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Primary tonsillar tuberculosis in a pediatric patient

Abstract Rationale: Tuberculosis is an entity that usually affects the lungs, although extrapulmonary sites can also be involved. Tonsils are rarely affected, especially in the absence of pulmonary disease, primary tonsillar tuberculosis being a diagnostic challenge for the clinician. Patient concerns: We present the case of a 14-year-old female teenager, presented to our Pediatric Service with a 14-day history of dysphagia, odynophagia and left reflex otalgia associated with a 5 kg weight loss. Clinical examination revealed mild pharyngeal erythema, marked enlargement of the left tonsil infiltrating the lateral pharyngeal wall and the uvula and painful, mobile, nonadherent to deep bilateral latero-cervical adenopathy. Diagnosis: Positive interferon-gamma release assay (QuantiFERON-TB gold). Mantoux test reading was 16 mm. Interventions: During hospitalization, the patient received Clindamycin and Gentamicin for 3 days i.v., with discrete relief of symptoms and inflammatory markers. On the 4th day of hospitalization, treatment with Imipenem/Cilastin is started for 7 days in micro-perfusion, with tonsil hypertrophy decrease in size and favorable clinical evolution. Outcome: Tonsil hypertrophy decreased in size and patient had a favorable clinical evolution. At discharge, the patient was given a 6-month course of anti-tuberculous drug. Lessons: The particularity of this case is represented by the rarity of primary tuberculosis of tonsils in children, with unilateral involvement, displaying at the same time a common issue encountered in the current practice: the limitations and the difficult course of setting the diagnosis due to the involvement of relatives in the medical act.


Introduction
Tuberculosis (TB) is an infectious malady frequently caused by Mycobacterium tuberculosis bacteria. Although it usually affects the lungs (90%), other organs can be involved, causing extrapulmonary tuberculosis. [1] The most common extrapulmonary site of tuberculosis is represented by the lymph nodes, the nasopharynx and oropharynx, having a less than 5% incidence. [2] Tonsils seem to acquire even in a smaller percentage of the disease due to the thickness of the protective epithelial covering of the oropharyngeal mucosa, to the oral cavity's saprophytes action or because of the antiseptic effect and cleansing action of the saliva. [3] The right diagnosis and the accurate treatment are vital for peoples' health, not ignoring the devastating social and economic impact, including poverty, stigma, and discrimination.
The most recent reports of the World Health Organization (WHO) show that 10 million people fell ill with TB in 2019, tuberculosis killing 5000 people every day. TB treatment saved about 58 million lives globally between 2000 and 2018, but important diagnostic and treatment gaps persist. Vaccination, pasteurization of milk to anti-TB treatments plays their role, but somehow the poor nutrition, low personal hygiene, immunode-ficiency diseases and the increasing rates of multiple drugresistant tuberculosis (MDR-TB) and extensively drug-resistant tuberculosis (XDR-TB) seem to frustrate the efforts of the healthcare providers. [4] Pediatric tuberculosis in particular can be troublesome to discover and treat because often in everyday practice this diagnostic is overlooked. Another ugly truth of our days is that due to the current epidemiological context of "Sars-Cov-2 infection" the access to medical care tends to be more difficult and Mycobacterium tuberculosis tends to be forgotten, fact that inevitable leads to a delay in diagnosis and treatment.
In this study, we report a primary form of tonsillar tuberculosis, a rare medical condition, in a 14-year-old female accompanied by the medical literature.

