Febrile Illness in 3 Adolescent Patients

CASE NUMBER 1 A 17-year-old male presented with fevers, neck and back pain, night sweats, dysuria, dysphagia and rash for 6 days. He was diagnosed with latent tuberculosis 10 years prior without receiving treatment and was currently sexually active. On day 4 of illness, he was prescribed amoxicillin-clavulanic acid by his physician for presumed bacterial pharyngitis, but then he developed a rash over his upper extremities the day after starting medication. There was no recent travel history, exposure to sick contacts or exposure to animals. Physical examination revealed a maculopapular, blanching, nonpruritic, nonpainful rash on the patient’s arms, trunk, back and palms. He had a 2 × 2 cm, tender, mobile, palpable lymph node in his posterior cervical chain, pharyngeal erythema with moderate white exudate and tenderness of the right upper abdominal quadrant on palpation. Liver edge was palpated 5 cm below the right costal margin and measured 19.8 cm in length on ultrasound. Initial blood tests showed leukopenia (3.51 K/µL) with differential of 54% bands, 30% neutrophils and 16% lymphocytes, thrombocytopenia (91 K/µL), transaminitis (aspartate aminotransferase [AST] 100 U/L, alanine aminotransferase [ALT] 43 U/L), elevated lactate dehydrogenase (LDH) (1682 U/L) and elevated inflammatory markers (erythrocyte sedimentation rate [ESR] 13 mm/h, C-reactive protein [CRP] 9 mg/dL). Urinalysis was normal. Rapid Group A streptococcal test and monospot test were negative. Chest radiograph was obtained because of his history of latent tuberculosis and did not show pneumonia. Dysuria resolved spontaneously. Because of concern for Kawasaki syndrome, an echocardiogram was performed demonstrating coronary ectasia only. The patient was treated with intravenous immunoglobulin with improvement of fever after 48 hours post infusion. Clinically, headaches improved. On follow-up echocardiograms, there was no worsening of coronary ectasia or aneurysm formation. In addition, the patient also underwent bone marrow biopsy for possible hemophagocytic lymphohistiocytosis demonstrating leukocytosis, thrombocytopenia, variable hypocellular bone marrow with trilineage hematopoiesis and plasmacytosis and without morphologic evidence of malignancy. CASE NUMBER 2 A 17-year-old, sexually active female presented with 4 days of fever, headache, nausea, vomiting, epigastric/right upper quadrant abdominal pain, suprapubic pain, dizziness, cough, chest and back pain and sore throat, followed by 2 days of dysuria and dark-colored urine. She had 2 new kittens at home but no recent travel or exposure to ill contacts. Physical examination was significant for fever of 39.1 °C, tachycardia, right upper quadrant and epigastric abdominal tenderness, cough and cervical motion tenderness on bimanual pelvic examination. Blood tests were notable for leukopenia (white blood cell 3.87 K/µL) with differential of 17% bands, 65% neutrophils, 15% lymphocytes and 3% monocytes, thrombocytopenia (51 K/µL), hyponatremia (133 mEq/L), hyperbilirubinemia (total bilirubin 3.0 mg/dL, conjugated bilirubin 0.9 mg/dL), elevated transaminases (AST 271 U/L, ALT 317 U/L) with elevated alkaline phosphatase (335 U/L), gamma-glutamyl transferase (387 U/L), elevated LDH (2298 U/L) and elevated inflammatory marker (CRP 8.0 mg/dL). Urinalysis was normal. Chlamydia trachomatis and Neisseria gonorrhoeae urine polymerase chain reaction were negative. Dysuria resolved. Chest radiograph showed atelectasis but no infiltrates. Abdominal and pelvic ultrasound showed hepatosplenomegaly with no evidence of cholecystitis or cholelithiasis. CASE NUMBER 3 A 13-year-old obese male with a history of nonalcoholic steatohepatitis presented with 7 days of fever and 3 days of rash. On day 2 of illness, he had dysuria. On day 4, he developed mouth sores and was prescribed cephalexin and nystatin by his physician. On day 5 of illness, he developed a nonpainful rash starting on the palmar surfaces of hands, spreading centripetally. There were exposures to pet dogs, iguana, turtle and cat. He reported 2 insect bites on his right wrist. There was no recent travel or exposure to ill contacts. Physical examination was notable for fever of 38.6 °C, tachycardia to 130 beats per minute, resting respiratory rate of 32 breaths per minute, blood pressure of 121/55 mm Hg, oxygen saturation of 97% in ambient air, fatigue and a diffuse, nonpruritic, nonblanching, erythematous maculopapular rash, involving the trunk, arms, legs, palms and soles, but sparing the face. Initial blood tests were remarkable for mild leukopenia (4.83 K/µL) with differential of 68.7% neutrophils, 7.1% bands, 18.8% lymphocytes, 4.5% monocytes, 1% basophils, thrombocytopenia (103,000 K/µL), hyponatremia (131 mEq/L), elevated transaminases (AST 268 U/L, ALT 143 U/L), elevated alkaline phosphatase (153 U/L), elevated LDH (1417 U/L) and elevated