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Alexis Redor, François Danion, Perrine Parize, Olivia Chandesris, Jonathan Dbjay, Amélie Duréault, Guillaume Le Guenno, Celine Cazorla, Delphine Vergnon-Miszczycha, Anne Sophie Bats, Christine Bodemer, Cyrille Hoarau, Caroline Charlier, Nizar Mahlaoui, Marc Lecuit, Fanny Lanternier, Olivier Lortholary, Devastating Gynecological Infections in Women with STAT3 Deficiency, Clinical Infectious Diseases, Volume 71, Issue 7, 1 October 2020, Pages e186–e190, https://doi.org/10.1093/cid/ciaa020
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Abstract
We provide the first description of a series of 9 severe gynecological infections (mastitis and pelvic cellulitis) occurring in the French national cohort of women with STAT3 deficiency. Each episode had unique features in terms of clinical presentation, microbial documentation, location, treatment duration, and related persistent esthetic damage.
STAT3 (signal transducer and activator of transcription 3) deficiency is a rare autosomal dominant primary immune deficiency [1] resulting from dominant-negative heterozygous loss-of-function mutations of the STAT3 gene. STAT3-deficient patients have multisystem disease, including eczematous dermatitis, dysmorphia, abnormalities of connective tissue and skeleton, and a particular susceptibility to cutaneous and pulmonary infections [2–4]. These infections begin in the neonatal period and are pauci-symptomatic [5, 6].
We report here the first series of severe gynecological bacterial infections in a nationwide cohort of women with STAT3 deficiency.
METHODS
We conducted a retrospective study of all gynecological infections in STAT3-deficient women in France. As of March 2019, a cohort of 104 patients with STAT3 deficiency, the largest nationwide cohort outside the United States, was being followed by the CEREDIH (French National Reference Center for Primary Immune Deficiencies) [7], based at Necker-Enfants Malades University Hospital, Paris. The patients’ physicians were contacted and ask to report any gynecological infections occurring in their patients between 2000 and 2019. We reviewed all the medical records, microbiological data, and radiological images of these patients and included only the patients with severe infection from mammary or genital origin. Severe infection was defined as requiring hospitalization, intravenous, and/or surgical treatment. Ethics board approval was obtained for research on patient care for the CEREDIH (06.327; 7 September 2006).
RESULTS
The 104 STAT3-deficient patients registered included 51 women. We identified 5 episodes of mastitis and 4 of pelvic cellulitis in 6 patients, corresponding to 12% of the female cohort.
Patients
All patients were diagnosed with hyper–immunoglobulin E (IgE) syndrome in childhood. They were aged between 18 and 53 years. Four patients carried STAT3 mutations affecting the SH2 domain, 1 carried a mutation affecting the transactivation domain, and 1 had a mutation affecting the DNA-binding domain. All patients had a history of eczema, dysmorphia, and high plasma IgE levels, together with recurrent bacterial skin abscesses, pneumonia, ear-nose-throat infections, and mucocutaneous candidiasis. Four patients had a history of bacteremia; visceral abscesses had been reported in 3 patients, pulmonary aspergillosis in 2 patients, bone and joint infections in 2 patients, and Kaposi-Juliusberg dermatitis in 1 patient. Many other common features of STAT3 deficiency were observed in these patients, including hyperlaxity in 5 patients and folliculitis and delayed shedding of milk teeth in 3 patients.
At the time of the gynecological episodes, all patients presented colonization (nasal or skin eczema sample) with Staphylococcus aureus, methicillin-resistant in 1 case.
