Rheumatic Manifestations of Infective Endocarditis in Non-Addicts

Introduction Abbreviations used in this article: CV, cutaneous vasculitis, IE, infective endocarditis Infective endocarditis (IE) is due to a microbial infection of the heart valves or of the endocardium in close proximity to either congenital or acquired cardiac defects. This infection may develop insidiously or abruptly and is associated with a high risk of complications. Patients with IE may present with variable manifestations, and its capacity to mimic other conditions may obscure the outcome in those cases where classic manifestations are not evident (19). Rheumatic manifestations are known to be complications of IE (22). Controversy exists about the incidence of these complications, perhaps due to the small number of series describing the frequency and type of rheumatic manifestations and the absence of uniform criteria used for the diagnosis of IE (6, 24, 29, 35, 38). Also, most studies of rheumatic manifestations in IE have been described from tertiary referral centers, which implicates associated problems of referral bias and uncertainty of denominator population. In addition, rheumatic manifestations in patients with IE may not be directly related to the valve infection. In this regard, although intravenous drug use is a well-defined risk factor for the development of IE, intravenous drug abusers may present with systemic necrotizing vasculitis or, more commonly, musculoskeletal complications without IE (26, 30, 37). Therefore, to investigate further the frequency and spectrum of rheumatic manifestations in patients with IE, we examined the rheumatic manifestations in an unselected population of patients with IE without a previous history of drug use. Patients were diagnosed by strict criteria at the single reference hospital for a defined population in northwestern Spain over a 12-year period. Patients and Methods We performed a retrospective study of the case records of all patients diagnosed with IE in the Department of Medicine of the Hospital Xeral-Calde (Lugo, Spain) from January 1987 through December 1998. The Hospital Xeral-Calde is the only referral center for a mixed urban and rural (60%) population of almost 250,000 people living in the Lugo region of northwestern Spain. The main characteristics of the Lugo population have been reported elsewhere (12, 14–17). Briefly, the population is relatively static, has its own regional language, and is considered to be descended from Celtic origin (8). During the past 2 decades the population has barely changed. Migratory flows have been relatively low during the past 15 years. Although mortality in the Lugo region is higher than in other parts of Spain, it is due to the older age-groups in Lugo: the population is older in the area of Lugo than in most regions of Spain. In this regard, in 1996 the population contained almost 25% of people older than 65 years of age. All patients with suspected IE were sent to the hospital by general practitioners or they self-referred to the emergency unit. Inclusion criteria Patients with IE were retrospectively classified according to the Duke criteria (1, 10). Based on those criteria, patients were included in this study if they had clinically definite IE. The Duke schema for clinical criteria defines 2 major criteria and 6 minor criteria. For a case to be considered clinically definite IE, the following criteria were required: Two major criteria, or 1 major criterion and 3 minor criteria, or 5 minor criteria. The 2 major criteria are the following: 1) Echocardiographic data disclosing evidence of endocardial involvement if 1 of the following findings was observed: a) echodense masses attached to valvular leaflets or mural endocardium, or b) periannular abscesses, or c) new dehiscence of a valvular prosthesis. 2) Blood cultures positive for IE: a) if typical microorganisms for IE were found from 2 separate blood cultures (classic IE pathogens such as Viridans streptococci, Streptococcus bovis. and members of the HACEK group of fastidious Gram-negative rods—Haemophilus spp., Actinobacillus actinomycetemcomitans, Cardiobacterium hominis, Eikenella cor-rodens, and Kingella kingae, or b) positive blood cultures for community-acquired Staphylococcus aureus and Enterococcus faecalis in the absence of a primary focus, or c) persistently positive blood cultures, defined as the recovery of a microorganism consistent with IE from blood cultures taken more than 12 hours apart, or, all of 3 or most of 4 or more separate blood cultures, with the first and the last drawn at least 1 hour apart. The 6 minor criteria are the following: 1) Predisposing heart disease or intravenous drug use (as discussed before, in the present study intravenous drug users were excluded). 2) Fever if temperature at diagnosis was 38 °C or greater. 3) Peripheral embolic event considered if 1 of the following vascular phenomena was found: major arterial emboli, septic pulmonary infarcts, mycotic aneurysms, intracranial hemorrhage, conjunctival hemorrhages, or Janeway lesions. 4) Immunologic phenomena such as glomerulonephritis, Osler nodes, Roth spots, and positive rheumatoid factor. 5) Echocardiogram consistent with IE but not fulfilling the major criterion described above. 