Signal transducer and activator of transcription 1, commonly known as STAT1, holds significant importance within the STAT family. It plays a crucial role in governing various cellular processes such as growth, differentiation, proliferation, metabolism and programmed cell death by engaging the JAK-STAT pathway.
1,2,3 initial reports documented the occurrence of germline STAT1 Loss of Function (LOF) mutations associated with Mendelian susceptibility to mycobacterial disease (MSMD) and STAT1 Gain of Function (GOF) mutations linked to chronic mucocutaneous candidiasis (CMC). Subsequent research has affirmed that both STAT1-GOF and LOF germline mutations lead to immune deficiency and immune dysregulation, manifesting a broad range of clinical manifestations. The patient under our consideration was found to have a STAT1 GOF mutation.
4,5,6
STAT1 Gain of Function (GOF) mutations can lead to a diverse spectrum of manifestations, encompassing mucocutaneous fungal infections resulting from Candida albicans, along with ear, nose and throat (ENT) infections, as well as lower respiratory infections provoked by Streptococcus species, Staphylococcus aureus and Pseudomonas aeruginosa.
7 Our patient had a prior medical history of recurring oral candidiasis, which required
Voriconazole prophylaxis. He was also on baricitinib (JAK inhibitor). Inspite of this, he presented with a wide range of infections which posed a significant management challenge. As per literature, management of patients with severe infectious and autoimmune symptoms stemming from STAT1-GOF mutations primarily involve hematopoietic stem cell transplantation and/or the administration of oral JAK inhibitors.
8
We adopted targeted treatment strategy to address the various infections. Extensive screening was conducted to identify the specific infections, leading to a treatment plan that encompassed the use of ATT with H, Z, E
Ofloxacin for TB, Liposomal
Amphotericin B and
Posaconazole to combat pulmonary candidiasis, oral
Valganciclovir for CMV,
Intravenous Immunoglobulin (IVIG) for adenovirus and
Oseltamivir to manage influenza A and H3N2. We preferred to give
IVIG instead of
Cidofovir for adenovirus infection inspite of it being recognised for use in immunocompromised state because of its drug interaction with
Amphotericin B leading to side effects like nephrotoxicity and ototoxicity.
9,10
Candida spp are considered a part of the normal microflora of the skin, oral cavity, gastrointestinal mucosa, respiratory tract and genitourinary tract.
11 It is not possible to distinguish between commensal, colonizer and true candida infection. In immunocompromised patients, candida might be isolated from respiratory specimens such as sputum and BAL, but it should be interpreted with caution. The true incidence of Candida spp pneumonia ranges from 0.23% to 0.4%.
12,13 The diagnosis of Candida spp pneumonia is difficult due to the nonspecific clinical and radiological features and the lack of specific biomarkers which necessitates the histopathological demonstration of the organism for confirmation of diagnosis. Colonization of the respiratory epithelium by Candida species is a prerequisite of invasive infections. The predominant risk factors for invasive candidiasis are immunocompromised host, repeated use of broad-spectrum antibiotics, severe neutropenia, chemotherapy-induced mucositis and prolonged hospital stay.
14,15
The treatment of candida in
BAL fluid is largely controversial. In our case we decide to treat the candida tropicalis isolate, as child was suffering from STAT1 mutation which made him prone to mucocutaneous candidiasis. In our case, Candida drug susceptibility testing was done by vitek automated system, which showed resistance to
Fluconazole and voriconazole.
Posaconazole MIC was 0.50 mcg/ml, however guidelines are not defined for interpretation. We started
Posaconazole at 18 mg/kg/day in 3 divided doses as oral suspension.
16 Since
Posaconazole interacts with rifampicin
17, the latter was stopped and ATT was shifted to HZE and ofloxacin. Oral
Valganciclovir for CMV and
Oseltamivir to manage influenza A is also indicated for use in immunocompromised children.
18,19 Hence while treating polymicrobial infection, it’s important to keep drug interactions in mind. On follow up,
Posaconazole trough levels were obtained which were <0.1 which is below the recommended range of 1 mcg/ml for treatment hence dose was increased and child was asked to follow up after 1 week with repeat levels.
