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PubMed1992

Transesophageal echocardiographic recognition of subaortic complications in aortic valve endocarditis. Clinical and surgical implications.

BACKGROUND: Secondary involvement of the mitral-aortic intervalvular fibrosa and the anterior mitral leaflet (subaortic structures) can occur in patients with aortic valve endocarditis. The secondary involvement of these structures occurs as a result of direct extension of the infection from the aortic valve or as a result of an infected aortic regurgitant jet striking the ventricular surfaces of the mitral-aortic intervalvular fibrosa and the anterior mitral leaflet. The abscess of mitral-aortic intervalvular fibrosa can expand to form an aneurysm. Subsequently, this mitral-aortic intervalvular fibrosa aneurysm can develop a perforation and communicate with the left atrium, resulting in the systolic regurgitation of blood from the left ventricular outflow tract into the left atrium. Secondary infection can also occur on the ventricular surface of the anterior mitral leaflet and result in the formation of an aneurysm or perforation of anterior mitral leaflet. METHODS AND RESULTS: This study examines the utility of transesophageal echocardiography in the detection of these subaortic complications in 55 consecutive patients with aortic valve endocarditis. A total of 24 patients (44%) had involvement of subaortic structures, including four with an abscess in the mitral-aortic intervalvular fibrosa, four with mitral-aortic intervalvular fibrosa aneurysm, seven with perforation of the mitral-aortic intervalvular fibrosa with communication into the left atrium, two with an aneurysm of the anterior mitral leaflet, and seven with perforation of the anterior mitral leaflet. The transesophageal echocardiographic findings were confirmed at surgery in 20 patients and at necropsy in two. By comparison, transthoracic echocardiography visualized these lesions in five of 24 patients (21%), including none of four with mitral-aortic intervalvular fibrosa abscesses, two of four with mitral-aortic intervalvular fibrosa aneurysms, one of seven with mitral-aortic intervalvular fibrosa perforations, one of two with anterior mitral leaflet aneurysms, and one of seven anterior mitral leaflet perforations. Eccentric mitral regurgitation-type systolic jets were noted in eight additional patients by transthoracic color flow imaging, and this finding suggested the possibility of these unusual subaortic complications. If these patients are included, then transthoracic echocardiography suggested the presence of these subaortic complications in 13 of 24 patients (54%). CONCLUSIONS: The results indicate that 1) involvement of the subaortic structures in patients with aortic valve endocarditis may be more common than previously recognized, 2) patients with aortic valve endocarditis and eccentric jets of mitral regurgitation on transthoracic echocardiography should undergo further evaluation by transesophageal echocardiography to exclude these unusual complications, 3) precise recognition of these complications is of value in the optimal medical and surgical management of these patients, and 4) these complications may be responsible for unexplained congestive heart failure and hemodynamic deterioration in some patients with aortic valve endocarditis.

Abscess↗
PubMed1995

The pathogenic role of Staphylococcus epidermidis capsular polysaccharide/adhesin in a low-inoculum rabbit model of prosthetic valve endocarditis.

BACKGROUND: The capsular polysaccharide/adhesin (PS/A) antigen of Staphylococcus epidermidis was required to produce endocarditis in a rabbit model in which infection resulted from hematogenous spread of bacteria from a contaminated catheter in the jugular vein. However, many prosthetic valve endocarditis (PVE) infections probably result from direct contamination of the valve with small numbers of bacteria during surgery. The role of PS/A in this situation was evaluated by modifying a rabbit model of endocarditis to partially mimic PVE. METHODS AND RESULTS: A Teflon catheter was contaminated with graded inocula of either PS/A-positive S epidermidis strain M187sp11 or the PS/A-negative, isogenic strain M187sn3 and inserted into the left ventricle through the aortic valve. The PS/A-positive strain had a 50% infectious dose of 1.1 x 10(2) cfu (95% CI, 3.3 to 3.7 x 10(3)) compared with 8.5 x 10(4) cfu of the PS/A-negative strain (95% CI, 8.6 x 10(3) to 8.5 x 10(5)). The odds for developing endocarditis were estimated to be 42 times higher for any given inoculum level of the PS/A-positive strain (P = .1). When the PS/A-positive strain was adherent to a catheter surface it survived in rabbit blood, whereas under the same conditions the PS/A-negative strain was killed approximately 90% in 1 hour. CONCLUSIONS: Direct contamination of an intraventricular foreign body by low levels of PS/A-positive S epidermidis results in endocarditis in rabbits, but at suitably high doses PS/A-negative strains have sufficient virulence to infect cardiac vegetations. PS/A enhances but is not absolutely required for bacterial virulence in a rabbit model of PVE.

