Intern Emerg Med DOI 10.1007/s11739-014-1072-9

IM - CASE RECORD

A young man with cough, fever and epigastric pain Maddalena Alessandra Wu • Elisa Ceriani • Armando Belloni • Ennio Leopaldi • Marco Cicardi • Nicola Montano • Eleonora Tobaldini

Received: 20 February 2014 / Accepted: 16 April 2014 Ó SIMI 2014

Case presentation and history

Physical examination

Dr. Wu: A 25-year-old man presented to our Emergency Department (ED) complaining of fever, productive cough, episodes of vomiting and epigastric discomfort. These symptoms had started over the previous 5 days. His prior medical history was negative. The family history was positive only for coronary artery disease. He denied any ongoing therapy, illicit drug abuse, allergy, alcohol consumption and smoking. He reported no contacts with sick persons and no recent travel. He came from a town in Southern Italy where he worked for a company of heavy goods transport. At admission, the patient was alert, well oriented and afebrile. Vital signs recorded in the ED were the following: heart rate (HR) 120 beats/min, blood pressure (BP) 140/90 mmHg, respiratory rate (RR) 28 breaths/min and SpO2 94 % while breathing ambient air.

On physical examination, the patient was pale and in apparent distress. No cyanosis was visible. Cardiac examination revealed only tachycardia with no murmurs or rubs. Chest examination was positive for pulmonary crackles at the right mid lung field. Abdominal examination revealed light tenderness to deep palpation over the epigastric and right upper quadrant. The rest of the physical examination was unremarkable. The first blood sample analysis showed a neutrophilic leukocytosis (white cell count of 25,250/mmc3 with 86 % neutrophils), plasmatic creatinine level 1.29 mg/dl, mild hypokalemia (serum potassium 3.2 mmol/l). C-reactive protein, liver function tests, troponin T and urinalysis were normal. An electrocardiogram showed sinus tachycardia, and a chest radiograph (CXR) revealed a right perihilar inferior opacity (Fig. 1a).

M. A. Wu  M. Cicardi Division of Internal Medicine, Department of Biomedical and Clinical Sciences ‘‘L. Sacco’’, L. Sacco Hospital, University of Milan, Milan, Italy

N. Montano International Clinical Research Center, St. Anne University Hospital, Brno, Czech Republic

E. Ceriani Division of Emergency Medicine, L. Sacco Hospital, University of Milan, Milan, Italy A. Belloni Coronary Care Unit, Division of Cardiology, L. Sacco Hospital, University of Milan, Milan, Italy

N. Montano  E. Tobaldini (&) Cardiovascular Neuroscience Lab., Department of Biomedical and Clinical Sciences ‘‘L. Sacco’’, Division of Medicine and Pathophysiology, L. Sacco Hospital, University of Milan, Milan, Italy e-mail: [email protected]

E. Leopaldi Division of Surgery, L. Sacco Hospital, University of Milan, Milan, Italy

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Intern Emerg Med Fig. 1 a First CXR showing a right perihilar inferior opacity. b Second CXR showing interstitial–alveolar edema and increased vascular redistribution

In the ED, the following iv therapy was administered: omeprazole 40 mg, metoclopramide 10 ? 10 mg, ondansetron 4 mg and acetaminophen 500 mg.

Preliminary diagnosis Dr. Tobaldini: Clinical signs and symptoms together with laboratory and imaging findings were consistent with the diagnosis of pneumonia. Therefore, blood samples for cultures were obtained and empiric antibiotic therapy for community-acquired pneumonia was started (Levofloxacin 500 mg iv od). The patient was admitted to the Emergency Medicine Department.

