) 4623-0377 - Móbil: (011) 4412-9991 - E-mail: elsibisero@yahoo.com.ar
ABSTRACT
Ocular
involvement is an extrapulmonary manifestation of tuberculosis (TB). It can
affect any element of the visual system. Ocular manifestations may be caused by
an active infection that invades the eye or by an immunological reaction of
retarded hypersensiÂtivity. The most common clinical presentations are: chronic
anterior uveitis, choroiditis, and sclero-keratitis. Despite the existence of
highly-sensitive molecular tools, making a diagnosis of uncommon or unknown
forms of the disease, such as ocular TB (OTB) in children is still a major
challenge, based on clinical presentation, systemic evaluaÂtion, and
therapeutic response. The treatment includes the use of antiphymics and, on
many occasions, steroids.
The
objective was to present a form of endophthalmic, pulmonary, miliary, and
meningeal tuberculosis, within the framework of drug-resistance.
Key
words: Tuberculosis
in children, Ocular tuberculosis, Meningeal tuberculosis, Resistance, Diagnosis
RESUMEN
El
compromiso ocular es una forma extrapulmonar de tuberculosis (TB). Puede comproÂmeter
cualquier componente del sistema visual. Las manifestaciones oculares pueden
ser causadas por una infección activa que invade el ojo o por una
reacción inmunológica de hipersensibilidad retardada. Las
presentaciones clínicas más comunes son: uveítis anterior
crónica, coroiditis y esclero-queratitis. A pesar de la existencia de
herramientas moleculares altamente sensibles, arribar
al diagnóstico de formas poco frecuentes
o no pensadas como la TB ocular (TBO) en un niño sigue siendo un gran
reto, se basa en la presentación clínica,
evaluación sistémica y la respuesta terapéutica. El tratamiento implica el uso de
antifímicos y muchas veces esteroides.
El
objetivo fue presentar una forma de tuberculosis endoftálmica, pulmonar
miliar y meníngea, en el marco de drogo resistencia.
Palabras
clave: Tuberculosis
infantil, Tuberculosis ocular, Tuberculosis meníngea, Resistencia,
Diagnóstico
Recibido: 03/03/2022
Aceptado: 10/09/2022
INTRODUCTION
OTB
is a severe form of TB. Ocular manifestaÂtions can be caused by an active
infection that invades the eye or by an immunological reaction of retarded
hypersensitivity, in absence of the infectious agent. In general, it is
secondary to a systemic infection. The most common presentaÂtions are: chronic
anterior uveitis, choroiditis and sclero-keratitis. Given the diagnostic
difficulties, the following criteria are used: a) proven: when the bacillus is
isolated from an ocular sample, b) probable: isolation in extra-ocular samples,
ocular lesions compatible with TB and adequate response to treatment, and c)
possible-probable, but without being able to evaluate the evolution.1
In
most cases, it isn’t microbiologically conÂfirmed. The general ophthalmologist
needs to know the various clinical presentations of TB-related uveitis to
timely detect this disease, reducÂing ocular and general morbidity.2
CASE REPORT
3-year-old
girl. Creole ethnic group. Comes from the town of La Matanza.
The
patient comes for consultation because she had been having fever for the last
15 days, with two to three recorded fever episodes per day (38-39 °C), and dry
cough.
Personal
history: left lung pneumonia treated as outpaÂtient, 3 months before admission.
Chest X-ray not available.
Family
history: TB in a bacilliferous, diabetic uncle undergoing treatment with whom
the patient has been cohabiting for 4 months. No contact testing has been done.
Physical examination on
admission
Regular
general condition. Eutrophic. Febrile. Bacillus Calmette-Guérin (BCG)
vaccine c/c. Serum and mucosal rhinitis, dry cough. Tachypnea. Global reduction
of air intake, with scarce bilateral fine sub crepitant rales. TenÂdency to
fall asleep.
Analytical data on
admission
Normal
blood count. Erythrocyte sedimentation (globular sedimentation rate, GSR):
35/mm3 (1st.
hr). Negative blood cultures (BC) (x2). Renal and liver function, coaguÂlation
profile, proteinogram, and immunoglobulins (Ig), all normal.
Nasopharyngeal
secretions viral testing (NPST) through indirect immunofluorescence (IIF):
isolated Rhinovirus.
Cerebrospinal
fluid (CSF): lymphocytic pleocytosis, hypoglycorrhachia. Remaining tests,
normal.