Animals↗
PubMed2006

Endocarditis and biofilm-associated pili of Enterococcus faecalis.

Increasing multidrug resistance in Enterococcus faecalis, a nosocomial opportunist and common cause of bacterial endocarditis, emphasizes the need for alternative therapeutic approaches such as immunotherapy or immunoprophylaxis. In an earlier study, we demonstrated the presence of antibodies in E. faecalis endocarditis patient sera to recombinant forms of 9 E. faecalis cell wall-anchored proteins; of these, we have now characterized an in vivo-expressed locus of 3 genes and an associated sortase gene (encoding sortase C; SrtC). Here, using mutation analyses and complementation, we demonstrated that both the ebp (encoding endocarditis and biofilm-associated pili) operon and srtC are important for biofilm production of E. faecalis strain OG1RF. In addition, immunogold electron microscopy using antisera against EbpA-EbpC proteins as well as patient serum demonstrated that E. faecalis produces pleomorphic surface pili. Assembly of pili and their cell wall attachment appeared to occur via a mechanism of cross-linking of the Ebp proteins by the designated SrtC. Importantly, a nonpiliated, allelic replacement mutant was significantly attenuated in an endocarditis model. These biologically important surface pili, which are antigenic in humans during endocarditis and encoded by a ubiquitous E. faecalis operon, may be a useful immunotarget for studies aimed at prevention and/or treatment of this pathogen.

Aminoacyltransferases↗
PubMed1994

Multiple brain infarction and hemorrhage by nonbacterial thrombotic endocarditis in occult lung cancer--a case report.

A fifty-four-year-old woman died from multiple brain infarction and hemorrhage in the bilateral cerebrum, cerebellum, and brainstem, with renal infarction. She developed hematuria and transient blindness sixteen days before admission. Low-grade fever, heart murmur, and aortic valve vegetation on ultrasonic cardiography suggested infectious endocarditis. Autopsy study revealed occult adenocarcinoma in the lung and nonbacterial thrombotic endocarditis, but infective endocarditis was not histologically confirmed. The patient was considered to be a rare case of nonbacterial thrombotic endocarditis who developed multiple small infarctions mainly in the brainstem and cerebellum. Nonbacterial thrombotic endocarditis seems to be still an important disease as the embolic source, even if cryptic, of systemic thromboembolism.

Adenocarcinoma↗
PubMed2004

Surgery for active, culture negative endocarditis.

Culture negative infective endocarditis (CNE) poses very difficult problems during treatment. In this study it was found that of 132 surgically treated patients with infective endocarditis, causative organism was not identified in 46 (34.8 %). Pre- and perioperative conditions and clinical results of these patients were evaluated. CNE remained very frequent even in these years, and it did not decrease with time. Antibiotic treatment prior to microbiological examinations was commonly observed (nearly 90% orally, and 70% intravenously). In average, it took more than 2 months to establish the diagnosis of CNE after the onset, and both aortic and mitral valves were affected frequently (19.0 %). New York Heart Association functional class IV was observed significantly more commonly (61.9%) than culture positive patients. Frequencies of prosthetic valve endocarditis (12.2%), periannular abscess (36.3%), and embolism (21.4%) were similar. Infection was fairly controllable before surgery in 43.9% of CNE patients and in-hospital mortality rate was 14.3%, both of which were comparable to those of all culture positive patients. However, recurrence rate was relatively higher (10.0%). The conditions and outcomes of CNE were comparable to Staphylococcal endocarditis in some aspects, and were relatively worse than overall culture positive endocarditis.

Adult↗
PubMedDate not supplied

Is antibiotic prophylaxis for bacterial endocarditis cost-effective?

