Acute rheumatic fever mimicking thyroid storm in an adolescent: a case report

Abstract

Background

Acute rheumatic fever (ARF) is caused by an autoimmune response to throat infection with group A Streptococcus. ARF and its sequel, chronic rheumatic heart disease, remain significant public health problems in many low-income countries. Rapid diagnosis and timely treatment of ARF are essential to avoiding serious adverse outcomes.

Case presentation

A 16-year-old adolescent with hyperthyroidism and treatment noncompliance presented with symptoms such as fever, difficulty lying flat at night, cough with expectoration, palpitations, and tachypnea. On the basis of the patient’s symptoms, physical signs, and laboratory test results, a preliminary diagnosis of thyroid storm (TS) was made, and hydrocortisone, antithyroid drugs, and anti-infective agents were promptly administered. However, subsequent examinations revealed hemorrhagic pericardial and pleural effusions, indicating that hyperthyroidism complicated by other conditions (including tuberculosis, malignancies, and certain autoimmune diseases) should be considered. Ultimately, the diagnosis of ARF was confirmed on the basis of his dramatic clinical response to hydrocortisone, cardiac inflammatory manifestations, and significantly elevated erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), and anti-streptolysin O (ASO) levels. Follow-up revealed that the patient’s rheumatic fever was well controlled and alleviated by treatment.

Conclusions

ARF may have multiple clinical manifestations, but hemorrhagic pericardial and/or pleural effusions are extremely rare. In children and adolescents from developing countries, even in the absence of pharyngitis or tonsillitis, ARF should always be considered when symptoms such as unexplained fever, diaphoresis, palpitations, emaciation and epistaxis are present.

Background

Acute rheumatic fever (ARF) is an inflammatory autoimmune disease that typically occurs two to three weeks after throat infection by group A Streptococcus. ARF and its sequel, chronic rheumatic heart disease, have high morbidity and mortality rates and remain significant public health problems in many low-income countries. ARF has various manifestations, and 50–70% of cases exhibit cardiac involvement [1]. However, massive hemorrhagic pericardial effusion in ARF patients is rare. Only a few such cases have been reported [2–6]. This article reports the case of an adolescent with hyperthyroidism who had a history of treatment noncompliance. The patient was initially diagnosed with thyroid storm (TS) upon admission. Subsequent examinations revealed hemorrhagic pericardial and pleural effusions. On the basis of his dramatic clinical response to hydrocortisone, cardiac inflammatory manifestations, and significantly elevated erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), and anti-streptolysin O (ASO) levels, the patient was ultimately diagnosed with ARF.

Case presentation

A 16-year-old male developed heat intolerance, diaphoresis, and hand tremors two years prior to admission, along with exertional fatigue, palpitations, and dyspnea. One year prior to admission, he was diagnosed with hyperthyroidism due to Graves’ disease at our outpatient clinic and was started on methimazole (MMI) therapy. However, the patient demonstrated poor treatment compliance and frequently discontinued the medication on their own, resulting in recurrent hyperthyroidism. Four months prior to admission, he experienced recurrent epistaxis. One month prior to admission, the patient experienced another recurrence of hyperthyroidism and was prescribed propylthiouracil (PTU) and propranolol. Twenty days prior, he developed fever with a peak temperature of 39 °C (without chills), worsening palpitations and tachypnea, difficulty lying flat at night, mild cough and expectoration, a significantly increased frequency of bowel movements, and a further decrease in appetite and body weight.

