THE CLINICAL SPECTRUM OF PATIENTS WITH DEFICIENCY OF SIGNAL ... : The Pediatric Infectious Disease Journal (original) (raw)
Mendelian susceptibility to mycobacterial disease syndrome is characterized by a selective predisposition to infection by low-virulence mycobacteria, such as BCG vaccines and environmental mycobacteria, as a result of impairment of the interleukin 12/interleukin 23 (IL-12/IL-23)–interferon gamma (IFNγ) pathway.1,2 Mutations in several genes have been found in affected patients.1,2 Very few patients have been described with STAT-1 deficiency, which is a key signaling component of IFNγ responses, and participates in IFNα/β cellular responses that mediate antiviral immunity. We present the long-term clinical manifestations of 2 siblings who have a recently found mutation in the STAT1 gene,3 and summarize the clinical manifestations of 7 other patients with STAT-1 deficiency previously described.4–7
REPORTS OF PATIENTS WITH STAT-1 DEFICIENCY
The 2 siblings were born to consanguineous parents of Muslim origin. Two other children of this family are healthy. The children received all routine vaccinations, including diphtheria, tetanus, pertussis, hepatitis A and B, measles, mumps, rubella, and annual parenteral influenza vaccine. They were not vaccinated with BCG.
The boy, currently 15 years old, has had mild asthma since he was 1 year old. At 2 years of age, he presented with prolonged fever, general deterioration, and hepatosplenomegaly. Laboratory results revealed white blood cell, 52,000 cells/mm3; platelets, 18,000 cells/mm3; hemoglobin, 6.7 g %; and impaired cholestatic liver function (gamma-glutamyl transpeptidase [GGT]), 1335 units (normal, 10–80); total bilirubin, 81 μmol/L (normal, 0–17); and direct bilirubin, 47 μmol/L (normal, 0). Blood cultures yielded Salmonella group D, which continued to grow for 10 days despite appropriate treatment with intravenous (i.v.) ampicillin and chloramphenicol. Abdominal ultrasound revealed gallbladder empyema. He recovered after 3 weeks' treatment. One month later, he was readmitted because of recurrent fever. His blood cultures were negative, but bone marrow culture yielded Salmonella D. He was treated with ceftriaxone for 2 weeks. At 4 years of age, he was hospitalized due to prolonged fever, rash, and hepatosplenomegaly. Serologic work-up showed positive cytomegalovirus (CMV) IgG and IgM, positive Epstein-Barr virus VCA IgM, and negative IgG and Epstein-Barr virus nuclear antigen (EBNA). He recovered without complications. During the following years, he had other infectious episodes, including: at 3 to 10 years, recurrent otitis media with 1 to 3 episodes a year; at 3 years of age, herpes simplex virus (HSV) gingivostomatitis and herpetic whitlow with 4 recurrences until 12 years; at 4 years of age, lobar pneumonia with a benign clinical course; at 5 to 7 years, molluscum contagiosum. At the age of 9 years, he developed fever and abdominal pain. Blood cultures yielded Salmonella B. He was treated with ceftriaxone for 3 weeks and oral cefixime for an additional 3 weeks, without relapse. His development is normal for his age, but he has short stature; at the age of 15 years, his weight is 44 kg (percentile 7%) and his height is 154.8 cm (percentile <3%).
