The second patient was an 18-year-old male, who, actually, was a roommate to the first patient, and admitted because of fever (38 C), pharyngodynia, and arthritis of the ankles during the last five days. The patient was also of Pakistani descent, immigrant to Greece for the last six months, and currently is occupied as a field worker. His symptoms began three weeks after those of the first patient. He reported never receiving medical care since early childhood, while he denied any current or past alcohol abuse, herbal or supplements, and nasal or intravenous drug use. Clinical examination revealed pharyngitis, warm, swollen, and painful ankle joints, hepatomegaly (2 cm below the right subcostal margin), and a loud precordial systolic and diastolic murmur (3 out of 6, Levine scale).
Laboratory work-up on admission revealed high serum levels of acute phase reactants, anemia, polyclonal hyperglobulinemia, and mild transaminasemia in both patients, while in the second case, additional cholestasis and hypoalbuminemia were recorded (Table 2). The remaining hematological, microbiological, and biochemical parameters including blood, stools, and urine cultures, as well as autoantibodies related to autoimmune rheumatic diseases including antinuclear antibodies, antineutrophil cytoplasmic antibodies, rheumatoid factors, antibodies against cyclic citrullinated peptides, and ferritin levels, were within normal limits in both patients. Multiple stool samples were also negative for ova and parasites such as Enterobius vermicularis, Entamoeba histolytica, Cryptosporidium, and Giardia species. Examination of the ankle joint synovial fluid showed increased neutrophil counts (patient 1: 21,600 neutrophils; patient 2: 24,000 neutrophils). X-rays of the chest and affected joints were unremarkable. Of note, patient 2 had an abnormal electrocardiogram (ECG) with third-degree atrioventricular block that, during hospitalization, interchanged with first-degree block and Mobitz I (Figure 1), even though he was completely asymptomatic.
Accordingly, the differential diagnosis was built in three major pillars. The first included infectious diseases manifesting with arthritis according to our local endemicity, the young age, and the epidemiological background of the patients. Actually, a serological work-up for zoonosis (Brucella, Coxiella, Rickettsia, Borrelia, Leptospira, Leishmania, and other parasites including investigation for Trichinella, Entamoeba, and Echinococcus), sexually transmitted diseases (syphilis, N. gonorrhoeae, U. urealyticum, M. hominis, and C. trachomatis), viral hepatitis A, B, C, and E, and human immunodeficiency virus tested negative. Tropheryma Whipple infection (Whipple's disease), which can be presented with arthritis that predates gastrointestinal symptoms, was also excluded by a polymerase chain reaction (PCR) assay performed in the synovial fluid. Tuberculosis was also ruled out based on a negative chest X-ray, negative tuberculin test, and negative synovial fluid microscopy and culture. Furthermore, the presence of aseptic arthritis was confirmed on the basis of a negative 16sRNA PCR test as we described previously along with sterile synovial fluid cultures.
The second pillar included diverse autoimmune rheumatic diseases such as rheumatoid arthritis, systemic lupus erythematosus, psoriatic arthritis, and ankylosing spondylitis which were excluded on the absence of several clinical and laboratory criteria. The third clinical entity which was considered highly likely in both cases was ARF with or without accompanied infectious endocarditis. In the first patient, infectious endocarditis was excluded based on repeatedly negative blood cultures and transesophageal echocardiogram (TOE) confirming the absence of structural valve disorders. The second patient had established valvular heart disease and possible endocarditis since TOE revealed bicuspid aortic valve with regurgitation (3+/4) and stenosis (peak gradient 67.2 mmHg) with possible presence of vegetation, mitral valve regurgitation (2+/4), and moderate stenosis along with moderately dilated left ventricle. However, multiple blood cultures were sterile though the safer way to exclude infectious endocarditis in patient 2 would be surgical excision and valve tissue culture. As expected, throat cultures and rapid antigen tests for GAS were negative in both patients. However, GAS was isolated in the pustular fluid culture from patient 1, while ASTO titers were elevated in both patients (Table 2). The diagnosis of ARF in the first patient was based on the presence of one major (polyarthritis) and two minor (fever >= 38.5 C, ESR >= 60 mm, and CRP >= 3 mg/dL) RJC while in the second patient was based on the presence of established RHD and two major (carditis and oligoarthritis) and two minor RJC (fever >= 38.5 C, ESR >= 60 mm, and CRP >= 3 mg/dL).
With respect to treatment, patient 1 received intravenous vancomycin (15 mg/kg/bd) and ceftriaxone (2 g bid) till culture reports and oral indomethacin for 14 days for pain relief. He was discharged in good health with recommendation to receive benzathine penicillin G (1.200.000 IU) intramuscularly every twenty-eight days for at least 5 years in an attempt to prevent recurrent ARF episodes. Patient 2 received oral indomethacin for 14 days for pain relief along with intravenous ceftriaxone (2 g bid) and vancomycin (15 mg/kg/bd) for six weeks as endocarditis could not be safely excluded at the clinical ground. Subsequently, the patient submitted to aortic valve replacement with a mechanical valve. The presence of vegetation was not confirmed during surgery, and the tissue culture was sterile. The patient was discharged in good health with recommendation to receive lifelong chemoprophylaxis with azithromycin (250 mg qd) in an attempt to prevent recurrent ARF episodes. After one-year of follow-up, both patients are still in good health afebrile, without joint involvement or new ARF episode, while the laboratory markers are steadily normal. Both patients gave written informed consent for potential publication at the time of discharge.