Physical examination revealed the following: a temperature of 38.7 °C, a pulse of 140 beats/min, a respiratory rate of 30 breaths/min, and a blood pressure of 120/80 mmHg. The patient appeared acutely ill and emaciated and was in a semirecumbent position. The generalized skin was moist and diaphoretic. A soybean-sized lymph node was palpable posterior to the occipital bone; several peanut-sized lymph nodes were palpable in the right supraclavicular fossa. The jugular veins were distended, and the trachea deviated to the right. The thyroid gland was enlarged to Grade II, with a palpable thrill. Percussion revealed dullness over the middle and lower zones of the left lung. The breath sounds were coarse over both upper lung fields, absent over the left lower, and diminished over the right lower; no moist or dry rales were auscultated in either. The apical impulse was diffuse and located at the 6th intercostal space (ICS) on the left midclavicular line. The left cardiac relative dullness border was at the anterior axillary line in the 4th and 5th ICSs; the right border was 4 cm lateral to the right sternal border at the 4th ICS. Rough systolic and diastolic murmurs were auscultated in the apical area. The inferior liver margin was palpable 2 cm below the costal margin. No edema was present in either lower extremity.

Laboratory tests revealed moderate anemia, with a hemoglobin concentration of 88.0 g/L. The white blood cell count was 8.6 × 10⁹/L, with 71.0% neutrophils and 24.0% lymphocytes. The qualitative urine protein test was positive (1+), with 14 red blood cells per high-power field. Thyroid function tests revealed a significantly suppressed thyroid-stimulating hormone (TSH) concentration of 0.005 mU/L (0.3–5.0). The free triiodothyronine (FT3) concentration was 7.5 pmol/L (3.6–7.5), and the free thyroxine (FT4) concentration was 12.67 pmol/L (13.0–23.0). Elevated titers of thyroid autoantibodies were detected: the TSH receptor antibody (TRAb) concentration was 5.26 IU/L (0–1.75), the thyroid peroxidase antibody (TPOAb) concentration was 170.7 IU/mL (0–34), and the thyroglobulin antibody (TGAb) concentration was 214.6 IU/mL (0–115). The level of lactate dehydrogenase was 312 IU/L (110–220). The ESR was elevated at 121 mm/h (0–15), and the CRP was elevated at 148 mg/L (0–5). A chest X-ray revealed marked cardiomegaly, indistinct pulmonary markings in both lower lung fields, consolidation in the right middle lobe, and left-sided pleural effusion (Fig. 1).

Fig. 1.

Chest radiograph of this patient

Thyroid function tests confirmed overt hyperthyroidism due to Graves’ disease. Combined with the patient’s history of poor compliance with hyperthyroidism treatment and a Burch–Wartofsky Point Scale score of 50 [7], TS was considered the most likely diagnosis upon admission. The therapeutic regimen administered to the patient was as follows: (1) Cedilanid (0.133 mg iv), furosemide (20 mg iv), and nitroglycerin (1 mg/h iv) to improve cardiac function. (2) Hydrocortisone (100 mg ivgtt q12h). (3) PTU (100 mg po tid). (4) Cefotaxime sodium (2.0 g ivgtt q12h) for infection control (given the high likelihood of pulmonary infection, which could also trigger TS).

Subsequent ultrasonography revealed massive pericardial effusion, with a maximum depth of 6 cm. In view of tachycardia, dyspnea, and profuse diaphoresis, pericardiocentesis and thoracentesis were needed. He underwent pericardiocentesis, and 400 mL of hemorrhagic pericardial effusion was drained. Postprocedural ultrasonography revealed that the depth of the residual effusion remained at 3 cm. On the following day, the patient’s symptoms of palpitations, dyspnea, and diaphoresis improved; the body temperature decreased to 37.1 °C, the heart rate decreased to 120 beats/min, and the respiratory rate decreased to 22 breaths/min. To further alleviate the patient’s symptoms, a repeat pericardiocentesis was planned. However, ultrasonography performed in the same position revealed a significant reduction in pericardial effusion as the previous day, with a maximum depth of only 1.5 cm; thus, the procedure was cancelled. Echocardiography revealed biatrial and left ventricular enlargement, severe mitral regurgitation, and mild pericardial effusion. Thoracentesis yielded 500 mL of hemorrhagic pleural effusion. The examination of pericardial and pleural effusions indicated that both were hemorrhagic exudates (Table 1).

Table 1.