BACKGROUND: Antibiotic prophylaxis for bacterial endocarditis is recommended by the American Heart Association (AHA) before undergoing certain dental procedures. Whether such antibiotic prophylaxis is cost-effective is not clear. The authors' objective is to estimate the cost-effectiveness of predental antibiotic prophylaxis in patients with underlying heart disease. METHODS: The authors conducted a cost-effectiveness analysis using a Markov model to compare cost-effectiveness of 7 antibiotic regimens per AHA guidelines and a no prophylaxis strategy. The study population consisted of a hypothetical cohort of 10 million patients with either a high or moderate risk for developing endocarditis. RESULTS: Prophylaxis for patients with moderate or high risk for endocarditis cost $88,007/quality-adjusted life years saved if clarithromycin was used. Prophylaxis with amoxicillin and ampicillin resulted in a net loss of lives. All other regimens were less cost-effective than clarithromycin. For 10 million persons, clarithromycin prophylaxis prevented 119 endocarditis cases and saved 19 lives. CONCLUSION: Predental antibiotic prophylaxis is cost-effective only for persons with moderate or high risk of developing endocarditis. Contrary to current recommendations, our data demonstrate that amoxicillin and ampicillin are not cost-effective and should not be considered the agents of choice. Clarithromycin should be considered the drug of choice and cephalexin as an alternative drug of choice. The current published guidelines and recommendations should be revised.

Adult↗
PubMed2005

Embolic stroke complicating Staphylococcus aureus endocarditis circumstantially linked to rectal trauma from foreign body: a first case report.

BACKGROUND: Diagnostic and therapeutic instrumentation of the lower gastrointestinal tract has been reported to result in bacteremia and endocarditis. No such case has been reported in persons with a history of rectal foreign body insertion despite its potential for greater trauma. CASE PRESENTATION: A 58-year-old male was admitted with confusion and inability to speak. His past history was notable for hospitalization to extract a retained plastic soda bottle from the rectosigmoid two years prior. On examination, he was febrile, tachycardic and hypotensive. There was an apical pansystolic murmur on cardiac examination. He had a mixed receptive and expressive aphasia, and a right hemiparesis. On rectal examination he had perianal erythema and diminished sphincter tone. Magnetic resonance imaging of the brain showed infarction of the occipital and frontal lobes. Transesophageal Echocardiography of the heart revealed vegetations on the mitral valve. All of his blood culture bottles grew methicillin sensitive Staphylococcus aureus. He was successfully treated for bacterial endocarditis with intravenous nafcillin and gentamicin. The rectum is frequently colonized by Staphylococcus aureus and trauma to its mucosa can lead to bacteremia and endocarditis with this organism. In the absence of corroborative evidence such as presented here, it is difficult to make a correlation between staphylococcal endocarditis and anorectal foreign body insertion due to patients being less than forthcoming CONCLUSION: There is a potential risk of staphylococcal bacteremia and endocarditis with rectal foreign body insertion. Further studies are needed to explore this finding. Detailed sexual history and patient counseling should be made a part of routine primary care.

Endocarditis, Bacterial↗
PubMed2000

Quantitative analysis of valvular lesions during Bartonella endocarditis.

Cardiac valve pathology was evaluated in 15 patients with confirmed diagnosis of Bartonella endocarditis. Ten were infected by Bartonella quintana and 5 by Bartonella henselae. Histologic features of these cases, including fibrosis, calcification, vegetation, pattern of inflammation, and vascularization, were compared with those of valves from 25 cases of non-Bartonella endocarditis as controls using a computerized quantitative image analysis. Pathologic and immunohistologic testing for localization of Bartonella species in resected valves included Warthin-Starry stain and polyclonal antibody-based immunodetection. Compared with other cases of infective endocarditis, cases of Bartonella endocarditis are more fibrotic and calcified, less vascularized, with less extensive vegetation and chronic inflammation. These pathologic changes are suggestive of a prolonged infection. Warthin-Starry stain and immunohistologic testing demonstrated the presence of the organism, respectively, in 11 and 10 of the 13 tested valves. Results of both staining methods showed microorganisms in extracellular locations and in regions unaccompanied by inflammation. Pathology and immunohistology may contribute to the etiologic diagnosis of Bartonella endocarditis when serology and molecular techniques are not available.

Adult↗
PubMed2002

Bacterial endocarditis and functional mitral stenosis: a report of two cases and brief literature review.