Mastitis
We identified 5 episodes of mastitis (Table 1) in 5 of the 51 (10%) STAT3-deficient women. Only 1 (2%) of these episodes was related to lactation. Three of these patients were on antimicrobial prophylaxis and the other 2 were on polyvalent immunoglobulin G (IgG) infusions at the time of the episode. Breast eczema was identified as a cutaneous point of entry for the infection in all 5 patients, and 2 patients were treated with topical steroids. All patients initially consulted for cutaneous breast erythema with induration of a few days’ duration, with breast swelling in 2 cases and breast pain in 2 other cases. Two of the patients had fever and 3 had abnormally high white blood cell counts and serum C-reactive protein concentrations. In all cases, computed tomography (CT) scan or magnetic resonance imaging (MRI) revealed the presence of multiple extensive abscesses. Bilateral breast extension was diagnosed in 3 cases. Initial drainage was required in all patients, either surgical (patients 1 and 4) or ultrasound-guided (patients 2, 5, and 6). Cultures of drainage samples from 4 patients were positive for S. aureus, and 2 of these patients were coinfected with other bacteria. Despite microbiologically active antibacterial therapy, all patients suffered abscess reconstitution or extension and had to undergo repeated drainage (with a median of 3 drainages per patient). All patients had persisting discharge localized in drainage site. Complete cure required at least 2 different antibacterial regimens in all patients. Improvement on treatment was very slow in all the patients, with a median duration of antibiotic treatment of 300 (150–540) days. Antibiotic treatments had to be switched in 3 patients due to toxicity or intolerance (patients 1, 2, and 4). Three patients had other infections during treatment (Table 1). Treatment was stopped after complete clinical cure characterized by complete cutaneous healing, end of cutaneous discharge, and normal breast volume, despite the persistence of radiological lesions. The median duration of hospitalization was 45 (7–85) days. All patients presented esthetic sequelae and patient 4 required breast esthetic surgery, which was performed on antibiotic prophylaxis without complications. None of the patients presented a relapse after treatment.
| Characteristic . | Patient 1 . | Patient 2 . | Patient 4 . | Patient 5 . | Patient 6 . |
|---|---|---|---|---|---|
| Age at infection, y | 19 | 16 | 16 | 19 | 35 |
| Weight, kg | 90 | 67 | NA | 110 | NA |
| BMI, kg/m2 | 33 | 25.5 | NA | 56 | NA |
| Prophylaxis, dosage/d | Itraconazole 200 mg Atovaquone 1500 mg Azithromycin 250 mg Cefpodoxime 200 mg | Cloxacillin 4 g | None | Cloxacillin 4 g | None |
| Immunoglobulin substitution | Weekly SC 5 g | Weekly SC 5 g | None | None | None |
| IgG level | High | Normal | NA | NA | Normal |
| Cutaneous point of entry | Eczema under the breast Subcutaneous abscess | Eczema under the breast | Eczema under the breast | Eczema under the breast | Eczema under the breast |
| Predisposing factors | Smoking Large breast volume | Topical steroids Large breast volume | Topical steroids | … | Breastfeeding |
| Staphylococcus aureus colonization | MSSA | MSSA | MSSA | MSSA | MRSA |
| Physical examination at diagnosis | Cutaneous erythema | Breast swelling Cutaneous erythema Fluctuating collections | Breast swelling Cutaneous erythema Breast pain | Cutaneous erythema Breast pain | Cutaneous erythema |
| Physical examination following first drainage | Persisting discharge Breast discharge Abscess reconstitution | Persisting discharge Breast swelling | Persisting discharge Breast swelling | Persisting discharge | Persisting discharge |
| Fever | + | − | + | − | − |
| White blood cells/µL | 11 600 | 12 100 | 9320 | 12 700 | NA |
| C-reactive protein, mg/L | 66 | 3.2 | 13.6 | 45 | NA |