Laboratory data of pericardial and pleural effusion of the patient

Variable	Pericardial effusion	Pleural effusion
Gross appearance	madder red, turbid-looking, no coagulum	bright red, turbid-looking, no coagulum
Karyocyte (106/L)	120	2750
Red Blood Cell	(+++)	(++++)
Pus cell	(–)	(–)
Multinucleate cell (%)	0.64	0.29
Monocyte (%)	0.32	0.49
Mesothelial cell (%)	0.04	0.22
Total Protein (g/L)	50.7	33.1
Glucose (mmol/L)	6.2	5.1
Cl (mmol/L)	99	110.2
Lactate dehydrogenase (IU/L)	1368	626
Adenosine deaminase (IU/L)	18.9	10.7
Ferritin (ng/ml)	> 2000	> 2000
CYF21-1 (ng/ml)	85	/
CA-125 (U/ml)	/	1367
Bacterial culture	(–)	(–)
Acid-fast staining smear	(–)	(–)
Mycobacterium tuberculosis real-time polymerase chain reaction	(–)	(–)
Mycobacterial culture	(–)	(–)
Malignant cells	(–)	(–)

Hemorrhagic exudates are commonly associated with tuberculosis, malignancies, and certain autoimmune diseases [8]; therefore, further examinations were performed. The cancer embryonic antigen concentration was 3.92 ng/mL (0–3.4), the CA-125 concentration was 141.80 U/mL (0–35), and the ferritin concentration was 454.60 ng/mL (24–336). Serum immunoglobulin levels were mildly elevated, with specific values as follows: IgG 20.5 g/L (8–15.5), IgA 4000 mg/L (836–3922), IgM 2910.0 mg/L (620–2260), and IgE 309.3 IU/mL (0.1–150). The tuberculin skin test, interferon-γ release assay, anti-nuclear antibody, anti-nuclear antigen extractable nuclear antigen, and anti-double stranded DNA were negative. Given that a definitive diagnosis could not be established on the basis of the current findings, a right supraclavicular lymph node biopsy was performed on the 5th day after admission. With respect to treatment, the dosages of PTU and hydrocortisone were gradually tapered. On the 7th day after admission, intravenous hydrocortisone infusion was discontinued and replaced with oral prednisone. The patient’s symptoms improved significantly that day, allowing for mild activity. Echocardiography revealed no pericardial effusion. A lymph node biopsy indicated reactive hyperplasia.

A review of the patient’s clinical course revealed that the pericardial and pleural effusions decreased significantly after only one day of hydrocortisone therapy. Such a dramatic therapeutic response would be unlikely in cases of tuberculosis or malignancy. Therefore, autoimmune disease was the primary consideration. In addition, the patient presented with systolic and diastolic murmurs in the apical area, along with biatrial and left ventricular enlargement and severe mitral regurgitation. These findings are more commonly observed in children and adolescents with ARF affecting the mitral valve, resulting in mitral regurgitation and relative mitral stenosis. Given the patient’s history of recurrent epistaxis, further detailed medical history revealed mild knee joint pain following the acute onset of this episode. Therefore, this episode should be considered to be caused by ARF. On the 8th day after admission, a serum anti-streptolysin O (ASO) test was performed. The serum ASO titer was significantly elevated at 1480 IU/mL. In accordance with the Jones criteria [9], the patient had evidence of streptococcal infection (elevated ASO titer), one major criterion (carditis), and two minor criteria (fever, elevated ESR and CRP), thus confirming the diagnosis of ARF.

The patient’s condition further improved, and he was discharged on the 13th day. Following discharge, the patient received monthly intramuscular injections of 1.2 million units of benzathine penicillin, oral administration of enteric-coated aspirin (0.3 g tid) and prednisone (10 mg qd), in addition to methimazole (10 mg qd) for the treatment of Graves’ disease. Follow-up was conducted monthly, and the data are summarized in Table 2. Three months after discharge, the patient’s thyroid function normalized, and hypermetabolic symptoms disappeared. The cervical lymph nodes gradually regressed in size, with only a rice-grain-sized lymph node being palpable six months post-discharge. Cardiac function improved significantly six months after discharge; however, the apical murmurs persisted one year after discharge.