Case report
We present the case of a 14-year-old female teenager, presented to our Pediatric Service with a 14-day history of dysphagia, odynophagia and left reflex otalgia associated with a 5 kg weight loss. During this time, the patient was treated with antibiotics (Amoxicillin/Clavulanate, Cefixime) and anti-inflammatory drugs, with no clinical improvement. There was no relevant personal or familial background of tuberculosis or other infectious. Immunized to date according to the national immunization scheme (BCG included).
On clinical examination, there was tender bilateral laterocervical adenopathy (∼25/20 mm-right side, ∼30/25mmleft side), painful, mobile and nonadherent to the deep planes; mild posterior pharyngeal wall erythema, marked enlargement of the left tonsil infiltrating the lateral pharyngeal wall and the uvula, moderate trismus. No other abnormal findings were found on the detailed examination.
Initial laboratory tests showed normal complete blood count (CBC), a mildly elevated erythrocyte sedimentation rate (ESR) at 57 mm/1 h and serum C-reactive protein (CRP): 7.79 mg/L, normal liver, and renal function, quantitative immunoglobulins, and urinalysis. Negative pharyngeal swab.
To dispel the suspicion of either malignancy, either a rare infectious disease (Tuberculosis, Actinomycosis) a CT scan of the head and neck was needed, followed by a local biopsy-not possible due to the refusal of the patient's legal relatives. Biopsy was postponed. Instead, a soft tissue and abdominal ultrasound was performed: bilateral latero-cervical inflammatory lymph nodes, mesenteric adenitis, right inguinal inflammatory lymph node.
Positive interferon-gamma release assay (QuantiFERON-TB gold). Mantoux test reading was 16 mm. There were no acid-fast bacilli (AFB) detected from his morning gastric lavage fluid analysis, negative GeneXpert. Normal Chest X-ray excluded pulmonary involvement.
Craniocerebral and cervical magnetic resonance imaging (MRI): chronic bilateral maxillary sinusitis, bilateral ethmoiditis; inflammatory aspect at the level of bilateral palatine tonsils and adenoid vegetation; multiple bilateral upper and middle jugular lymphadenopathy.
During hospitalization, the patient received Clindamycin and Gentamicin for 3 days i.v., with discrete relief of symptoms and inflammatory markers. On the 4th day of hospitalization, treatment with Imipenem/Cilastin is started for 7 days in microperfusion, with tonsil hypertrophy decrease in size and favorable clinical evolution.
The case was diagnosed as a form of primary tonsillar tuberculosis. At discharge, the patient was given a 6-month course of anti-tuberculous drug.

Literature review methodology
A literature search was conducted using PubMed and Scopus to search case reports, clinical trials and case series published from January 1960 through September 2020 for the following keywords (tuberculosis or Mycobacterium tuberculosis) and tonsil. Scientific articles were selected and reviewed to assess the epidemiology, presentation, diagnosis and treatment of tonsillar tuberculosis. Studies reporting the simultaneous presence of tonsillar tuberculosis and tuberculosis of another site or oral malignancy in the same lesion site were also included. We excluded reports available only as abstracts or published in other language than English or Romanian.
The literature search identified 177 studies, of which 17 were not in English or Romanian, 45 concerned other sites of primary or secondary tuberculosis, and 52 were available only as abstracts. The remaining 63 studies consisted of 46 unique case reports and 17 case series, leaving 86 patients included in the analysis (Table 1).