His younger sister, currently 13 years old, has had mild asthma from an early age. She had the following infections: at 2 months, severe respiratory syncytial virus (RSV) pneumonitis; at 1 year, pneumonia with leukocytosis (60,000/mm3), including eosinophilia (15,000/mm3), with very slow recovery of 3 weeks. At 16 months, she was hospitalized for 5 days with severe gingivostomatitis and interstitial pneumonitis of unknown etiology (HSV negative). At 18 months, she developed bilobar pneumonia and at 2 years she developed varicella complicated by severe Staphylococcus aureus facial cellulitis, treated with parenteral clindamycin and acyclovir. At 4 years of age, she developed interstitial pneumonitis with hypoxia and generalized, including mediastinal and hilar lymphadenopathy. Laboratory tests revealed leukocytosis with 26,000 cells/mm3, absolute neutrophil count of 18,200 cells/mm3, and eosinophilia of 2100 cells/mm3. PPD was negative. Lymph node biopsy showed nonspecific inflammation but no granulomas. Acid-fast stain and cultures for Mycobacterium were negative from gastric aspiration, bronchoalveolar lavage, and mediastinal lymph node biopsy. Bronchoalveolar lavage polymerase chain reaction for Mycobacterium was negative. Serology for CMV and Epstein-Barr virus showed evidence of past infection. Mycoplasma serology was negative. She was treated empirically with i.v. cefuroxime for 17 days with gradual improvement, and her blood counts, including eosinophil count, normalized. Two months later, she was hospitalized for suspected appendicitis. Appendectomy was performed, but the appendix was not inflamed.
At the age of 5 years, she was hospitalized because of 3 weeks' fever and headache. Urine culture yielded Escherichia coli and Klebsiella pneumoniae. Blood and bone marrow cultures were negative for Mycobacterium and any other bacteria. A computed tomography revealed sinusitis and nephronia. She was treated with i.v. cefuroxime for 3 weeks, as recovery was very slow. A few days after termination of the antibiotics, she developed meningitis and Salmonella D was cultured from her cerebrospinal fluid (CSF). She was treated with ceftriaxone for 2 weeks and oral cefixime for an additional 2 weeks. After 3 months, she was hospitalized due to bilateral pneumonia which was treated with parenteral ceftriaxone. During the following 6 months, she was hospitalized for aseptic meningitis and later due to severe Shigella sonei dysentery, treated with i.v. fluids and ceftriaxone. At 8 years of age, she developed severe interstitial RSV pneumonitis, requiring hospitalization with supplemental oxygen for 10 days. At 9 years, she developed right anterior iliac crest osteomyelitis which was treated with 6 weeks of ceftriaxone. Blood cultures yielded no bacterial pathogens. At 10 years of age, she developed abdominal pain without fever. Abdominal ultrasonography revealed several hypodense lesions in liver and spleen. Spleen biopsy revealed granulomatous lesions compatible with mycobacterial disease. Acid-fast stain was negative and culture did not yield any organism. Gradual but complete resolution of the findings occurred after 12 months of therapy with azithromycin, rifampin, and ethambutol. At 11 years of age, she suffered another episode of severe interstitial RSV pneumonitis, requiring hospitalization with supplemental oxygen for 1 week.
While we were completing this manuscript, she developed abdominal pain. Ultrasound showed multiple lesions in her liver and spleen. Spleen biopsy revealed granulomas, whereas acid-fast smear was negative. We suspect another episode of mycobacterial infection.
During these years, the girl underwent investigation for recurrent infections and lymphadenopathy. Respiratory mucosal biopsy showed no evidence of immotile cilia. Serologic tests for C-ANCA and P-ANCA and antinuclear factor were negative, and C3 and C4 values were normal. Immunologic investigation, including IgE values and functions of T-cells, B-cells, and neutrophils were normal; serum immunoglobulins, including IgG subclass values were normal; and serology for HIV and HTLV-1, 2 was negative.
Investigation of the IL-12/IFNγ pathway in both children revealed a new mutation, P696S, in the STAT1 gene, which causes abnormal splicing of STAT1 mRNA and diminishes STAT-1 expression, leading to impaired but not abolished responses after stimulation with IFNα and IFNγ.3 This describes the first autosomal recessive mutation in the STAT1 gene resulting in a partial deficiency. Our 2 sick children were homozygous for P696S/P696S, whereas both parents and another sibling, all healthy, were found heterozygous for this mutation (P696S/WT) and another sibling, healthy as well, was WT/WT.
Data on 7 other patients with STAT-1 deficiency previously described in the literature are summarized in Table 1.