| First-line antibiotic, dose/d | Pristinamycin 3 g Azithromycin 1 g | Amoxicilin-clavulanic acid 6 g Clindamycin 2400 mg | Amoxicilin/clavulanic acid 3 g | Amoxicillin 3 g | Pristinamycin 3 g Gentamicin injection |
| Drainage 1 | Streptococcus intermedius | MSSA | MSSA | Enterococcus faecalis Proteus mirabilis | MRSA |
| Drainage 2 | S. intermedius MSSA Citrobacter koseri | MSSA | MSSA Streptococcus dysgalactiae | E. faecalis P. mirabilis | MRSA |
| Drainage 3 | S. intermedius | MSSA | MSSA | … | … |
| Drainage 4 | S. intermedius | … | Sterile culture | … | … |
| Drainage 5 | S. intermedius | … | … | … | … |
| Drainage 6 | S. intermedius Enterobacter aerogenes MSSA | … | … | … | … |
| Other infections during treatment | Acute otitis media due to Citrobacter koseri and Pseudomonas aeruginosa | Candida albicans intertrigo under the breast Campylobacter colitis | Acute media otitis | … | … |
| No. of antibiotic strategies | 5 | 6 | 7 | 2 | 2 |
| Days of antibiotic treatment | 509 | 540 | 300 | 150 | 180 |
| Days of hospitalization | 85 | 45 | 53 | < 7 | < 7 |
| Esthetic damage | + | + | + | + | + |
| Characteristic . | Patient 1 . | Patient 2 . | Patient 4 . | Patient 5 . | Patient 6 . |
|---|---|---|---|---|---|
| Age at infection, y | 19 | 16 | 16 | 19 | 35 |
| Weight, kg | 90 | 67 | NA | 110 | NA |
| BMI, kg/m2 | 33 | 25.5 | NA | 56 | NA |
| Prophylaxis, dosage/d | Itraconazole 200 mg Atovaquone 1500 mg Azithromycin 250 mg Cefpodoxime 200 mg | Cloxacillin 4 g | None | Cloxacillin 4 g | None |
| Immunoglobulin substitution | Weekly SC 5 g | Weekly SC 5 g | None | None | None |
| IgG level | High | Normal | NA | NA | Normal |
| Cutaneous point of entry | Eczema under the breast Subcutaneous abscess | Eczema under the breast | Eczema under the breast | Eczema under the breast | Eczema under the breast |
| Predisposing factors | Smoking Large breast volume | Topical steroids Large breast volume | Topical steroids | … | Breastfeeding |
| Staphylococcus aureus colonization | MSSA | MSSA | MSSA | MSSA | MRSA |
| Physical examination at diagnosis | Cutaneous erythema | Breast swelling Cutaneous erythema Fluctuating collections | Breast swelling Cutaneous erythema Breast pain | Cutaneous erythema Breast pain | Cutaneous erythema |
| Physical examination following first drainage | Persisting discharge Breast discharge Abscess reconstitution | Persisting discharge Breast swelling | Persisting discharge Breast swelling | Persisting discharge | Persisting discharge |
| Fever | + | − | + | − | − |
| White blood cells/µL | 11 600 | 12 100 | 9320 | 12 700 | NA |
| C-reactive protein, mg/L | 66 | 3.2 | 13.6 | 45 | NA |
| First-line antibiotic, dose/d | Pristinamycin 3 g Azithromycin 1 g | Amoxicilin-clavulanic acid 6 g Clindamycin 2400 mg | Amoxicilin/clavulanic acid 3 g | Amoxicillin 3 g | Pristinamycin 3 g Gentamicin injection |
| Drainage 1 | Streptococcus intermedius | MSSA | MSSA | Enterococcus faecalis Proteus mirabilis | MRSA |
| Drainage 2 | S. intermedius MSSA Citrobacter koseri | MSSA | MSSA Streptococcus dysgalactiae | E. faecalis P. mirabilis | MRSA |
| Drainage 3 | S. intermedius | MSSA | MSSA | … | … |
| Drainage 4 | S. intermedius | … | Sterile culture | … | … |
| Drainage 5 | S. intermedius | … | … | … | … |
| Drainage 6 | S. intermedius Enterobacter aerogenes MSSA | … | … | … | … |
| Other infections during treatment | Acute otitis media due to Citrobacter koseri and Pseudomonas aeruginosa | Candida albicans intertrigo under the breast Campylobacter colitis | Acute media otitis | … | … |
| No. of antibiotic strategies | 5 | 6 | 7 | 2 | 2 |
| Days of antibiotic treatment | 509 | 540 | 300 | 150 | 180 |
| Days of hospitalization | 85 | 45 | 53 | < 7 | < 7 |
| Esthetic damage | + | + | + | + | + |
Abbreviations: BMI, body mass index; IgG, immunoglobulin G; MRSA, methicillin-resistant Staphylococcus aureus; MSSA, methicillin-sensitive Staphylococcus aureus; NA, not available; SC, subcutaneous.