16| References : |
- Yang Q, Yu C, Wu Y, Cao K, Li X, Cao W, et al. Unusual Talaromyces marneffei and Pneumocystis jirovecii coinfection in a child with a STAT1 mutation: A case report and literature review. Front Immunol. 2023;14:1103184. doi: 10.3389/fimmu.2023.1103184.
- Stark GR, Darnell JE. The JAK-STAT pathway at twenty. Immunity. 2012;36:503-514. doi: 10.1016/j.immuni.2012.03.013
- Ivashkiv LB. IFNγ: signalling, epigenetics and roles in immunity, metabolism, disease and cancer immunotherapy. Nat Rev Immunol. 2018;18:545-558. doi: 10.1038/s41577-018-0029-z
- Dupuis S, Dargemont C, Fieschi C, Thomassin N, Rosenzweig S, Harris J, et al. Impairment of mycobacterial but not viral immunity by a germline human STAT1 mutation. Science. (2001) 293:300-3. doi: 10.1126/science.1061154
- Liu L, Okada S, Kong XF, Kreins AY, Cypowyj S, Abhyankar A, et al. Gain-of-function human STAT1 mutations impair IL-17 immunity and underlie chronic mucocutaneous candidiasis. J Exp Med. (2011) 208:1635-48. doi: 10.1084/jem.20110958
- van de Veerdonk FL, Plantinga TS, Hoischen A, Smeekens SP, Joosten LAB, Gilissen C, et al. STAT1 mutations in autosomal dominant chronic mucocutaneous candidiasis. N Engl J Med. (2011) 365:54-61. doi: 10.1056/NEJMoa1100102
- Zhang W, Chen X, Gao G, Xing S, Zhou L, Tang X, et al. Clinical Relevance of Gain- and Loss-of-Function Germline Mutations in STAT1: A Systematic Review. Frontiers in Immunology [Internet]. 2021;12.
- Okada S, Asano T, Moriya K, Boisson-Dupuis S, Kobayashi M, Casanova JL, et al. Human STAT1 Gain-of-Function Heterozygous Mutations: Chronic Mucocutaneous Candidiasis and Type I Interferonopathy. J Clin Immunol. 2020/08/27 ed. 2020 Nov;40(8):1065-81.
- Wade RL, Chaudhari P, Natoli JL, Taylor RJ, Nathanson BH, Horn D. Comparison of adverse events and hospital length of stay associated with various amphotericin B formulations: sequential conventional amphotericin b/lipid versus lipid-only therapy for the treatment of invasive fungal infections in hospitalized patients. P T. 2013 May;38(5):278-87.
- Alcamo AM, Wolf MS, Alessi LJ, Chong HJ, Green M, Williams JV, et al. Successful Use of Cidofovir in an Immunocompetent Child With Severe Adenoviral Sepsis. Pediatrics. 2020;145:e20191632.
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- Masur H, Rosen PP, Armstrong D. Pulmonary disease caused by Candida species. Am J Med. 1977 Dec;63(6):914-25.
- Haron E et al. Primary Candida pneumonia. Experience at a large cancer center and review of the literature. Medicine. 1993;72:137-42
- Petty LA et al. Candida dubliniensis pneumonia: a case report and review of literature. Mycopathologia. 2016;181: 765-8
- Tan M, Wang J, Hu P, Wang B, Xu W, Chen J. Severe pneumonia due to infection with Candida krusei in a case of suspected Middle East respiratory syndrome: a case report and literature review. Exp Ther Med. 2016;12:4085-4088.
- Bernardo VA, Cross SJ, Crews KR, Flynn PM, Hoffman JM, Knapp KM, et al. Posaconazole therapeutic drug monitoring in pediatric patients and young adults with cancer. Ann Pharmacother. 2013;47:976-983.
- Hohmann C, Kang EM, Jancel T. Rifampin and Posaconazole Coadministration Leads to Decreased Serum Posaconazole Concentrations. Clinical Infectious Diseases. 2010;50:939-940.
- Reusser P. Oral valganciclovir: a new option for treatment of cytomegalovirus infection and disease in immunocompromised hosts. Expert Opinion on Investigational Drugs. 2001 Sep 1;10(9):1745-53.
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