key: cord-1051227-v18vrsh0
authors: San-Juan, Daniel; Pérez Melgoza, Misael; Zavaleta Martínez, Oscar; López, Raúl Aguilar; Salazar, Alvaro Contreras; Bastida, Jesús del Moral; Ojeda, Raúl Miranda
title: “Disseminated multidrug-resistant tuberculosis and SARS-CoV-2 co-infection in a child with IL-12Rβ1 deficiency”()
date: 2022-04-30
journal: Indian J Tuberc
DOI: 10.1016/j.ijtb.2022.04.008
sha: d0e0a57a173c46ac5e621f8bc928259d97aeb4da
doc_id: 1051227
cord_uid: v18vrsh0

Mendelian Susceptibility to Mycobacterial Disease describes a spectrum of inherited defects, of which complete deficiency of the interleukin-12 receptor β subunit 1 (IL-12Rβ1) is the most common cause. This condition results in a predisposition to severe disease caused by mycobacteria. We report a case of disseminated multidrug-resistant tuberculosis with extensive central nervous system affection with SARS-CoV-2 co-infection, in a 4-year-old child with IL-12Rβ1 complete deficiency.

Complete deficiency of the interleukin-12 receptor β subunit 1 (IL-12Rβ1 or MIM:614891) is the most common genetic etiology of Mendelian Susceptibility to Mycobacterial Disease (MSMD) (1) . To present, only 213 patients from 164 families worldwide have been reported to have complete IL-12Rβ1 deficiency and possibly many others may have been diagnosed (2). Mycobacterial disease is the most prevalent infection in IL-12Rβ1 deficiency due to an increased susceptibility to the manifestation of severe type infection in these patients and has been reported in 80% of them (2,3). Complete IL12Rβ1 deficiency has incomplete clinical penetrance; In other words, some patients are asymptomatic (4) .

Each year, 1 million children contract tuberculosis (TB), of whom 210,000 die because of the disease. Approximately 10% of all TB cases have been reported to occur in children, and in this age group deaths are usually caused by Central Nervous System (CNS) TB or disseminated disease (5).

To our knowledge, only three patients with IL-12Rβ1 deficiency and disseminated multidrug-resistant tuberculosis with CNS TB have been reported (3,6,7).

We reported a child with disseminated multidrug-resistant tuberculosis and SARS-CoV-2 co-infection due to IL-12Rβ1 deficiency.

Case report J o u r n a l P r e -p r o o f consanguineous marriage, from Tenango del Valle, México. He was premature (32 weeks). Neonatal screening test of congenital hypothyroidism, galactosemia, adrenal hyperplasia, phenylketonuria, and biotinidase deficiency, was normal and his sibling is healthy. Neurodevelopment was normal. History of non-specified severe infections in her family and any other relevant medical information.

He received BCG vaccine at birth, and 3 months later a local edema appeared, which self-resolved one month later without treatment. Seven months later, showed 2 retro auricular masses that got resolved without treatment. In June 2019, (at 2 years), a regional left armpit lymphadenitis due to BCGitis was diagnosed, and received rifampicin for unknown time without improvement.

On April 2020, the patient was remitted for the first time to our hospital and a ganglionic tuberculosis was diagnosed by a lymph node biopsy. Blood cell count analysis showed leukocytosis, neutrophilia, and lymphocytosis and was treated for nine months with isoniazid (6 mg/kg/day), rifampicin (12mg/kg/day), pyrazinamide (32mg/kg/day), and ethambutol (24mg/kg/day). On January 3 rd 2021, at the age of After recovering from SARS-CoV-2 infection, the patient had persistent fever and paroxysmal hemoptysis requiring blood transfusion on January 21 st ; and ceftriaxone IV 75mg/kg/12hrs was initiated. Simple and contrasted computed tomography (CT) scans found bilateral pleural effusions and brain abscesses, so thoracentesis, gastric liquid sampling and drainage of brain abscesses were done on January 22 nd . Bacilloscopy and GenExpert analysis were positive to Mycobacterium tuberculosis resistant to rifampicin and isoniazid in the brain abscess and pleural effusions. Serology for HIV, HBV, HCV and adenosine deaminase in pleural liquid, were normal. Levofloxacin (20mg/kg/day), amoxicillin with clavulanic acid (75mg/kg/day), linezolid (20mg/kg/day), propionamid (18mg/kg/day), cicloserin (18mg/kg/day) and fluconazole (6mg/kg/day) were given. However, unlike previously published cases, our patient showed substantially more severe neurological manifestations which have led him to be surgically intervened by the neurosurgery service on multiple occasions. All the patients reported above were vaccinated with BCG and had developed BCGitis (3, 4, 6, 7) .