Mitral valve endocarditis typically results in mitral regurgitation. However, endocarditis leading to functional mitral stenosis is uncommon and, when present, fungal organisms are typically implicated. Thus, obstructive-type bacterial endocarditis due to large vegetations blocking the mitral valve orifice is a rare occurrence, with approximately 20 reported cases in the literature. We report on two patients with bacterial endocarditis and severe functional mitral stenosis requiring emergent surgery. Additionally, this is the first report of vancomycin-resistant enterococcus causing endocarditis and functional mitral stenosis. The discussion emphasizes the hemodynamic instability of these patients and need for early surgical intervention.

Endocarditis, Bacterial↗
PubMed1979

Surgery for mitral valve endocarditis.

The records of 20 patients who underwent mitral valve replacement for complications of bacterial endocarditis were reviewed. Although the indications for surgery were the same as those for patients with aortic endocarditis, major emboli (cerebral, coronary or retinal) prompted surgery in 8 of 20 patients, a much higher incidence than reported for surgery in aortic valve endocarditis. Eighteen of the patients had mitral regurgitation; 14 of these had severe congestive heart failure, but the development of congestive failure tended to be more insidious than in patients with aortic endocarditis. Continued septicemia despite appropriate antibiotics was the least common indication for surgery. Sixteen of the 20 patients were salvaged by surgery, although some had major residual deficits, related mainly to preoperative emboli. These results are a marked improvement in the expected 90-100 percent mortality rate for patients with these complications of endocarditis. The main reason for a poor result following surgery was temporization leading to continued deterioration of vital functions preoperatively. Reinfection of the prosthesis did not occur, and we do not consider duration of preoperative antibiotic therapy an important factor in the decision to perform surgery.

Adult↗
PubMed2004

Infective endocarditis: a review of the best treatment options.

Despite significant advances in antimicrobial therapy and an enhanced ability to diagnose and treat complications, infective endocarditis is still associated with substantial morbidity and mortality today, and its incidence has not decreased over the past decades. This apparent paradox may be explained by a progressive change in risk factors, leading to an evolution in its epidemiological and clinical features. In fact, new risk factors for endocarditis have emerged, such as intravenous drug abuse, diffusion of heart surgery procedures and prosthetic valve implantation, atherosclerotic valve disease in elderly patients, and nosocomial disease. Recently identified microorganisms (including Bartonella spp., Abiotrophia defectiva, and the HACEK group of bacteria [including Haemophilus spp., Actinobacillus spp., Cardiobacterium hominis, Eikenella corrodens and Kingella kingae]) are sometimes the cause of culture-negative endocarditis, and emerging resistant bacteria (such as methicillin- or vancomycin-resistant Staphylococci and vancomycin-resistant Enterococci) are becoming a new challenge for conventional antibiotic therapy. New therapeutic approaches need to be developed for the treatment of infective endocarditis caused by drug-resistant Gram-positive cocci, and some antimicrobial compounds recently introduced in clinical practice (such as streptogramins and oxazolidinones) may be an effective alternative, but further clinical studies are needed in order to confirm their effectiveness and safety. This review should help redefine the best therapeutic and preventive strategies against infective endocarditis.

Anti-Bacterial Agents↗
PubMed2005

Treatment of Brucella endocarditis: our surgical experience with 6 patients.

BACKGROUND: Endocarditis is a rare but life-threatening complication of brucellosis. Its mortality rate has recently been reduced with the use of combined medical and surgical treatment. METHODS: Between March 2002 and April 2004, 6 patients with Brucella endocarditis underwent surgery at the Siyami Ersek Cardiovascular Center in Istanbul, Turkey. The diagnosis of Brucellosis was based on the presence of clinical signs and symptoms compatible with brucellosis, serology and/or a positive blood culture. All patients with suspected Brucella endocarditis were studied by echocardiography. The diagnosis of Brucella endocarditis was made in accordance with Duke's criteria. RESULTS: The most commonly affected valve was the aortic valve (4 patients). Four patients had prosthetic valves because of a previous history of rheumatic fever. In 5 patients, elective surgery was performed. Five patients underwent valve replacement with prosthetic valves, but 1 patient underwent excision of the abscess cavity without valve replacement. There was no operative mortality. All patients continued antibiotic treatment for at least 3 months postoperatively. The median duration of follow-up after surgery was 12 months. During the follow-up period, 1 patient died, while the others remained alive with no recurrences. CONCLUSION: Prosthetic valve replacement is a safe procedure in patients with Brucella endocarditis. Surgical interventions combined with triple antibiotic therapy yield good results with no recurrence in the long-term follow-up.