Further investigations Dr. Ceriani: At admission to our Department, the clinical picture rapidly changed. The vital signs worsened, with hypotension and tachycardia (HR 140 beats/min, BP 80/60 mmHg, RR 40 breaths/min, SpO2 85 % in ambient air, T 35 °C). On chest auscultation, crackles were heard over the middle and lower fields bilaterally. There was neither lower-extremity edema nor jugular venous distention. Arterial blood gas parameters were suggestive of a worsening respiratory distress with severe hypoxemia (pH 7.45, pCO2 31 mmHg, pO2 39 mmHg, HCO321.5 mmol/l, lactate 1.8 mmol/l, O2 sat 77 %). An urgent CXR showed an increased vascular redistribution (Fig. 1b). ECG revealed sinus tachycardia, left atrial overload, incomplete right bundle branch block and atypical repolarization abnormalities. A transthoracic cardiac ultrasound showed left ventricular dilatation and global severe hypokinesis, with markedly impaired

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ejection fraction (EF, approximately 10 %) and right ventricle hyperkinesis; no pericardial effusion was detected; inferior vena cava normally collapsed during inspiration. This clinical picture was compatible with respiratory distress in acute decompensated heart failure, possibly due to sepsis or myocarditis. Therefore, the patient was transferred to the intensive care unit (ICU).

Presumptive diagnosis and subsequent tests Dr. Belloni: When the patient was admitted to ICU, he was still tachycardic (HR 130 beats/min), tachypneic (RR 40 breaths/min), with normal blood pressure (120/59 mmHg). Arterial blood gas analysis confirmed moderate hypoxemia with a trend to respiratory alkalosis: O2 sat 93 % on a Venturi mask at 60 %, P/F ratio 105 (n.v. [400), alveolar arterial oxygen gradient 324 mmHg (n.v. for a young adult nonsmoker breathing air 5–10 mmHg). Therefore, the patient underwent noninvasive mechanical ventilation with continuous positive airway pressure (FiO2 50 %, PEEP 7.5 cmH2O). Antibiotic therapy was improved by adding Azithromycin. Dr.Wu: To further investigate a possible hypothesis of acute myocarditis, we decided to perform viral and bacterial tests (CMV, EBV, Chlamydia, Parvovirus, Cocksackie, Legionella, Streptococcus pneumoniae) and autoimmunity tests (ANA, ENA, ANCA) which were all negative (except for a mild positivity for Adenovirus IgM). An HIV test was negative as well. Blood analyses revealed a gradual decrease of inflammatory markers. A second cardiac ultrasound performed 4 days later showed a significant improvement of cardiac function (EF 40 %). When clinical conditions improved, the patient was transferred to the Cardiology division.

Intern Emerg Med Fig. 2 a, b Cardiovascular magnetic resonance showing increased wall thickness consistent with myocardial edema and late gadolinium enhancement (more intense in the subepicardial layer of the lateral–inferior left ventricle segments). A right adrenal mass is also detectable

Dr. Belloni: The most remarkable clinical data was an unexplainable tachycardia with normal arterial pressure and improvement of congestive heart failure, in absence of fever, anemia and abnormal thyroid function. The patient underwent a 24 h Holter ECG that revealed max HR 115 beats/ min, min HR 52 beats/min, rare supraventricular premature beats, atypical repolarization abnormalities (already present at basal ECG), but no significant dysrhythmias. Cardiovascular magnetic resonance was performed to obtain supportive evidence of myocarditis. It showed increased wall thickness consistent with myocardial edema and late gadolinium enhancement more intense in the subepicardial layer of the lateral–inferior left ventricle segments. Incidentally, a right adrenal mass (35 9 25 mm) was detected, suggesting the hypothesis of pheochromocytoma and possible adrenergic myocarditis (Fig. 2) [1]. Betablocker therapy was added to ongoing therapy and the patient was transferred to the Internal Medicine Department.

