Author
¹Frances Flanagan, MB, BCh, BAO, ¹Lana Mukharesh, MD, ¹Kenan Haver, MD
¹Division of Pulmonary Medicine, Department of Pediatrics, Boston Children’s Hospital,
and Harvard Medical School, Boston MA.

Case

A 17-month-old previously healthy girl presented with a 6-week history of fever, poor appetite and fatigue. She had no exposure or travel history of note. An initial evaluation during week 1 of her illness included a normal physical examination, a CXR that was interpreted as normal, negative blood and urine cultures, a normal echocardiogram but elevated inflammatory markers (ESR 50mm/hr, CRP 5.3mg/dL). Due to continued fevers, weight loss of 1lb during her illness, persistently elevated inflammatory markers and a negative tuberculin skin test (TST), a repeat CXR was undertaken. Due to concerning features of hilar and paratracheal lymphadenopathy, a chest CT scan was subsequently performed (see images 1-3 below).

Question

The CT findings are most suggestive of infection due to:

A. Aspergillus fumigates
B. Human metapneumovirus
C. Mycobacterium flavescens
D. Streptococcus pneumoniae
E. Mycobacterium tuberculosis

Answer

C. Mycobacterium flavescens

Discussion

The chest CT reveals a large conglomerate of diffuse bulky hilar andmediastinal non-calcified lymphadenopathy, with mild neck adenopathy,bilateral mainstem airway compression, scattered atelectasis and a postobstructive left lower lobe pneumonia. These findings are mostconsistent with an infection due to non-tuberculous Mycobacterium (NTM).It is notoriously difficult to differentiate TB from NTM on imaging inchildren and hence the need for laboratory organism confirmation. Thisis in comparison to adult patients where NTM are more commonlyassociated with bronchiectasis than TB and patients with TB tend to havemore cavitary lesions, nodules and pleural effusions than those withNTM¹. Human metapneumovirus infections typically appear withill-defined patchy consolidation and may have mediastinal lymph nodeenlargement but not typically the large conglomerate of diffuse bulkylymphadenopathy seen on this child’s CT. Findings on CT in children withAspergillus fumigates most often include segmental and multilobarconsolidation, peripheral infiltrates, multiple small nodules, andlarger peripheral nodular masses². Bacterial infection in thelungs, including from Streptococcus pneumoniae, typically present withalveolar consolidation in a lobar and segmental distribution³.

Anextensive work up for malignancy, autoinflammatory conditions andinfectious processes was undertaken. She had a negative TST and anInterferon-γ release assay (IGRA) was not performed due to its reducedsensitivity in children under 2 years of age compared to TST⁴.A cervical lymph node biopsy returned positive on day 18 for acid fastbacilli (AFB). Subsequently one of three gastric aspirates was found tohave acid-fast bacilli.

She was placed on empiric tuberculosistherapy (rifampicin, isoniazid, pyrazinamide & ethambutol), whilstawaiting further speciation. Simultaneously she underwent immunologicaltesting which showed compound heterozygous variants in the IFNGR1 gene(Interferon Gamma Receptor 1 ) (C.523del, p.Tyr175Metfs*2 (frameshift),heterozygous and C.200+1G>A (splice site) heterozygous), which havebeen reported with disseminated mycobacterial infections. This diagnosiswas supported by normal lymphocyte counts but no expression of CD119/IFN-γR on monocytes, and no activation of IFN-γ stimulated by pSTAT inmonocytes.