| Characteristic . | Patient 1 . | Patient 2 . | Patient 4 . | Patient 5 . | Patient 6 . |
|---|---|---|---|---|---|
| Age at infection, y | 19 | 16 | 16 | 19 | 35 |
| Weight, kg | 90 | 67 | NA | 110 | NA |
| BMI, kg/m2 | 33 | 25.5 | NA | 56 | NA |
| Prophylaxis, dosage/d | Itraconazole 200 mg Atovaquone 1500 mg Azithromycin 250 mg Cefpodoxime 200 mg | Cloxacillin 4 g | None | Cloxacillin 4 g | None |
| Immunoglobulin substitution | Weekly SC 5 g | Weekly SC 5 g | None | None | None |
| IgG level | High | Normal | NA | NA | Normal |
| Cutaneous point of entry | Eczema under the breast Subcutaneous abscess | Eczema under the breast | Eczema under the breast | Eczema under the breast | Eczema under the breast |
| Predisposing factors | Smoking Large breast volume | Topical steroids Large breast volume | Topical steroids | … | Breastfeeding |
| Staphylococcus aureus colonization | MSSA | MSSA | MSSA | MSSA | MRSA |
| Physical examination at diagnosis | Cutaneous erythema | Breast swelling Cutaneous erythema Fluctuating collections | Breast swelling Cutaneous erythema Breast pain | Cutaneous erythema Breast pain | Cutaneous erythema |
| Physical examination following first drainage | Persisting discharge Breast discharge Abscess reconstitution | Persisting discharge Breast swelling | Persisting discharge Breast swelling | Persisting discharge | Persisting discharge |
| Fever | + | − | + | − | − |
| White blood cells/µL | 11 600 | 12 100 | 9320 | 12 700 | NA |
| C-reactive protein, mg/L | 66 | 3.2 | 13.6 | 45 | NA |
| First-line antibiotic, dose/d | Pristinamycin 3 g Azithromycin 1 g | Amoxicilin-clavulanic acid 6 g Clindamycin 2400 mg | Amoxicilin/clavulanic acid 3 g | Amoxicillin 3 g | Pristinamycin 3 g Gentamicin injection |
| Drainage 1 | Streptococcus intermedius | MSSA | MSSA | Enterococcus faecalis Proteus mirabilis | MRSA |
| Drainage 2 | S. intermedius MSSA Citrobacter koseri | MSSA | MSSA Streptococcus dysgalactiae | E. faecalis P. mirabilis | MRSA |
| Drainage 3 | S. intermedius | MSSA | MSSA | … | … |
| Drainage 4 | S. intermedius | … | Sterile culture | … | … |
| Drainage 5 | S. intermedius | … | … | … | … |
| Drainage 6 | S. intermedius Enterobacter aerogenes MSSA | … | … | … | … |
| Other infections during treatment | Acute otitis media due to Citrobacter koseri and Pseudomonas aeruginosa | Candida albicans intertrigo under the breast Campylobacter colitis | Acute media otitis | … | … |
| No. of antibiotic strategies | 5 | 6 | 7 | 2 | 2 |
| Days of antibiotic treatment | 509 | 540 | 300 | 150 | 180 |
| Days of hospitalization | 85 | 45 | 53 | < 7 | < 7 |
| Esthetic damage | + | + | + | + | + |
| Characteristic . | Patient 1 . | Patient 2 . | Patient 4 . | Patient 5 . | Patient 6 . |