Fig. 3 Abdominal CT showing an ovalar image (32.9 9 28.2 mm) on the cranial part of the right adrenal gland; no masses on the left adrenal gland; no abnormal formations or lesions affecting the other abdominal organs; no lymphadenopathy

Final investigations and definitive diagnosis Dr. Montano, Dr. Tobaldini: The above-mentioned hypothesis of adrenergic myocarditis (possibly associated with pheochromocytoma) warranted deeper investigation. A 24-h urine fractionated catecholamines as well as plasma catecholamines were significantly increased: U-Epinephrine 138.7 lg/24 h (n.v. 1.7–22.4 lg/24 h); U-Norepinephrine 917 lg/24 h (n.v. 12.1–85.5 lg/24 h); PEpinephrine 629 pg/ml (n.v. 10–196 pg/ml); P- Norepinephrine 6,678 pg/ml (n.v. 80–520 pg/ml). Chromogranin A was also markedly above the upper reference limit

(655 lg/l, n.v. \94 lg/l). Endocrine function tests (including TSH, fT4, ACTH, basal cortisol level, PRL, 5-HIAA, PTH) were within normal range. Considering the patient’s young age and the possibility of pheochromocytoma being part of a familial syndrome as multiple endocrine neoplasia (MEN), additional tests were performed. Increased serum calcitonin values (588.7 pg/ml, n.v. \10 pg/ml) were consistent with medullary thyroid carcinoma (MTC). MTC was confirmed by thyroid ultrasound, which showed multiple hypoecogenic nodules with calcifications and peripheral and intra-nodular vascular pattern

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Intern Emerg Med

and by fine needle aspiration cytology diagnostic for MTC (chromogranin and calcitonin positive cells). The patient appeared to be suffering from MEN. Considering that the PTH level was within normal range (42 pg/ml, n.v. 15–65 pg/ml), the final diagnosis was MEN type 2B [2]. The patient’s clinical conditions were stable during hospitalization with a single episode of epigastric discomfort, responsive to iv proton pump inhibitor. Neither changes in ECG tracings nor alterations of cardiac biomarkers were identified, while cardiac ultrasound imaging highlighted a further improvement in left ventricular systolic function (EF 70 %). Dr. Cicardi, Dr. Leopaldi: Considering that MEN is an autosomal-dominant disorder with high penetrance whose phenotypic expression is closely related to genetic pattern, we suggested a genetic analysis to assess RET gene mutations [3]. Dr. Leopaldi: The patient was then transferred to our Surgery Department (Endocrine Surgery Unit). To stage the disease, he underwent an abdominal CT scan, which confirmed an oval image (32.9 9 28.2 mm) with high enhancement and slow washout during the venous phase in the cranial part of the right adrenal gland, behind the inferior vena cava; no masses in the left adrenal gland; no abnormal formations or lesions affecting the other abdominal organs; no lymphadenopathy (Fig. 3). Before surgery, a control cardiac ultrasound revealed a completely restored left ventricular EF. Despite MTC being strictly linked to worst prognosis in MEN, it is well known that it is mandatory to perform surrenalectomy as first intervention due to immediate quoad vitam risks induced by pheochromocytoma. When the clinical conditions were stable, the patient underwent a posterior endoscopic surgical resection of the adrenal mass. This surgical approach is the less invasive one and it allows quick recovery. After this first operation, without complications, a-blocker therapy was discontinued and 1 week later a total thyroidectomy was performed with modified radical neck dissection (MRND) extended at VII level. No significant complications occurred either during the surgery or in the post-operative follow-up. Dr.Tobaldini, Dr.Wu: The genetic testing confirmed heterozygous substitution (c.1901 G[C, p.C634S) in the sequence of exon 11 of RET gene (chromosome 10). Family screening was also started and a sister of the patient resulted positive too. Dr. Cicardi: Considering the strict genotype–phenotype correlation, the evidence that MTC in MEN 2B tends to be an aggressive disease and that surgery is often not curative [4], we may wonder if a targeted therapy may be useful in this case. It is known that cytotoxic chemotherapy is not able to modify progression-free survival. There are studies

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whose endpoint is to investigate the efficacy and safety of tyrosine kinase inhibitors that selectively target signalling mediated by growth factor receptor tyrosine kinase RET (such as vandetanib and others) [5]. However, conclusive results are still lacking and nowadays the approved indication for tyrosine kinase inhibitors (above all vandetanib) is for symptomatic, progressive, metastatic MTCs [6]. For this reason, we opted for a close follow-up and a possible re-intervention in case of recurrence or evidence of nonradical surgery. Dr. Leopaldi, Dr. Wu: After 10 months, the patient has not complained of any symptom and his clinical condition and biochemical parameters are stable. Calcitonin levels decreased to normal values (2.0 pg/ml, n.v. \10 pg/ml). 24-h urine fractionated catecholamines resulted normal as well: U-Epinephrine 4.3 lg/24 h (n.v. 1.7–22.4 lg/24 h); U-Norepinephrine 44.7 lg/24 h (n.v. 12.1–85.5 lg/24 h). He needed to change his task at work in favour of a less tiring occupation but his global quality of life self assessment is fairly good.