Table 2.

Clinical parameters in follow-up of the patient

Variable	Reference range	On admission	On discharge	1 Mo	2 Mo	3 Mo	4 Mo	5 Mo	6 Mo	12 Mo
ASO	0–116 IU/ml	1480.0	1010.0	763.0	509.0	154.0	56.0	35.0	37.0	26.0
CRP	0–5 mg/L	148.0	7.12	4.33	/	/	2.56	2.31	1.34	2.45
ESR	0–15 mm/h	121.0	19.0	15.0	/	/	7.0	4.0	6.0	4.6
Urine red blood cell count	0–3 /HP	14.0	1.0	/	/	/	/	/	1.0	0.0
CA-125	0–35 U/ml	141.80	/	26.71	/	/	/	/	23.69	20.57
Ferritin	24–336 ng/ml	454.60	/	66.74	/	/	/	/	50.63	67.89

ASO Anti-streptolysin O, CRP C-reactive protein, ESR Erythrocyte sedimentation rate

Combined with the patient’s medical history and subsequent follow-up findings, the diagnosis of ARF was further confirmed. The final diagnoses were as follows: (1) Hyperthyroidism (Graves’ disease); (2) acute rheumatic fever, acute rheumatic carditis, acute rheumatic pericarditis, and acute rheumatic pleurisy; and (3) chronic rheumatic heart disease, mitral stenosis, and mitral regurgitation.

Discussion

Rheumatic fever is an acute or chronic systemic connective tissue inflammation that recurs following Group A streptococcal throat infections. It can occur at any age but is most common between 5 and 15 years of age and is prone to recurrence. ARF presents with diverse clinical manifestations, primarily including carditis and arthritis, and may be accompanied by fever, erythema marginatum, subcutaneous nodules, and chorea. General malaise, lethargy, anorexia, fatigue, diaphoresis, epistaxis, and abdominal pain are also frequently observed [10, 11]. ARF with pericarditis accounts for 5–10% of cases and is often accompanied by pancarditis, typically presenting only as mild pericardial effusion with no clinical signs. Acute rheumatic pericarditis can be dry or exudative, rarely hemorrhagic, with fluid volume generally less than 300 mL [12, 13]. Acute rheumatic pleurisy is even less common, presenting with fibrinous serous pleural effusion in small volumes, and may be accompanied by rheumatic pneumonia [14]. Salicylates and glucocorticoids demonstrate significant therapeutic efficacy for acute rheumatic pericarditis and rheumatic pleurisy [13, 15].

TS is an extremely severe form of thyrotoxicosis. Its clinical manifestations include high fever, profuse diaphoresis, tachycardia, vomiting, diarrhea, and agitation; in severe cases, heart failure, shock, and coma may occur. The main triggers include abrupt discontinuation of antithyroid drugs, infection, stress, and radioactive iodine therapy [16, 17]. The patient in this case had a confirmed previous diagnosis of hyperthyroidism and was admitted because of fever, profuse diaphoresis, tachycardia, difficulty lying flat at night, cough, significant anorexia, and weight loss. These symptoms could be attributed to hyperthyroidism; combined with the patient’s history of inconsistent compliance with hyperthyroidism treatment, an initial diagnosis of TS was considered upon admission. However, subsequent examinations revealed hemorrhagic pericardial and pleural effusions, which are commonly associated with malignancies and tuberculosis. Hyperthyroidism complicated by hemorrhagic pericardial effusion is extremely rare, with only a few such cases reported [18–24]. Among these reported cases, hemorrhagic pericardial effusion in two patients was considered to be associated with anticoagulant therapy for atrial fibrillation; in another patient with hyperthyroidism complicated by systemic lupus erythematosus (SLE), the hemorrhagic pericardial effusion was thought to be attributable to SLE-associated vasculitis. Therefore, the hemorrhagic effusions in this patient warrant thorough investigation for other underlying conditions, particularly tuberculosis, malignancies, and autoimmune diseases.