|---|---|---|---|---|---|
| Age at infection, y | 19 | 16 | 16 | 19 | 35 |
| Weight, kg | 90 | 67 | NA | 110 | NA |
| BMI, kg/m2 | 33 | 25.5 | NA | 56 | NA |
| Prophylaxis, dosage/d | Itraconazole 200 mg Atovaquone 1500 mg Azithromycin 250 mg Cefpodoxime 200 mg | Cloxacillin 4 g | None | Cloxacillin 4 g | None |
| Immunoglobulin substitution | Weekly SC 5 g | Weekly SC 5 g | None | None | None |
| IgG level | High | Normal | NA | NA | Normal |
| Cutaneous point of entry | Eczema under the breast Subcutaneous abscess | Eczema under the breast | Eczema under the breast | Eczema under the breast | Eczema under the breast |
| Predisposing factors | Smoking Large breast volume | Topical steroids Large breast volume | Topical steroids | … | Breastfeeding |
| Staphylococcus aureus colonization | MSSA | MSSA | MSSA | MSSA | MRSA |
| Physical examination at diagnosis | Cutaneous erythema | Breast swelling Cutaneous erythema Fluctuating collections | Breast swelling Cutaneous erythema Breast pain | Cutaneous erythema Breast pain | Cutaneous erythema |
| Physical examination following first drainage | Persisting discharge Breast discharge Abscess reconstitution | Persisting discharge Breast swelling | Persisting discharge Breast swelling | Persisting discharge | Persisting discharge |
| Fever | + | − | + | − | − |
| White blood cells/µL | 11 600 | 12 100 | 9320 | 12 700 | NA |
| C-reactive protein, mg/L | 66 | 3.2 | 13.6 | 45 | NA |
| First-line antibiotic, dose/d | Pristinamycin 3 g Azithromycin 1 g | Amoxicilin-clavulanic acid 6 g Clindamycin 2400 mg | Amoxicilin/clavulanic acid 3 g | Amoxicillin 3 g | Pristinamycin 3 g Gentamicin injection |
| Drainage 1 | Streptococcus intermedius | MSSA | MSSA | Enterococcus faecalis Proteus mirabilis | MRSA |
| Drainage 2 | S. intermedius MSSA Citrobacter koseri | MSSA | MSSA Streptococcus dysgalactiae | E. faecalis P. mirabilis | MRSA |
| Drainage 3 | S. intermedius | MSSA | MSSA | … | … |
| Drainage 4 | S. intermedius | … | Sterile culture | … | … |
| Drainage 5 | S. intermedius | … | … | … | … |
| Drainage 6 | S. intermedius Enterobacter aerogenes MSSA | … | … | … | … |
| Other infections during treatment | Acute otitis media due to Citrobacter koseri and Pseudomonas aeruginosa | Candida albicans intertrigo under the breast Campylobacter colitis | Acute media otitis | … | … |
| No. of antibiotic strategies | 5 | 6 | 7 | 2 | 2 |
| Days of antibiotic treatment | 509 | 540 | 300 | 150 | 180 |
| Days of hospitalization | 85 | 45 | 53 | < 7 | < 7 |
| Esthetic damage | + | + | + | + | + |
Abbreviations: BMI, body mass index; IgG, immunoglobulin G; MRSA, methicillin-resistant Staphylococcus aureus; MSSA, methicillin-sensitive Staphylococcus aureus; NA, not available; SC, subcutaneous.