IFN-γR1 deficiency is caused by a heterozygous orhomozygous loss of function mutation in IFNGR1, leading toimmunodeficiency 27A (autosomal recessive) or 27B (autosomal dominant).40 unique mutations in IFNGR1 have been reported to date⁵.IFN-γR1 deficiency amongst other immunodeficiencies affecting IFN-γproduction and/or signaling are often designated as Mendeliansusceptibility to mycobacterial disease (MSMD)⁶. IFN-γ plays akey role in innate immunity against mycobacteria (via the type 1cytokine pathway), and hence the hallmark feature of IFN-γR1 deficiencyis disseminated disease with weakly virulent mycobacteria (e.g.environmental non tuberculous mycobacteria) and the live, attenuatedMycobacterium bovis bacille calmette-guerin (BCG) strain that is used inthe vaccine against tuberculosis⁷. Of note TSTs use purifiedprotein derivative (PPD) as the test reagent, which is a heterogeneousmixture of more than 200 mycobacterial peptides, some of which areexpressed by both Mycobacterium tuberculosis and NTM. Studies report apositive TST in only 30-60% of children with NTM infections, whereasIGRAs are specifically designed to detect infection with Mycobacteriumtuberculosis and thus usually negative in NTM⁸. Infectionswith other pathogens such as Salmonella, Histoplasma, Toxoplasma andviruses are occasionally found in patients with IFN-γR1 deficiency⁷.Four case reports to date have also linked IFN-γR1 to malignanciesincluding Kaposi sarcoma, pineal germinoma and B cell lymphomas⁵.

Ultimatelyher culture returned with an isolate with 99% similarity toMycobacterium flavescens. Thereafter her antimicrobial therapy wasadjusted, based on sensitivities, to azithromycin, linezolid,ciprofloxacin and continuation of rifampicin. She has responded well totherapy and is currently asymptomatic with resolution of herleukocytosis and normalization of inflammatory markers. A follow upchest x-ray showed resolution of her previously noted adenopathy and wasotherwise grossly normal. Definitive treatment for mendeliansusceptibility to mycobacterial disease (due to IFNGR1 heterozygosity)is a hemopoietic stem cell transplant, which is planned for the nearfuture⁹.

References

Yuan MK, Chang CY, Tsai PH, Lee YM, Huang JW, Chang SC. Comparative chest computed tomography findings of non-tuberculous mycobacterial lung diseases and pulmonary tuberculosis in patients with acid fast bacilli smear-positive sputum. BMC Pulm Med. 2014;14(1). doi:10.1186/1471-2466-14-65
Ankrah AO, Sathekge MM, Dierckx RAJO, Glaudemans AWJM. Imaging fungal infections in children. Clin Transl Imaging. 2016;4(1):57-72. doi:10.1007/s40336-015-0159-2
Cherian T, Mulholland EK, Carlin JB, et al. Standardized interpretation of paediatric chest radiographs for the diagnosis of pneumonia in epidemiological studies. Bull World Health Organ. 2005;83(5):353-359. doi:/S0042-96862005000500011
Kay AW, Islam SM, Wendorf K, Westenhouse J, Barry PM. Interferon-? Release assay performance for tuberculosis in childhood. Pediatrics. 2018;141(6). doi:10.1542/peds.2017-3918
van de Vosse E, van Dissel JT. IFN-γR1 defects: Mutation update and description of the IFNGR1 variation database. Hum Mutat. 2017;38(10):1286-1296. doi:10.1002/humu.23302
Wu UI, Holland SM. Host susceptibility to non-tuberculous mycobacterial infections. Lancet Infect Dis. 2015;15(8):968-980. doi:10.1016/S1473-3099(15)00089-4
van de Vosse E, van Dissel JT, Ottenhoff TH. Genetic deficiencies of innate immune signalling in human infectious disease. Lancet Infect Dis. 2009;9(11):688-698. doi:10.1016/S1473-3099(09)70255-5
Zimmermann P, Curtis N, Tebruegge M. Nontuberculous mycobacterial disease in childhood – update on diagnostic approaches and treatment. J Infect. 2017;74:S136-S142. doi:10.1016/S0163-4453(17)30204-9
Roesler J, Horwitz ME, Picard C, et al. Hematopoietic stem cell transplantation for complete IFN-γ receptor 1 deficiency: A multi-institutional survey. J Pediatr. 2004;145(6):806-812. doi:10.1016/j.jpeds.2004.08.021

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