The diagnostic breakthrough in this patient occurred when pericardial and pleural effusions rapidly diminished within just one day of glucocorticoid administration and almost completely resolved after one week. Concurrently, symptoms, including fever and diaphoresis, improved significantly, indicating a dramatic therapeutic response to glucocorticoid treatment. Although the potential contribution of anti-infective therapy to effusion resolution cannot be completely ruled out, the patient exhibited no definitive clinical signs of bacterial infection: the peripheral white blood cell count was normal, the percentage of neutrophils was only slightly elevated, and no pathogens were isolated from blood cultures and serosal effusion cultures. Thus, infection was unlikely to have been the primary cause of symptom resolution. Meanwhile, such a rapid therapeutic response is uncommon in tuberculosis or malignancy, and further examinations failed to reveal any evidence suggestive of tuberculosis or malignancies. Additionally, the patient presented characteristic manifestations of rheumatic carditis, prodromal symptoms of fever, and markedly elevated ESR, CRP, and ASO levels, meeting the Jones criteria for ARF. Following discharge, the patient remained afebrile, with marked improvement in cardiac function and gradual normalization of ESR, CRP, and ASO levels. One year after discharge, a biphasic murmur persisted at the cardiac apex. Echocardiography revealed rheumatic heart disease with mitral stenosis and regurgitation, without pericardial effusion. These follow-up findings further supported and confirmed the patient’s diagnosis.

We reviewed and summarized the currently reported literature on ARF complicated by pericardial effusion and/or pleural effusion (Table 3) [2–6, 25–32]. These cases indicate that ARF is one of the etiologies of pericardial effusion. Massive pericardial effusion is a rare and atypical manifestation of rheumatic carditis in the context of ARF. While such effusion is typically serous, hemorrhagic pericardial effusion has been reported in extremely rare cases and is often associated with life-threatening cardiac tamponade. The mechanism underlying the massive hemorrhagic pericardial and pleural effusions observed in this case of ARF remains unclear. We hypothesize that this may be related to intense inflammatory and immune responses, which lead to marked increases in pericardial and pleural capillary permeability, vascular wall rupture, and impaired lymphatic drainage. However, this hypothesis requires further investigation to provide pathological and clinical evidence to elucidate it.

Table 3.

Summary of published case reports

Authors	Year of publication	Patient(s)	Diagnosis	Pericardial effusion	Pleural effusion	Valvular involvement	Others	ASO IU/mL
Tan AT et al. [2]	1983	12-year-old female	Acute rheumatic carditis	Yes, massive, hemorrhagic, with cardiac tamponade	Yes, bilateral	Mitral and aortic regurgitation	ND	716
Colombo A et al. [3]	1988	24-year-old male*	Acute rheumatic fever	Yes, massive, hemorrhagic, with cardiac tamponade	ND	ND	ND	ND
Livneh A et al. [25]	1991	58-year-old male	Acute rheumatic fever	No	Yes, left	No	Hematuria, proteinuria, glomerulonephritis, palpable purpura, penile ulcer, sterile subdermal abscess	500
Kamblock J et al. [26]	2003	7 of 95 patients*	Rheumatic carditis	Yes	ND	Mitral and/or aortic regurgitation	Congestive heart failure	116–413
Unal N et al. [4]	2005	12-year-old female	Acute rheumatic fever	Yes, massive, hemorrhagic, with cardiac tamponade	No	Severe mitral and moderate aortic regurgitation	ND	1600
Cetin II et al. [27]	2008	13-year-old female	Rheumatic carditis	Yes, minimal	No	Severe mitral and mild aortic regurgitation	Multiple recurrences of carditis, congestive heart failure, iatrogenic Cushing syndrome	517/ 665/ 358/ 692/ 248
Rocha Araújo FD et al. [28]	2010	11-year-old female	Rheumatic carditis	Yes, massive, serous, with cardiac tamponade	No	Severe mitral and mild to moderate aortic regurgitation	ND	200/ 600
Güzeltaş A et al. [5]	2013	7-year-old male	Acute rheumatic fever	Yes, massive, serosanguinous, with cardiac tamponade	No	Severe mitral and mild aortic regurgitation	ND	580
Ertel AW et al. [29]	2016	28-year-old male	Acute rheumatic fever	Yes, moderate, serous	No	Mild aortic regurgitation	ND	1450/ 1940
Howard A et al. [30]	2017	10-year-old male	Rheumatic fever	Yes, massive, serous, with cardiac tamponade	Yes, left	Mild mitral regurgitation	Recurrent pericarditis with cardiac tamponade	200
Edwards A et al. [6]	2017	10-year-old female	Rheumatic fever	Yes, massive, serosanguinous, with cardiac tamponade	No	ND	Recurrent pericarditis with cardiac tamponade	1570
Wilson ZM et al. [31]	2021	24-year-old male	Acute rheumatic fever	Yes, moderate	Yes, left, serous	Mild mitral regurgitation	Left shoulder pain (diaphragmatic irritation), reduced systolic function	200
Nguyen A et al. [32]	2025	60-year-old male	Rheumatic myopericarditis	Yes, moderate, serous	No	Trace mitral regurgitation	Reduced systolic function without valvular disease	1320