Summary of Patients With STAT-1 Deficiency
DISCUSSION
On the basis of the findings in our 2 patients, invasive salmonellosis joins mycobacterial and viral pathogens as significant pathogens in patients with STAT-1 deficiency. Invasive salmonellosis occurs in less than half of the patients with Mendelian susceptibility to mycobacterial disease; it is significantly more frequent in patients with an IL-12/IL-23 pathway defect (44%) than those with an IFNγR1/IFNγR2/STAT-1 pathway defect (7%) (P < 0.0001).2,8 The IL-12/IL-23 pathway activates different complexes than the IFNγ signaling pathways that participate in human host against Salmonella, and therefore invasive salmonellosis should occur less frequently in patients with STAT-1 deficiency.8_Salmonella_ has been shown to induce IL-27 which induces _STAT-1_-containing GAS-binding proteins and _STAT-1_-dependent IRF1 transcription; this response was impaired but not abolished in our patients, which may have contributed to the development of salmonellosis.3
Nontuberculous mycobacterial infection is a classic manifestation in patients who have IL-12/IL-23–IFNγ pathway deficiency. One of our patients had probable Mycobacterium infection and all 7 previously reported patients with STAT-1 deficiency had disseminated Mycobacterium bovis (n = 5) or pulmonary Mycobacterium avium infections (n = 2). Despite the underlying immune deficiency, all the patients with this infection were controlled with antimicrobial therapy.
Viral infections may be lethal in complete STAT-1 deficiency. The 3 patients (P7–9) with autosomal recessive mutations causing complete absence of STAT-1 with impairment of both IFNγ and IFNα-induced immunity died of proven or suspected viral infection.6,7 The other 4 children (P3–6) survived their viral infection; they had autosomal dominant mutations, causing partial STAT-1 deficiency that are recessive for IFN-α sequence response elements, transcriptional activity, and antiviral immunity.4,5 The course of viral infections in our children is consistent with the laboratory data published earlier,3 which shows that the defect in the IFN-stimulated gene factor 3 antiviral immunity pathway (requiring only one STAT-1 molecule) is milder than that of the gamma-activating factor antimycobacterial pathway (requiring 2 STAT-1 molecules).
An interesting observation is the recurrent severe RSV pneumonitis in our female patient, which recurred at an older age than usual, and required prolonged hospitalization with supplemental oxygen. RSV is ubiquitous; it infects virtually 100% of young children in the first few years of life.9 RSV infection was not reported in the other STAT-1 deficient patients, including those with complete STAT-1 deficiency, maybe because the latter died at about 1 year of age, before being exposed to RSV. Infection with RSV activates the IFNα pathway and is able to inhibit IFNα-dependent antiviral effects, resulting in establishment of productive infections in human airway epithelia.10_STAT-1_ activation by both IFNα/β and IFNγ plays an important role in establishing a TH1 immune response to RSV infection, and STAT-1 deficient mice infected with RSV showed poor lung resistance and airway responsiveness.11 Moreover, in vitro studies showed that the antiviral agent, ribavirin stimulates IFN-stimulated gene factor 3-induced IFNα antiviral response by stabilizing the binding of STAT-1 to ISRE elements.12 Nevertheless, the predisposition to severe and recurrent RSV pneumonitis in STAT-1 deficient patients has still to be established.
The opportunity to follow these children for years enabled us to shed light on the clinical course of this unique immune deficiency. Worthy of note is our finding that the clinical course of both children has become milder over the years.
In conclusion, STAT-1 deficiency should be suspected in children with invasive Salmonella infections or recurrent severe RSV pneumonitis, as well as unusually low-virulent mycobacterial infections, HSV, and other severe viral infections. Indeed, another family with a partial form of recessive STAT-1 deficiency (caused by a distinct mutation) was recently diagnosed (Kong XF, Casanova JL, and Boisson-Dupuis S, unpublished data).
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Keywords:
mycobacterial diseases; Mycobacterium; Salmonella; RSV; interleukin 12/23-interferon gamma (IFNγ) pathway
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