Pelvic Cellulitis
We identified 4 episodes of pelvic cellulitis (Table 2) occurring in 2 of the 51 (4%) STAT3-deficient women of the cohort. In both patients, the first episode resolved completely, but a recurrence was diagnosed 3 years later. The patients were on antibiotic prophylaxis and polyvalent IgG infusions at the time of each episode. We identified a cutaneous point of entry for each episode. At each episode, the patients were admitted to hospital with fever and pain or cutaneous erythema with a necrotic lesion of the pelvis of a few days’ duration. Clinical and radiological examinations (MRI or CT scan) revealed extensive lesions, from the vulvar to gluteal muscles. Serum C-reactive protein concentration and white blood cell counts were high. Cultures of local samples provided evidence of polymicrobial infection with Enterobacteriaceae and anaerobic microbes but no S. aureus. Extensive surgical debridement was necessary for all episodes, with early surgical revision in 3 episodes due to poor local improvement. The median duration of antimicrobial treatment was 40 (27–485) days, with a particularly long course (485 days) for the first episode in patient 1. Hospitalization was required in all cases, for a median of 31 (8–49) days, and all women had esthetic sequelae.
| Patient . | Patient 1 . | Patient 1 . | Patient 3 . | Patient 3 . |
|---|---|---|---|---|
| Episode | First episode | Second episode | First episode | Second episode |
| Age at infection | 21 | 24 | 28 | 31 |
| Weight, kg | 88 | 91 | 59 | 62 |
| BMI, kg/m2 | 32 | 33 | 23.6 | 25 |
| Prophylaxis, dose/d | Itraconazole 400 mg Cloxacillin 4 g | Itraconazole 800 mg Cloxacillin 4 g | Itraconazole 400 mg Pristinamycin 2 g | Amphotericin B 150 mg/3 days Azithromycin 250 mg/3 days Cloxacillin 4 g |
| Immunoglobulin substitution | 3 weeks IV 40 g | Monthly IV 50 g | 3 weeks IV 40 g | 3 weeks IV 30 g |
| IgG level, g/L | 22.9 | 22.32 | 19.5 | 22 |
| Cutaneous point of entry | Gluteus abscess | Elective medical abortion | Cutaneous mycosis Shaving injury | Vulvar eczema |
| Predisposing factor | Smoking | Smoking | … | … |
| Staphylococcus colonization | MSSA | MSSA | MSSA | MSSA |
| Physical examination | Pain | Pain Purulent drainage | Thrills Cutaneous erythema | Edema Cutaneous erythema |
| Fever | + | + | + | + |
| White blood cells/µL | 11 600 | 18 800 | 14 000 | 11 600 |
| C-reactive protein, mg/L | 199 | 356 | 240 | 127 |
| First-line antibiotic | Piperacillin/tazobactam 16 g | Piperacillin/tazobactam 16 g Amikacin 20 mg/kg Vancomycin Caspofungin 50 mg | Piperacillin/tazobactam 16 g Amikacin 20 mg/kg | Piperacillin/tazobactam 16 g Linezolid 1200 mg |
| Drainage 1 | Streptococcus anginosus Anaerobic flora Corynebacteria spp | Proteus mirabilis Peptostreptococcus anaerobius | Escherichia coli Citrobacter freundii Fusobacterium spp | No sample |
| Drainage 2 | Bacteroides fragilis P. anaerobius Actinomyces spp | … | Corynebacterium amycolatum | … |
| Drainage 3 | E. coli Enterococcus faecalis Streptococcus anginosus | … | … | … |
| Other infections during treatment | Acute media otitis due to E. coli and Pseudomonas aeruginosa | None | None | None |
| No. of antibiotic strategy | 6 | 2 | 2 | 3 |
| Days of antibiotic | 485 | 45 | 27 | 34 |
| Days of hospitalization | 49 | 8 | 27 | 34 |
| Esthetic prejudice | + | + | + | + |
| Patient . | Patient 1 . | Patient 1 . | Patient 3 . | Patient 3 . |
|---|---|---|---|---|
| Episode | First episode | Second episode | First episode | Second episode |
| Age at infection | 21 | 24 | 28 | 31 |
| Weight, kg | 88 | 91 | 59 | 62 |
| BMI, kg/m2 | 32 | 33 | 23.6 | 25 |
| Prophylaxis, dose/d | Itraconazole 400 mg Cloxacillin 4 g | Itraconazole 800 mg Cloxacillin 4 g | Itraconazole 400 mg Pristinamycin 2 g | Amphotericin B 150 mg/3 days Azithromycin 250 mg/3 days Cloxacillin 4 g |
| Immunoglobulin substitution | 3 weeks IV 40 g | Monthly IV 50 g | 3 weeks IV 40 g | 3 weeks IV 30 g |
| IgG level, g/L | 22.9 | 22.32 | 19.5 | 22 |
| Cutaneous point of entry | Gluteus abscess | Elective medical abortion | Cutaneous mycosis Shaving injury | Vulvar eczema |
| Predisposing factor | Smoking | Smoking | … | … |
| Staphylococcus colonization | MSSA | MSSA | MSSA | MSSA |
| Physical examination | Pain | Pain Purulent drainage | Thrills Cutaneous erythema | Edema Cutaneous erythema |
| Fever | + | + | + | + |
| White blood cells/µL | 11 600 | 18 800 | 14 000 | 11 600 |
| C-reactive protein, mg/L | 199 | 356 | 240 | 127 |
| First-line antibiotic | Piperacillin/tazobactam 16 g | Piperacillin/tazobactam 16 g Amikacin 20 mg/kg Vancomycin Caspofungin 50 mg | Piperacillin/tazobactam 16 g Amikacin 20 mg/kg | Piperacillin/tazobactam 16 g Linezolid 1200 mg |
| Drainage 1 | Streptococcus anginosus Anaerobic flora Corynebacteria spp | Proteus mirabilis Peptostreptococcus anaerobius | Escherichia coli Citrobacter freundii Fusobacterium spp | No sample |
| Drainage 2 | Bacteroides fragilis P. anaerobius Actinomyces spp | … | Corynebacterium amycolatum | … |
| Drainage 3 | E. coli Enterococcus faecalis Streptococcus anginosus | … | … | … |
| Other infections during treatment | Acute media otitis due to E. coli and Pseudomonas aeruginosa | None | None | None |
| No. of antibiotic strategy | 6 | 2 | 2 | 3 |
| Days of antibiotic | 485 | 45 | 27 | 34 |
| Days of hospitalization | 49 | 8 | 27 | 34 |
| Esthetic prejudice | + | + | + | + |
Abbreviations: BMI, body mass index; IgG, immunoglobulin G; IV, intravenous; MSSA, methicillin-sensitive Staphylococcus aureus.
