Recurrent Fever and Back Pain Associated With Septic Shock in a Healthy 16-Year-Old Girl

A previously healthy 16-year-old girl presents with a 3-day history of fever, headache, back pain, and dysuria. She also reports nausea, vomiting, and diarrhea. She denies sick contacts, recent travel, or substance use. She endorses sexual activity with consistent condom use, and recently finished her typically regular menses. She is up to date on vaccinations except for the second meningococcal quadrivalent vaccine. She received a filling for dental caries the day before presentation.She is febrile (maximum temperature [Tmax] 40.6 °C), hypotensive (blood pressure [BP] of 80/40 mm Hg), tachycardic (heart rate [HR] of 128 beats per minute), and has a respiratory rate of 21 breaths per minute. She is ill-appearing with bilateral costovertebral angle tenderness and generalized erythema. Her oropharyngeal, cardiac, pulmonary, abdominal, and neurologic examinations are unremarkable. A speculum examination demonstrated neither retained hygiene products nor abnormal discharge in the vaginal canal, and cervical motion tenderness is absent. Her initial laboratory evaluation is summarized in Table 1. She remains hypotensive despite 4 L of intravenous (IV) crystalloids and is admitted to the pediatric intensive care unit for septic shock with acute kidney injury requiring initiation of epinephrine.She receives an extensive workup for sepsis. A computed tomography abdomen and pelvis (CTAP) scan does not show evidence of an acute intra-abdominal process, except for an appendicolith without inflammatory changes. Urine pregnancy test and urine toxicology results are negative. An echocardiogram and ultrasound scan of the bilateral internal jugular veins to evaluate for rheumatic fever and Lemierre syndrome, respectively, are unremarkable. Extensive microbiologic studies are unrevealing (Table 2).She initially receives vancomycin and piperacillin-tazobactam and is narrowed to piperacillin-tazobactam for presumed pyelonephritis for 48 hours. Her hemodynamics improve, and she is weaned off epinephrine after improvement of her fever and her creatinine over the first 24 hours. On hospital day 2, she reports glossitis with oral pain, which improves over the following week. She is discharged home after resolution of her illness on hospital day 5. Her discharge diagnosis is septic shock of unknown etiology, and she completes a 10-day course of amoxicillin-clavulanate given concern for an odontogenic source from her recent dental filling.She completes her antibiotic course and remains asymptomatic, apart from a desquamating rash shortly after completion. However, 1 month after her initial presentation, she re-presents with fever, neck and back pain, and photosensitivity. She denies dysuria and sick contacts. She has been menstruating for the past 4 days and has been changing her tampon at least once daily.She is febrile (Tmax 38.3 °C), hypotensive (BP 90/50 mm Hg), and slightly tachycardic (HR 102 beats per minute). Her physical examination demonstrates neck stiffness and pain with extension as well as tenderness in her trapezius and latissimus dorsi bilaterally. Her oropharyngeal examination demonstrates tongue erythema with prominent papillae. The remainder of her examination is unremarkable. The initial laboratory evaluation is summarized for comparison in Table 1.Magnetic resonance imaging scans of the brain and total spine do not demonstrate an etiology of her recurrent neck and back pain. CT chest angiography and CTAP scans to evaluate for pulmonary embolism and acute intra-abdominal process, respectively, are also unremarkable. The patient does not tolerate a lumbar puncture given severe generalized pain; her neck stiffness improves rapidly following the initiation of antibiotics overnight. She is started on ceftriaxone, clindamycin, and vancomycin with significant clinical improvement within 24 hours and discharges on doxycycline on hospital day 4. Additional infectious workup during this admission clarifies the diagnosis.The differential diagnosis was broad and included localized infection (pyelonephritis, appendicitis, tubo-ovarian abscess, pelvic inflammatory disease, meningitis, or discitis), a systemic infectious process (toxic shock syndrome [TSS], HIV, or Rocky Mountain spotted fever), or an autoimmune process (juvenile idiopathic arthritis or multisystem inflammatory syndrome in children [MIS-C]). MIS-C was unlikely given the patient’s vaccination status and absence of a severe acute respiratory syndrome coronavirus 2 nucleocapsid antibody. Intensive imaging and microbiologic evaluation were unrevealing across both hospitalizations except for a vaginal culture on her second admission, which grew more than 4 methicillin-susceptible Staphylococcus aureus.She was diagnosed with recurrent TSS. She met the criteria for confirmed TSS per the US Centers for Disease Control and Prevention definition based on history and physical examination (see Table 3).1 Her menses coinciding with symptom onset for 2 consecutive months was also highly suggestive.TSS is an acute-onset illness consisting of hypotension, fever, rash, and multi-organ system involvement2 (Table 3). The annual incidence in the United States is approximately 7 cases per million persons.3 The most common causes of TSS are toxigenic strains of S. aureus and Streptococcus pyogenes,4 which produce several pyrogenic toxins called superantigens.4 These superantigens nonspecifically crosslink T cells and antigen-presenting cells, leading to an exuberant inflammatory response and multi-organ dysfunction.5–7 Nearly all menstrual-associated TSS (mTSS) is caused by