Discussion Drs. Montano, Cicardi, Leopaldi, Belloni, Tobaldini and Wu: This case report underlines that myocarditis can have a variety of underlying causes, which include catecholamine overproduction. In this case, we think that the iv metoclopramide administered in the ED could have acted as provocative test, leading to a massive catecholamine release and adrenergic myocarditis in a patient with undiagnosed pheochromocytoma [7, 8]. It is worth noting that pheochromocytoma, especially in young patients, can be part of a more complex syndrome and a thorough investigation is warranted to exclude/ identify a MEN; in fact, the evidence that some diseases, such as MEN, have an underlying genetic basis with a strong genotype–phenotype correlation raises the need for accurate family screening and evaluation of new target therapies as compared to surgical intervention alone. In these complex cases, it is important to rely on a multidisciplinary approach, especially in conditions which require a step-by-step diagnostic and therapeutic management. Conflict of interest On behalf of all authors, the corresponding author states that there is no conflict of interest.

References 1. Roghi A, Pedrotti P, Milazzo A, Bonacina E, Bucciarelli-Ducci C (2011) Adrenergic myocarditis in pheochromocytoma. J Cardiovasc Magn Reson 13:4. doi:10.1186/1532-429X-13-4

Intern Emerg Med 2. Raue F, Frank-Raue K (2010) Update multiple endocrine neoplasia type 2. Fam Cancer 9(3):449–457. doi:10.1007/s10689-010-93202 3. Frank-Raue K, Rondot S, Raue F (2010) Molecular genetics and phenomics of RET mutations: impact on prognosis of MTC. Mol Cell Endocrinol 322:2–7. doi:10.1016/j.mce.2010.01.012 4. O’Riordain DS, O’Brien T, Crotty TB, Gharib H, Grant CS, van Heerden JA (1995) Multiple endocrine neoplasia type 2B: more than an endocrine disorder. Surgery 118:936–942 5. Giunti S, Antonelli A, Amorosi A, Santarpia L (2013) Cellular signaling pathway alterations and potential targeted therapies for medullary thyroid carcinoma. Int J Endocrinol 2013:803171. doi:10.1155/2013/803171 6. Thornton K, Kim G, Maher VE, Chattopadhyay S, Tang S, Moon YJ, Song P, Marathe A, Balakrishnan S, Zhu H, Garnett C, Liu Q, Booth B, Gehrke B, Dorsam R, Verbois L, Ghosh D, Wilson W,

Duan J, Sarker H, Miksinski SP, Skarupa L, Ibrahim A, Justice R, Murgo A, Pazdur R (2012) Vandetanib for the treatment of symptomatic or progressive medullary thyroid cancer in patients with unresectable locally advanced or metastatic disease: US Food and Drug Administration drug approval summary. Clin Cancer Res 18:3722–3730. doi:10.1158/1078-0432 7. Sheinberg R, Gao WD, Wand G, Abraham S, Schulick R, Roy R, Mitter N (2012) Case 1—2012. A perfect storm: fatality resulting from metoclopramide unmasking a pheochromocytoma and its management. J Cardiothorac Vasc Anesth 26:161–165. doi:10. 1053/j.jvca.2011.10.003 8. Eisenhofer G, Rivers G, Rosas AL, Quezado Z, Manger WM, Pacak K (2007) Adverse drug reactions in patients with phaeochromocytoma: incidence, prevention and management. Drug Saf 30:1031–1062

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A young man with cough, fever and epigastric pain.

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