Discussion
Tonsillar tuberculosis is a rare medical condition, both in children and adults. In addition to the general immunesuppressing conditions known to influence the incidence of TB in its pulmonary form, poor oral hygiene, periodontitis, dental extraction and leukoplakia seem to be predisposing factors for tuberculous tonsillitis. [5] Its primary form is presented only as a tonsillar involvement without pulmonary touch. [6] Medical history and clinical examination may raise the suspicion of tuberculosis. TST and IGRA provide evidence for infection but for confirmation, histological examination, Ziehl Neelsen staining, and mycobacterial culture must be done. Treatment of primary tonsillar tuberculosis consists of antituberculous therapy, 6 months of standard anti-tuberculous regimen. [4,6] Although due to the atypical clinical appearance there is a delay in treatment initiation, there is a general good outcome when treated. [7] Unlike its pulmonary form, tonsillar tuberculosis is a multidrug-resistant TB strain free, no case being reported in the literature. [8] Related to our literature search, of the 63 included studies, 66.67% were conducted in Asia, 22.22% in Europe, 5.56% USA, 3.7% in Africa, and 1.85% in Australia, leaving Asia in a front position in TB incidence and total number of cases, just as WHO reports described. Asia had 44% of the new cases diagnosed in 2019, with the highest incidence of 4.34. The age varied from 3 to 80 years with a mean age of 34.9. Most tonsillar tuberculosis cases were identified among 20 to 50 years old adults: 62.74%, with a preponderance of male cases-67.25%, while women represented 37.25%. The male sex seemed predominant as well in the pediatric population (15.6% children < 18 years), were was identified only 1 case of secondary tonsillar tuberculosis. [9] Findings are similar to WHO's distribution of cases reported in 2019: 56% men ≥15 years old, 32% women ≥15 years old, 12% children <15 years old. [4] Moisa et al. Medicine (2021) 100: 44 Medicine Table 1 Main characteristics and results of the eligible studies.
Year      The commonest presentation of TB tonsil was sore throat (59%) just as Nadia Syafeera Naserrudin et al [10] also observed. 15.11% of tonsils infected with TB appear to have ulceration, masses and white patches. In 46% of cases, both tonsils were involved, although a similar percentage of 41.2% of left tonsil lesions was found. Latero-cervical adenopathies were identified in 61.5% of patients. Isolated palatine tonsil lesions are acquired by inhalation and many times are related to pure oral hygiene or are seen in patients with a low immune status. [11] Our review of literature identified only 7% of immunocompromised patients, most of the tonsillar tuberculosis cases being free of comorbidities, just as the presented patient.
All patients had diagnostic based on histopathological examination (54.4% tonsil-lectomy, 45.6% fine needle aspiration biopsy) with 95.58% positive results. Only 40 of them had their sputum examined with 42.5% positive direct smear microscopy. A tuberculosis skin test (TST) was conducted in 33 patients with 60.60% positive results. Forty-one percent of patients had pulmonary form of tuberculosis was confirmed by a positive chest X-ray, only 1 patient confirmed by CT-scan after initial negative X-ray assessment.
All patients received anti TB treatment, just as our presented case. Almost a quarter of them (26.7%) received anterior antibiotic treatment without any clinical improvement, exactly as our 14 old patient who took both betalactam antibiotics and cephalosporins at home, and lincosamide associated with an aminoglycoside during hospital admission, responding only to imipenem/cilastin, a 5th category of antituberculosis drug. [64][65][66][67][68][69] Regarding our case report, we must admit that we had some limitations and the patient's medical management was not the one initially desired. We had a strong clinical suspicion of either malignancy, either infectious disease but despite explaining the patient's relatives the risks that inadequate treatment could expose the patient to, we faced their refusal for a CT scan, forward making a biopsy impossible to obtain. We had no other option than to wait and see the evolution under antibiotic treatment. After a MRI scan was performed, its result with the local clinical remission no longer recommended a local biopsy, leaving us no other way than establishing a diagnosis based only on a positive TST and QuantiFERON-TB gold result.
While both the patient's and doctor's autonomy are a dynamic interface influencing decision making, we faced the ethical dilemma of respecting patient's legal tutors right to refuse investigation knowing the risks that the patient could be exposed to. Unfortunately, an increasing number of patients tend to make an abuse of their legal rights because of present media propaganda, finally leading only to longer admission duration, higher costs and of course, more severe medical cases. [70,71] The purpose of the present paper, a precise analysis of previous presented cases is to come as a support for the medical practitioners' global efforts of reducing the TB medical, social and economic burden.

Conclusion
Primary tonsillar tuberculosis is a rare condition, especially in the pediatric age but must be considered when facing a persistent tonsillitis in countries with a high prevalence of tuberculosis. Histopathological findings and bacteriological confirmation are ideal for establishing a positive diagnosis and immediate initiation of adequate treatment. The particularity of this case is represented by the rarity of primary tuberculosis of tonsils in children, with unilateral involvement, displaying at the same time a common issue encountered in the current practice: the limitations and the difficult course of setting the diagnosis due to the involvement of relatives in the medical act.