Adult↗
PubMed2006

Daptomycin for the treatment of gram-positive bacteremia and infective endocarditis: a retrospective case series of 31 patients.

STUDY OBJECTIVE: To evaluate the outcomes in patients with bacteremia and/or infective endocarditis who were treated with daptomycin. DESIGN: Retrospective chart review. SETTING: A university-affiliated medical center in Chicago, Illinois, and a regional hospital in Fountain Valley, California. PATIENTS: Thirty-one inpatients treated with daptomycin for bacteremia and/or infective endocarditis. MEASUREMENTS AND MAIN RESULTS: Patients were given daptomycin 4-6 mg/kg intravenously every 24-48 hours based on the practitioner's discretion and depending on the patient's clinical condition and presence of comorbidities. Primary end points were resolution of signs and symptoms of infection and discharge from the hospital. Methicillin-resistant Staphylococcus aureus ([MRSA] 11 patients) and vancomycin-resistant entercocci ([VRE] 11 patients) were the most common pathogens, whereas 7 patients had methicillin-sensitive S. aureus infection and 1 patient had coagulasenegative Staphylococcus infection. One patient with endocarditis had a negative culture result. Overall, 24 (77%) of the 31 patients achieved clinical resolution and were discharged, including all patients infected with MRSA; 7 patients died, 6 of whom had VRE infection. Duration of treatment for infective endocarditis lasted longer (typically 22-43 days) than that for bacteremia only (< or = 14 days), and no patients discontinued daptomycin because of adverse events. CONCLUSION: In these patients, daptomycin was safe and well tolerated even for extended durations of treatment. Daptomycin may provide an effective option for treating drug-resistant gram-positive bloodstream infections and endocarditis.

Adult↗
PubMed1988

Listeria monocytogenes endocarditis: a review of the literature 1950-1986.

34 cases of Listeria monocytogenes endocarditis reported in the literature from 1950-1986 were reviewed. The male to female ratio was 2: 1. The average age was 49 years, and 35% of patients were 60 years of age or older. A single case of polymicrobial endocarditis was identified. There were 8 cases of prosthetic valve endocarditis. Left-sided cardiac involvement predominated, with only a single case of right-sided endocarditis reported. Aortic and mitral valvular involvement accounted for 32 and 29% of cases respectively. Underlying cardiac disease was present in over half of the cases, with rheumatic heart disease being the most common underlying cardiac condition. Noncardiac underlying conditions were found in 38% of cases. These included chronic hemodialysis, alcoholism, pregnancy, malignancies, diabetes mellitus, steroid therapy and malnutrition. Onset of the disease was varied as was initial presentation. There was a high incidence of vascular phenomena (59%), with large vessel emboli seen late in the course of many cases. Many cases were diagnosed late. Overall mortality was 50%. Treatment of listeria endocarditis varied from case to case. A review of in vitro and in vivo studies as well as case reports suggests that ampicillin or penicillin plus an aminoglycoside may be the treatment of choice.

Adolescent↗
PubMed1996

Comparison of the von Reyn and Duke criteria for the diagnosis of infective endocarditis: a critical analysis of 161 episodes.

The newly proposed diagnostic criteria for infective endocarditis (Duke criteria) were evaluated in 161 consecutive episodes treated for suspected infective endocarditis (IE) at one institution over a 5-year period. A significantly higher proportion of episodes were diagnosed as definite endocarditis by the new Duke criteria compared with a diagnosis as definite or probable endocarditis by the older von Reyn criteria (68% vs 56%; p < 0.05). If all 161 episodes were to be reclassified, excluding pathological data, which are seldom available at the start of treatment, the Duke criteria classified significantly more episodes as 'definite' compared with the analogous category 'probable' endocarditis by the von Reyn criteria (60% vs 44%; p < 0.01). Forty-four pathologically proven episodes were reclassified in the same way, and 73% of these episodes were classified as 'definite' IE by the Duke criteria compared to 55% classified as 'probable' IE using the von Reyn criteria In 33 (20%) episodes no heart murmur could be detected on admission and the Duke criteria provided an initial diagnosis of 'definite' IE in 58% of these episodes compared with only 6% classified as 'definite' or 'probable' IE by the von Reyn criteria (p < 0.0001). The newly proposed Duke criteria are an improvement on the older von Reyn criteria in the clinical diagnosis of IE, especially in initial phase of treatment. However, the sensitivity when establishing a correct clinical diagnosis of 'definite' IE for the pathologically proven cases was only 73%. The category of 'possible' IE by the Duke criteria is confusing, since it does not say anything of the likelihood on an actual IE; the only objective fact is that no alternative diagnosis has been proven.