Chest
X-ray: micronodular infiltrate with predominant right hemithorax. (Figure 1)
The
patient remained hospitalized at the Hospital Posadas, with the following tests
requested: a) tuberculin test: PPD (purified protein derivative) RT 23 (2TU):
0mm; b) gastric lavage (GL): negative Ziehl Neesel (ZN) and positive culÂture
(C) for Mycobacterium tuberculosis (MT); c) serology for human
immunodeficiency virus (HIV), hepatitis (A, B, C),
toxoplasmosis, herpes simplex virus, syphilis (VDRL, venereal disease research
laboratory), chagas Mycoplasma pneumoniae: all negative; d) nuclear
magnetic resonance of the brain: normal; f) chest high-resolution computed
axial tomography (HRCT): pathological; and g) fundoscopic exam: infiltrates at
posterior pole compatible with miliary TB in both eyes. Pupils with clear, well-defined
borders. (Figure 2)
Due
to clinical symptoms, family history and suppleÂmentary tests, the condition
was assumed as disseminated pulmonary TB with pulmonary (miliary), ophthalmic
and central nervous system (CNS) involvement. Negative focus control test.
Indicated
treatment: ceftriaxone 100 mg/kg/day. IsoÂniazid (H) 10 mg/kg/day, rifampicin
(R) 15 mg/kg/day, pirazinamide (Z) 25 mg/kg/day, ethambutol (E) 20 mg/kg/ day.
Meprednisone 1 mg/kg/day, with progressive reduction in 30 days.
The
CSF report showed direct common germs and negaÂtive culture. Negative ZN and
positive culture. Gene Xpert® (MT/RIF) for MT:
not detected. Meningeal TB confirmed.
After
32 days of hospitalization, positive PCR (polymeraÂse chain reaction) for MT.
Gene Xpert® (MT/RIF) negative D, and
positive C (MT). Resistant to R. Geno Type MTDRsl. No mutations
detected in genes gyrA gyarB, which confer resistance to
fluoroquinolones in genes, nor in genes rrs and eis, which confer
resistance to capreomycin (Cm) and aminoglycosides. Sensitive to: streptomicin
(S), E, amikacin (Km), Cm, H and kanamycin (Km).
After
finding there was resistance to R, the treatment remained with H, E, Z and
levofloxacin (Lfx) 15 mg/kg/day, in accordance with experts’ recommendations.
18 months of treatment suggested.
2
months after the indicated treatment, GL was perÂformed: negative ZN and C.
Ophthalmologic control after 2 months of treatment: macula with normal shine.
Vessels of normal caliber. Raised off-white lesions compatible with tuberculous
granuloma outside both vascular arcades. (Figure 3)
After
3 months, there was a reduction in the number and size of tuberculous
granulomas in both eyes. Attached retina. (Figure 4)
Good
clinical evolution. No adverse drug reactions (ADRs). After completing 18
months of treatment, both the chest X-ray and the ophthalmologic examination
were normal.
DISCUSSION
TB
is an infectious disease produced by MycobacÂterium tuberculosis that
affects mainly the lungs, but also other organs of the body.
OTB
is rare, and its impact is unknown. AccordÂing to the regional endemicity of
TB, it represents between 0.5% and 18% of the cases of uveitis.3
Children
show higher inflammatory response and predisposition to meningeal and miliary
TB. In cases of disseminated or miliary TB, it has been described that it
represents between 1% and 20%. According to the work of Guadalupe Tenorio et al,
the association between miliary TB and ocular involvement accounts for 17.9%.4-6
Within
the historical framework, in the study of M. Elena De Benedetti Z et al, the
oldest description belongs to Maitre-Jan (1707), who described the case of a
patient with a lesion in the iris attributed to TB. Gueneau de Mussy (1830)
acknowledged the presence of choroidal tubercula in miliary TB; Manz (1858)
described a choroidal tuberculum histologically. The ophthalÂmologic exam is
attributed to von Jaeger (1855), Fraenkel (1867) or Von Graefe and Leber
(1868). Cohnheim (1867) provided a detailed description in 7 necropsies and
produced choroidal tubercula experimentally. Julius von Michel identified the
bacillus in the eye.2, 7, 8
There
is a broad spectrum of clinical presentaÂtions, which aren’t exclusive to this
infectious disease. They vary, depending on the virulence of mycobacteria, the
resistance of the host to that mycobacteria, and the degree of tissue hypersenÂsitivity
to it.2, 9, 10
It
can be primary or secondary, unilateral or bilateral. It is caused by an active
infection that invades the eye (with the presence of the microorÂganism in the
ocular tissues) or by an immunologiÂcal reaction of type IV retarded
hypersensitivity to various antigenic components of the mycobacteria itself (in
the absence of the infectious agent).
Francisco
Infante explains that the ethiopathogÂeny of the infection can be: a) primary:
it occurs through saliva or sputum particles, through soil, dust, detritus of
animals or plants that infect the eroded conjunctiva, and b) secondary to blood
or lymphatic dissemination. They can both be uniÂlateral or bilateral.2, 4, 11
The
most common clinical presentations of OTB are: a) uveitis. It can be anterior,
intermediate, posÂterior or panuveitis. The most common is posterior uveitis
(33%-42%), with lesions mostly present in the choroid; b) choroidal granulomas.