*, The data were derived from a cohort. ND Not reported in the original article

In reviewing this patient’s case, several points are noteworthy: (1) The clinical manifestations of ARF, including fever, diaphoresis, fatigue, palpitations, and weight loss, were similar to those of hyperthyroidism and TS. Recurrent epistaxis also warrants attention. (2) This patient did not present with prodromal manifestations of upper respiratory tract streptococcal infection, such as pharyngitis or tonsillitis. However, even in the absence of prodromal streptococcal infection, ARF could not be ruled out. (3) The massive hemorrhagic pericardial and pleural effusions observed in this patient are extremely rare in the context of ARF. (4) The persistence of cardiac murmurs in the patient six months after anti-rheumatic therapy suggested that this episode of ARF was a recurrence. The initial episode was subclinical and had already caused cardiac damage. The above points constitute the diagnostic challenges and key reasons for the initial missed diagnosis in this patient.

This study has the following limitations: First, as a single-case retrospective report, it carries an inherent risk of bias, and its conclusions cannot be generalized to other ARF patients. Second, it only describes the clinical phenomenon of massive hemorrhagic pericardial and pleural effusion in this ARF patient, and cannot confirm the causal relationship between the two nor rule out interference from accidental and potential confounding factors. Finally, the underlying mechanism of the hemorrhagic effusions in this patient has not been further investigated.

Conclusion

This case highlights that in children and adolescents who present with unexplained symptoms such as fever, diaphoresis, fatigue, palpitations, weight loss, and epistaxis, even in the absence of pharyngitis or tonsillitis, the possibility of ARF should be considered. Massive hemorrhagic pericardial and pleural effusions are extremely rare in ARF cases. ARF should be diagnosed early and treated promptly to prevent the development of chronic rheumatic heart disease.

Authors’ contributions

TZ and YR conceptualized and drafted the initial manuscript; TZ, YL and CL collected clinical information and analyzed data; TZ completed the follow-up of the patient; HT, TC and YR critically revised the manuscript. All authors have approved the submitted version and agreed to be accountable for all aspects of the work.

Funding

No funding was used for the creation of this article.

Data availability

The original contributions presented in the study are included in the article, further inquiries can be directed to the corresponding author.

Declarations

Ethics approval and consent to participate

The study was approved by the Biomedical Ethics Review Committee of West China Hospital, Sichuan University (approval number 2021(1504)) and performed in accordance with the Helsinki Declaration of 1964, and its later amendments.

Consent for publication

Written informed consent was obtained from the parents of the patient for the publication of any potentially identifiable images or data included in this article.

Competing interests

The authors declare no competing interests.