| Patient . | Patient 1 . | Patient 1 . | Patient 3 . | Patient 3 . |
|---|---|---|---|---|
| Episode | First episode | Second episode | First episode | Second episode |
| Age at infection | 21 | 24 | 28 | 31 |
| Weight, kg | 88 | 91 | 59 | 62 |
| BMI, kg/m2 | 32 | 33 | 23.6 | 25 |
| Prophylaxis, dose/d | Itraconazole 400 mg Cloxacillin 4 g | Itraconazole 800 mg Cloxacillin 4 g | Itraconazole 400 mg Pristinamycin 2 g | Amphotericin B 150 mg/3 days Azithromycin 250 mg/3 days Cloxacillin 4 g |
| Immunoglobulin substitution | 3 weeks IV 40 g | Monthly IV 50 g | 3 weeks IV 40 g | 3 weeks IV 30 g |
| IgG level, g/L | 22.9 | 22.32 | 19.5 | 22 |
| Cutaneous point of entry | Gluteus abscess | Elective medical abortion | Cutaneous mycosis Shaving injury | Vulvar eczema |
| Predisposing factor | Smoking | Smoking | … | … |
| Staphylococcus colonization | MSSA | MSSA | MSSA | MSSA |
| Physical examination | Pain | Pain Purulent drainage | Thrills Cutaneous erythema | Edema Cutaneous erythema |
| Fever | + | + | + | + |
| White blood cells/µL | 11 600 | 18 800 | 14 000 | 11 600 |
| C-reactive protein, mg/L | 199 | 356 | 240 | 127 |
| First-line antibiotic | Piperacillin/tazobactam 16 g | Piperacillin/tazobactam 16 g Amikacin 20 mg/kg Vancomycin Caspofungin 50 mg | Piperacillin/tazobactam 16 g Amikacin 20 mg/kg | Piperacillin/tazobactam 16 g Linezolid 1200 mg |
| Drainage 1 | Streptococcus anginosus Anaerobic flora Corynebacteria spp | Proteus mirabilis Peptostreptococcus anaerobius | Escherichia coli Citrobacter freundii Fusobacterium spp | No sample |
| Drainage 2 | Bacteroides fragilis P. anaerobius Actinomyces spp | … | Corynebacterium amycolatum | … |
| Drainage 3 | E. coli Enterococcus faecalis Streptococcus anginosus | … | … | … |
| Other infections during treatment | Acute media otitis due to E. coli and Pseudomonas aeruginosa | None | None | None |
| No. of antibiotic strategy | 6 | 2 | 2 | 3 |
| Days of antibiotic | 485 | 45 | 27 | 34 |
| Days of hospitalization | 49 | 8 | 27 | 34 |
| Esthetic prejudice | + | + | + | + |
| Patient . | Patient 1 . | Patient 1 . | Patient 3 . | Patient 3 . |
|---|---|---|---|---|
| Episode | First episode | Second episode | First episode | Second episode |
| Age at infection | 21 | 24 | 28 | 31 |
| Weight, kg | 88 | 91 | 59 | 62 |
| BMI, kg/m2 | 32 | 33 | 23.6 | 25 |
| Prophylaxis, dose/d | Itraconazole 400 mg Cloxacillin 4 g | Itraconazole 800 mg Cloxacillin 4 g | Itraconazole 400 mg Pristinamycin 2 g | Amphotericin B 150 mg/3 days Azithromycin 250 mg/3 days Cloxacillin 4 g |
| Immunoglobulin substitution | 3 weeks IV 40 g | Monthly IV 50 g | 3 weeks IV 40 g | 3 weeks IV 30 g |
| IgG level, g/L | 22.9 | 22.32 | 19.5 | 22 |
| Cutaneous point of entry | Gluteus abscess | Elective medical abortion | Cutaneous mycosis Shaving injury | Vulvar eczema |
| Predisposing factor | Smoking | Smoking | … | … |
| Staphylococcus colonization | MSSA | MSSA | MSSA | MSSA |
| Physical examination | Pain | Pain Purulent drainage | Thrills Cutaneous erythema | Edema Cutaneous erythema |
| Fever | + | + | + | + |
| White blood cells/µL | 11 600 | 18 800 | 14 000 | 11 600 |
| C-reactive protein, mg/L | 199 | 356 | 240 | 127 |
| First-line antibiotic | Piperacillin/tazobactam 16 g | Piperacillin/tazobactam 16 g Amikacin 20 mg/kg Vancomycin Caspofungin 50 mg | Piperacillin/tazobactam 16 g Amikacin 20 mg/kg | Piperacillin/tazobactam 16 g Linezolid 1200 mg |
| Drainage 1 | Streptococcus anginosus Anaerobic flora Corynebacteria spp | Proteus mirabilis Peptostreptococcus anaerobius | Escherichia coli Citrobacter freundii Fusobacterium spp | No sample |
| Drainage 2 | Bacteroides fragilis P. anaerobius Actinomyces spp | … | Corynebacterium amycolatum | … |
| Drainage 3 | E. coli Enterococcus faecalis Streptococcus anginosus | … | … | … |
| Other infections during treatment | Acute media otitis due to E. coli and Pseudomonas aeruginosa | None | None | None |
| No. of antibiotic strategy | 6 | 2 | 2 | 3 |
| Days of antibiotic | 485 | 45 | 27 | 34 |
| Days of hospitalization | 49 | 8 | 27 | 34 |
| Esthetic prejudice | + | + | + | + |
Abbreviations: BMI, body mass index; IgG, immunoglobulin G; IV, intravenous; MSSA, methicillin-sensitive Staphylococcus aureus.