The choroid receives the highest rate of blood flow and creates an oxygen rich
atmosphere that favors the multiÂplication of bacilli and manifests as focal,
multifoÂcal or serpiginous choroiditis, solitary or multiple choroidal nodules
(tubercula), choroidal granuÂloma (tuberculoma), neuroretinitis, subretinian
abscess, endophthalmitis, panophthalmitis and retinal vasculitis; and c)
sclero-keratitis.2, 6, 12-14.
The
ophthalmologic exam detects choroidal tubercula, which can be one of the first
signs of disseminated disease. Tubercular choroidal granulomas can be solitary
or multiple, as those presented in our case. Their size can vary from 0.5 to 3
mm and they are most commonly located at the posterior pole. They have a grey,
greyish-white or yellowish color, with ill-defined borders. Vasculitis can be
observed, associated with bleedÂing and/or exudation in the affected area. When
it evolves, the center of the lesion turns pale and the borders become more
defined, surrounded by a halo of dark pigment.1,
8, 9
Other
diagnostic and evolution control methÂods: a) fluorangiography and indocyanine
green angiography, an up to 100% useful technique to detect choroidal
granulomas; b) ecography with variable expressions of the choroidal
tuberculoma, which allows us to discard other etiologies such as choroid
melanoma and cystic lesions (these methods weren’t used in this case report);
and c) optical coherence tomography (OCT) that detects retinal diseases.6
The
presence of a positive C-reactive protein (CRP) test at the aqueous or vitreous
humor with positive ZN or C, associated with ocular lesion, must be considered
a definitive diagnosis. HowÂever, this rarely happens.
The
finding of choroidal tubercula is specific and allows early use of anti-TB
therapy, even before the diagnosis is confirmed by other positive samples.
The
chest X-ray has good sensitivity to compatÂible lesions; HRCT with contrast
media can early reveal signs of miliary TB.8,
12
Tuberculin
hyperergia and/or the histology of caseous granuloma are also illustrative.
Despite
the existence of highly sensitive molecuÂlar tools, the diagnosis of OTB is
still probable, and this entity is difficult to detect and difficult to treat.
For a diagnosis to be considered as conÂfirmed, the ocular material and the
puncture of the aqueous or vitreous humor must be positive for polymerase chain
reaction, bacilloscopy or culÂture, or both. Multinational retrospective cohort
studies have been organized in an effort to unify nomenclature, diagnosis, and
treatment criteria. Global efforts to simplify and standardize the OTB approach
could be useful to provide faster and more effective care.12
In
our case, the diagnosis was based on the positive epidemiological family
history, the images with miliary pattern, the meningeal involvement, the
positive bacilloscopy and the abnormal ophÂthalmologic exam.
Other
causes of uveitis with granulomatous lesions in infections are: toxocariasis,
toxoplasÂmosis, syphilis, cat scratch disease, herpes, CMV (cytomegalovirus),
histoplasmosis, etc. Also in systemic diseases such as autoimmune diseases or
sarcoidosis. Among non-infectious diseases, we must highlight primary and
metastatic neoplasia.
Treatment
regimens are the same as those for pulmonary TB, but they last longer. We recomÂmend
a fully oral regimen consisting of H, Z, and E for 12 months without using any
injectable agent. Longer regimens have the purpose of treating the infection
and reducing the antigenic stimulus that is responsible for maintaining
retarded immunity. Benedetti et al say that access to infected ocular tissue by
the systemic agents is limited by the lack of ocular vascularization. Longer
treatments would ensure access by chemotherapeutic drugs, thus avoiding
sequelae.2
In
certain patients, it is necessary to use sysÂtemic steroids or
immunosuppressants to reduce the damage of the hypersensitivity reaction.
Severe cases use intravitreal methotrexate. In this case report, corticosteroid
therapy was used, due to the meningeal and ophthalmologic components.4
Despite
the existence of highly sensitive molecuÂlar tools, OTB diagnosis is still
presumptive. In our case, the diagnosis was based on the positive
epidemiological family history, the images with miliary pattern, the meningeal
involvement, the positive bacilloscopy and the abnormal ophthalÂmologic exam.
During
evolution, resistance to R was detected. Cases of isolated resistance to R with
sensitivity to H are very rare. They represent a problem for the treatment,
since there are multiple conditioning factors, experts must be consulted, and a
second-line drug resistance test has to be done, rotating the therapeutic
regimen for the purpose of obtainÂing good evolution, avoiding sequelae, and
achievÂing patient recovery. There are several tools to avoid their appearance,
one of them being the use of directly observed therapy, avoiding the severe threat they represent for the control of TB.14, 15
CONCLUSIONS
OTB
is a mycobacterial disease that can go unÂnoticed because it is very rare. It
is important to perform routine ophthalmologic exploration in patients with
miliary tuberculosis in order to make a timely OTB diagnosis. Bacilloscopy and
culture are still essential for the diagnosis of sensitive and resistant TB.
The appearance of pharmacological resistance in children implies bad
epidemiological control and failure in prevention.
Conflict
of interest
None
to declare
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