Adult↗
PubMed1982

Valve replacement for bacterial endocarditis.

During the 10-year period 1970-79, 88 patients underwent valve replacement for complications of bacterial endocarditis. The mean age of the patients was 42 (15-60) years. There were 64 men and 22 women. Thirty-three patients had a history of rheumatic fever. In 11 cases the murmur was heard already in childhood. In 44 cases (50%) no heart disease was diagnosed before the onset of symptoms of bacterial endocarditis. Strepto- and staphylococci were the most common organisms found in culture. In 12 cases a dental and in 12 a respiratory tract infection preceded the endocarditis. In 51 cases, however, the origin of the infection remained unestablished. Intractable heart failure and embolizations were most common indications for operation. Only 9 patients underwent operation in the acute phase. Aortic valve replacement (AVR) was performed in 58 cases, mitral valve replacement (MVR) in 19, both AVR and MVR in 6, AVR and aneurysm of sinus Valsalva repair in 3 cases, AVR and repair of VSD in one and AVR combined with myocardial revascularization and replacement of the ascending aorta for aneurysm in one case. The early mortality was 9 patients (10%) and late mortality 9 patients. During follow-up times of up to 10 years, 7 patients experienced embolic complications. They recovered uneventfully. One valve prosthesis was replaced because of thrombosis and another due to paraprosthetic leak. Two patients had a late recurrent bacterial endocarditis 5 and 8 years postoperatively. They were treated conservatively and recovered. It was concluded that after valve replacement for bacterial endocarditis, the risk of recurrent infection is relatively low and that results approaching those for elective valve replacement can be achieved.

Adolescent↗
PubMed1983

Intravenous drug addiction--staphylococcal septicemia--pulmonary embolism: a triad pathognomonic for tricuspid valve endocarditis?

28 patients (29 episodes) presenting the triad of intravenous narcotic drug addiction, Staphylococcus aureus septicemia and septic pulmonary embolism were examined for the presence of tricuspid valve endocarditis. In a prospective study, 12/13 patients examined by echocardiography had vegetations on the tricuspid valve, in 6 detected by M-mode, in 5 by 2-D technique, and in one by both methods. In 4 patients with tricuspid endocarditis, no significant murmurs were heard. Similarly, in a retrospective study, 5/16 patients not subjected to echocardiography had no murmurs consistent with tricuspid valve endocarditis. One of these patients died. In 2/16 patients the diagnosis was verified at autopsy and in 1 at heart surgery. In both groups, altogether 11 patients never developed murmurs, in 7 of them despite demonstrable vegetations. Therefore, we consider the triad to be pathognomonic for tricuspid valve endocarditis, provided that no peripheral source of emboli is present. Consequently, patients fulfilling these criteria should be treated as suffering from endocarditis. Echocardiographic examination does not seem necessary in patients with a typical clinical picture but may be helpful when chest X-rays are inconclusive or complications are suspected.

Adult↗
PubMed1985

Unfavourable prognostic factors in Staphylococcus aureus septicemia and endocarditis.

Factors predictive of a fatal outcome were retrospectively studied in 248 patients admitted with Staphylococcus aureus septicemia during 1965-1982, 78 of whom had endocarditis. 77 patients were intravenous drug addicts and 47 of them had endocarditis. 48 patients (19.4%) died. The fatality rate in addicts and non-addicts from septicemia was 0% and 17.9% and from endocarditis 8.5% and 61.3%, respectively. After analyzing clinical and laboratory data available early in the course of the disease 4 risk factors were found both in septicemia and endocarditis: age greater than or equal to 60 yr, pre-existing cardiovascular disease, prior hospitalization within 30 days of onset of illness, and neurological symptoms and/or signs. In addition, in endocarditis a platelet count before therapy less than 100 X 10(9)/l and left-sided involvement were unfavourable prognostic factors.

Adolescent↗