DISCUSSION
STAT3 deficiency is associated with a particular susceptibility to recurrent and protracted infections of the skin and lungs. These infections are usually characterized by the pauci-symptomatic presentation consistent with deficient interleukin 6 responses [1, 2, 8]. The gynecological infections observed here, mostly pelvic cellulitis, had a different presentation. They were febrile, symptomatic, and associated with acute inflammation, highlighting their unusually invasive nature. Any clinical abnormality in STAT3-deficient patients should therefore prompt clinicians to look for invasive infections. The susceptibility of STAT3-deficient patients to cutaneous infections can be explained partly by a defect of the T-helper 17 (Th17) pathway [9, 10], as keratinocytes are dependent on Th17 for the synthesis of antimicrobial peptides and CXCL8 [11]. According to clinical data for skin infections in patients with STAT3 deficiency, microbiological investigations identify S. aureus in 94% of cases [2].
Mastitis has already been described in 1 patient with hyper-IgE syndrome [12]. Infectious mastitis is a rare entity outside of pregnancy and breastfeeding. This single-abscess infection requires drainage and documented antibiotic therapy. Our patients presented with multiple peripheral mastitis lesions, probably due to skin barrier rupture. Their predisposing factors were breastfeeding for 1 patient but also smoking, being overweight, a large mammary volume, and cutaneous wounds. The decision as to whether surgery should be performed is difficult. On the one hand, surgery is complicated, and the risk of complications is high in STAT3-deficient patients, but on the other, surgery may shorten the duration of antibiotic treatment and decrease the bacterial inoculum, the latter being potentially associated with subsequent antibiotic resistance and toxicity.
Cellulitis is a classic infectious complication in STAT3-deficient patients, but to our knowledge no cases of pelvic cellulitis have ever been reported in this context. Cellulitis is generally caused by S. aureus and requires antibiotic treatment but not surgery. Our cases of pelvic cellulitis were extensive and necrotic and were secondary to a wound of perineal origin. These infections were polymicrobial, with mostly gram-negative bacilli and anaerobic bacteria identified. Surgical treatment with a large skin resection was necessary in all cases. These infections are exceptional in women, and their recurrence is particularly striking. Great efforts should therefore be made to prevent gynecological infections, by monitoring and treating any skin breach and addressing other risk factors.
Another significant finding of this study was the need to repeat microbiological sampling. Indeed, on several occasions, even after several months of antibiotic treatment, polymicrobial infections were documented, and different bacteria were identified during the course of infection.
Our observations demonstrate that prophylaxis cannot prevent S. aureus colonization, which was found in all patients. This observation may be explained by poor IgG responses to S. aureus [13]. However, the pathogens identified were not particularly resistant to the antibiotics used for prophylaxis, with the exception of 1 methicillin-resistant strain of S. aureus (patient 6).
All of these young adult women have suffered long-term esthetic and psychological damage, complicating a multisystem disease that they have had since childhood. Reparative surgery does not currently appear to be a viable option, due to the risk of superinfection. Psychological supportive care is therefore essential for these patients.
CONCLUSIONS
The gynecological infections observed in these women with STAT3 deficiency were particularly devastating. They highlight the need for prolonged medical and surgical treatment but also for preventive measures in the management of STAT3-deficient patients. Prophylaxis, the elimination of risk factors, and early treatment of possible cutaneous sites of entry are essential to prevent these infections, which cause significant morbidity and sequelae in young adult women.
Notes
Acknowledgments. The European Society for Immunodeficiencies Online Database was used for the collection of data for the French National Reference Center for Primary Immune Deficiencies (CEREDIH) registry. The CEREDIH is funded by the French Ministry of Health and has received additional, unrestricted educational grants from the several pharmaceutical companies (CSL Behring, Shire, Octapharma, Grifols, and Binding Site) and patient associations (AT-Europe and Trophée Guillaume).
Potential conflicts of interest. D. A. reports grants from Gilead, outside the submitted work. C. H. reports grants from Octapharma and personal fees from Octapharma, ALK, and Stallergenes-Greer, outside the submitted work. F. D. reports personal fees from Gilead, outside the submitted work. All other authors report no potential conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.
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