inflammatory markers (ESR 53 mm/h, CRP 13.1 mg/dL). Urinalysis had moderate proteinuria only. Respiratory viral polymerase chain reaction panel (coronavirus 229E/HKU1/NL63/OC43, metapneumovirus, rhino/enterovirus, influenza A/B, parainfluenza 1–4 and respiratory syncytial virus), monospot test and rapid Group A streptococcal test were negative. Additional serologic testing revealed a common diagnosis for all 3 patients. For Denouement see P. 86. DENOUEMENT (Pediatr Infect Dis J 2022;41:86) Continued from P. 85. The differential diagnoses considered in all 3 patients included bacterial sepsis, disseminated intravascular coagulation, severe viral infection, hemophagocytic lymphohistiocytosis syndrome, hepatitis, sexually transmitted infections, pelvic inflammatory disease (in the female patient), Kawasaki disease, rheumatologic diseases and pneumonia (in cases 1 and 2). All 3 patients were ultimately found to have murine typhus infection with Rickettsia typhi IgG and IgM screen positive and R. typhi IgM and IgG titers >1:256. Each of our patients recovered from the acute illness but required prolonged hospital stays of 10 days, 8 days and 6 days, respectively. Two were treated with doxycycline hastening recovery, while the other recovered without antibiotic therapy. Murine typhus, a zoonotic disease caused by R. typhi, is an often-unrecognized cause of febrile illness throughout the world. Although typically a self-limited, mild disease in children, especially with antibiotic treatment, severe illness and mortality can occur in up to 5% of patients.1 Presenting symptoms are nonspecific making diagnosis difficult. In the United States, there is an average of 300 cases every year, and the incidence is continuing to increase.2 Increases in population density, shifts in population density from rural to urban areas, increases in domestic and international mobility, rising rates of homelessness, increasing presence of homeless encampments on neighborhood streets and the decline of inner-city neighborhoods have all been implicated in the rise of vector-borne diseases.3 R. typhi is a Gram-negative obligate intracellular bacterium that is transmitted by the rat flea (Xenopsylla cheopis), the cat flea (Ctenocephalides felis) and the mouse flea (Leptopsylla segnis).1 These fleas are carried by rats, cats and opossums, which then come into contact with humans, who then acquire the infection when the infected flea feces come into contact with damaged skin, scratches from fleabites or by inhalation or inoculation of dust carrying infectious flea dirt. The classic triad of fever, headache and rash is encountered in about one-third of patients.3 Fever (T > 38 °C) occurs in >90% of patients, headache in 80.9% and rash in 47.5%.4 In pediatric patients, abdominal pain, diarrhea and sore throat are common manifestations. Myalgias, cough, conjunctivitis and back pain were less common. Other common symptoms include malaise, chills, myalgia, anorexia, back pain, cough, arthralgia, vomiting, nausea, hepatomegaly, conjunctivitis, splenomegaly, diarrhea, abdominal pain, pharyngitis, lymphadenopathy and photophobia. Case reports show varied presentations that include acute psychosis with magnetic resonance imaging findings of leptomeningeal enhancement,5 disseminated intravascular coagulation,5 typhus encephalitis,5 bilateral pulmonary consolidations leading to acute respiratory distress syndrome,6 pancreatitis1 and status epilepticus.7 Common laboratory findings include elevated AST/ALT (79.0% of cases), LDH elevation (72.9%), hypoalbuminemia (60.1%), elevated ESR (59.9%), thrombocytopenia, alkaline phosphatase elevation, anemia, microscopic hematuria, hyponatremia, proteinuria, creatine kinase elevation, leukopenia and leukocytosis.1 Children typically have lower rates of hypoalbuminemia, hematuria and proteinuria compared with adults. We present 3 cases of confirmed murine typhus, each presenting with prolonged fever, myalgias and dysuria with varied physical findings and concerning laboratory findings that resulted in prolonged hospitalization (average of 7 days) and extensive evaluation. Our 3 adolescent cases continue to highlight challenges in diagnosing endemic typhus. Knowledge of travel and exposures to vectors are always important in the evaluation of patients presenting with fever of unknown source. But the absence of epidemiologic risk does not preclude infection with R. typhi. Inconsistent clinical presentations, nonspecific constitutional symptoms and laboratory findings mimicking infectious and noninfectious febrile syndromes and the long turnaround time of available serologies add to the challenge of earlier diagnosis. To prevent complications, earlier suspicion of murine typhus is important so that empiric treatment can be considered, even while assessing and treating other serious life-threatening illnesses and while awaiting confirmatory serologic evidence.