S. aureus strains that produce the superantigen TSS Toxin-1 (TSST-1).5–7 Risk factors for mTSS include tampon and other intravaginal device use, colonization with TSST-1–producing S. aureus, and lack of protective immunoglobulin (Ig) G1 and IgG4 antibody titers against TSST-1.2These risk factors reflect complex host-pathogen interactions in the presentation of mTSS. Levels of S. aureus in the vaginal flora peak during menses, although only a minority of these colonizing strains produce TSST-1.8–10 Tampons and other intravaginal devices are thought to modulate levels of oxygen, magnesium, and other physiochemical factors that promote TSST-1 production.2 However, mTSS may occur even in the absence of tampon use, suggesting that an intravaginal device is not the sole determinant of mTSS development.Host immunity also contributes to pathogenesis. Because S. aureus is a common colonizer of the nasal cavity, vaginal canal, and human skin, most women are exposed to a TSST-1–producing S. aureus strain and develop protective TSST-1 antibodies without developing signs of TSS.11–15 The prevalence of any detectable TSST-1 antibody titer is slightly less frequent in adolescents (80%–90% for adolescents compared with >90% for adult women).12,16–18 TSST-1 IgG1 and IgG4 is often low or absent in acute sera from patients with mTSS, suggesting insufficient TSST-1 antibody response as a major risk factor.19,20The overall recurrence rate of mTSS is approximately 10% to 30% following the index episode.2,21,22 In individuals without pre-existing TSST-1 IgG1, there is a low rate of seroconversion following their first episode of mTSS.19,23–26 Consistent with this, most recurrent TSS illness occurs in the 1 to 2 months following the initial TSS episode, when a protective systemic antibody response may have not fully developed.25 The tendency for recurrent TSS to be less severe is consistent with the gradual development of at least partial protective immunity against TSST-1.25Acute management of TSS includes admission to acute or intensive care for fluid resuscitation, antibiotics, and other supportive care.2,27 Blood cultures and cultures of the nares, vagina, urine, and other sites as clinically indicated should be collected, and intravaginal or other retained foreign objects should be removed.2,27 Beta-lactamase–resistant penicillin should be administered with clindamycin for antitoxin production effect.2,27 Vancomycin or linezolid should be added if there is a high suspicion for methicillin-resistant S. aureus.2,27 Often, broad spectrum antibiotics are indicated when patients with TSS present in undifferentiated septic shock, like our patient. In treatment unresponsive or high-risk patients, the administration of IVIG may improve outcomes through dampening of the superantigen-mediated hyperimmune response.2,27 However, there is limited high-quality evidence supporting the efficacy of this intervention, and most studies to date have evaluated IVIG for TSS caused by Streptococcus pyogenes rather than S. aureus.28Treatment with antistaphylococcal antibiotics during the first and any subsequent episodes of TSS and discontinuation of tampon use is associated with reduced frequencies of recurrent episodes.21,25 Oral contraceptive pill (OCP) use may also decrease risk.2 Total body S. aureus decolonization with antibacterial soaps, bleach baths, and nasal mupirocin is often performed; however, this has not been rigorously evaluated and decolonization may not be durable.29,30On her second presentation, our patient received ceftriaxone, vancomycin, and clindamycin empirically and was transitioned to doxycycline on discharge after 48 hours of clinical improvement.She received a doxycycline refill with instructions to start if her symptoms recurred. She started combined OCPs for suppression of her menses (skipping placebo weeks for full suppression) and was counseled to discontinue use of all intravaginal devices. She and her family members were instructed to apply nasal mupirocin for a 7-day course to reduce S. aureus burden. Postdischarge nasal and vaginal swabs were negative for S. aureus.Despite no known family history of immunodeficiency, Ig levels and childhood vaccine titers were drawn. These were normal except for IgG1 (low at 261 mg/dL (2.61 g/L), reference range 284–772 mg/dL) and IgG4 (low-normal at 6 mg/dL (0.06 g/L), reference range 0.3–111.0 mg/dL). These findings were consistent with the correlation of IgG1 and IgG4 and TSST-1 neutralization.19 Laboratory evaluation of TSST-1 antibodies was not available at the time of this publication.Approximately 1 month after discharge, the patient had breakthrough bleeding despite not missing any OCP doses and experienced fever, backache, headache, and nausea. She was not hypotensive, and her symptoms subsided following doxycycline initiation and observation at another hospital. She was using antibacterial soaps and bleach baths but had not been applying nasal mupirocin. Her OCPs were adjusted, and at the time of this report, 7 months after discharge, she has not had a recurrence of TSS.Consider TSS as an etiology of unexplained septic shock in healthy adolescent girls, independent of prolonged tampon use.Acute management of TSS should focus on source control, fluid resuscitation, and antistaphylococcal antibiotics, including clindamycin, for antitoxin production effects.Recurrent menstrual TSS occurs in 10% to 30% of adolescents and young adults following an initial episode; this risk of recurrence can be mitigated with treatment with antistaphylococcal antibiotics during the index episode, menstrual suppression, and on-hand prophylactic antistaphylococcal antibiotics.