The basic model is that macrophages are infected by mycobacteria, leading to the elaboration of IL-12 by the infected cell. IL-12 acts on the IL-12 receptor on T and NK cells to elaborate interferon-gamma (IFNγ). IFN-γ, in turn, acts on the initiating macrophage through its interferon-gamma receptor phosphorylating the signal transducer and activator of transcription 1 (STAT1) and upregulating IFNγ responsive genes Co-expression of both β1 and β2 subunits is required for IL-12 J o u r n a l P r e -p r o o f binding and high-affinity signaling (9). IL-12Rβ1 also combines with IL-23R to transmit the IL-23 signal, and therefore, mutations in IL-12p40 and IL-12Rβ1 affect IL-23 signaling as well (3, 4) .

There are multiple ways in which diagnosis of complete deficiency IL-12R can be made. Among the options is the evaluation of the expression of IL-12Rβ1 by Real-time PCR. Another option is a whole-exome sequencing revealing where the molecular alteration lies (2).

There is a standardized procedure for the evaluation of the IL-12Rβ1 expression by fluorescence-activated cell sorting and stimulation of T cells by rhIL12 and PHA to assess the production of IFN-γ (10). These are the methods whereby diagnosis was achieved in our patient.

Treatment remains in debate because no evidence demonstrates the superiority of any treatment against others. In some cases, it has been reported the use of IFN-γ, prophylactic antimicrobials, and hematopoietic progenitor cell transplantation (11) .

However, due to the lack of solid evidence, none of the treatments mentioned above was implemented in our patient.

Unfortunately, due to limitations in processing samples in our institution, the precise genetic mutation in our patient could not been identified. However, IL-J o u r n a l P r e -p r o o f 

A Variety of Alu-Mediated Copy Number Variations Can Underlie IL-12Rβ1 Deficiency

XDR TB in a case of IL12Rβ1 deficiency: a case report of Mendelian Susceptibility to Mycobacterial Disease from India

Infección diseminada por vacuna con bacilo de Calmette-Guérin y coinfección por SARS-CoV-2 en paciente con deficiencia de la subunidad β1 del receptor de IL-12

Tuberculosis in Infants and Children. Microbiol Spectr

Susceptibility to mycobacterial disease due to mutations in IL-12Rβ1 in three Iranian patients

Congenital IL-12R1β receptor deficiency and thrombophilia in a girl homozygous for an IL12RB1 mutation and compound heterozygous for MTFHR mutations: A case report and literature review

European journal of microbiology & immunology

Central Nervous System Tuberculosis

Evaluation of interleukin-12 receptor β1 and interferon gamma receptor 1 deficiency in patients with disseminated BCG infection

Mendelian susceptibility to mycobacterial disease-Challenges in hematopoietic stem cell transplantation. Pediatr Blood Cancer

Complete deficiency of the IL IL-12Rβ1 is the most common cause of MSMD 2. We report a child with complete deficiency of the IL-12Rβ1 and SARS-CoV-2 coinfection

The child presents severe impairment of the CNS by multi-drug resistant tuberculosis 4. SARS-CoV-2 co-infection got resolved without complications

IFN-γ remains in debate as treatment for complete deficiency of the IL IL-12Rβ1

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