6) Microbiologic evidence consisting of positive blood culture but not meeting the major criterion described above (excluding single positive cultures for coagulase-negative staphylococci and organisms that do not cause IE) or serologic evidence of active infection by an organism consistent with IE, such as a positive serology for Q fever. To avoid an overestimation of the actual frequency of rheumatic manifestations in IE patients, intravenous drug abusers were excluded. Moreover, cases of IE in which the patients had been diagnosed with other conditions that might cause musculoskeletal manifestations (mainly rheumatic diseases) before the onset of IE were also excluded. Clinical definitions We defined the clinical features as follows: Fever was defined as oral or axillary temperature at diagnosis of 38 °C or greater. A constitutional syndrome was defined if a patient diagnosed as having IE had asthenia, anorexia, and weight loss of at least 4 kg. Arthralgia and myalgia complaints are subjective symptoms and may vary in different populations. However, we decided to include patients with only arthralgia and myalgia manifestations into the group of patients with musculoskeletal manifestations of IE if these symptoms were recorded whenever reference had been made to joint or muscle pain without clinically apparent synovitis or inflammatory muscle involvement. As previously described, peripheral synovitis was documented by the number of peripheral joints with obvious inflammatory signs, tenderness, effusion, or stress pain (pain provoked by gentle stretching at the extremes of joint movement) (17). Cervical, dorsal, or low back pain was considered present if the patient presented with back pain in the absence of previous back injury or previous episodes of back pain. Sacroiliitis was defined as unrelieved pain and tenderness provoked with direct percussion over the sacroiliac joint along with changes of the sacroiliac joint observed by plain radiographs or computed tomography scan. Also, a positive radionuclide bone scan with technetium-99m methylene diphosphonate of the symptomatic sacroiliac joint in those patients with clinical manifestations and absence of radiographically apparent lesions was also considered to be positive for sacroiliitis. Infectious spondylitis (septic discitis) was defined in the case of inflammatory back pain and stiffness along with changes of the spine suggestive of disc lumbar infection confirmed by plain radiographs or computed tomography scan. Also, a positive radionuclide bone scan with technetium-99m methylene diphosphonate was considered sufficient for the diagnosis in those patients with inflammatory back pain without a radiographically apparent lesion. Septic bursitis was defined by inflammation of a bursa in the presence of positive cultures drawn from blood or from the synovial fluid of the bursa. A patient was considered to have osteomyelitis if there was infection of a bone supported by radiographic or radionuclide studies and a positive culture from the bone tissue or blood. However, patients with vertebral osteomyelitis following spondylitis were not included in this group. Cutaneous vasculitis (CV) in the setting of IE was diagnosed by characteristic histologic findings on skin biopsy, such as neutrophilic infiltration, leukocytoclasis, and fibrinoid necrosis into the vessel wall of arterioles, capillaries, and postcapillary venules. As previously reported (11, 16), CV related to bacterial infection was considered if the vasculitis was confirmed by a skin biopsy showing leukocytoclastic vasculitis, no drug intake was registered before the development of skin lesions, and bacteriologic evidence of infection was obtained. Patients were considered to have a condition suggestive of polymyalgia rheumatica if they met the following criteria: a) aged 50 years or older at the onset of symptoms, b) severe and bilateral pain associated with morning stiffness of at least 30 minutes for more than 1 month in at least 2 of 3 areas: neck, shoulder, and pelvic girdles, c) erythrocyte sedimentation rate (ESR by Westergren method) at the time of diagnosis of 40 mm/hr or higher (19). Nephropathy was defined according to previous studies (12, 16) as follows: 1) renal manifestations if hematuria (≥5 red blood cells/hpf) and/or proteinuria (>300 mg/24 hr) was present, 2) renal insufficiency was considered if the plasma creatinine concentration was more than 125% the upper limit of normal. Levels of liver enzymes (aspartate aminotransferase, alanine aminotransferase) were considered elevated if values at diagnosis were more than twice the upper limit of normal range. Anemia was considered if hemoglobin was <12 g/dL. Leukocytosis was defined as a white blood and as a Clinical and data at the time of diagnosis of the patients with IE were from clinical records according to a and in a data on the following were to diagnosis from the onset of symptoms, heart disease or other conditions such as renal or other 1 month before the onset of Also, history of intravenous drug use or of previously diagnosed other than IE that might the development of rheumatic manifestations was The following clinical data were constitutional cardiac skin lesions, and those rheumatic manifestations discussed above. In to the valve in the IE, studies blood and liver and renal performed at the time of diagnosis were also In addition, bacteriologic data from blood cultures data from other such as from cultures from skin or synovial fluid were Also, data on rheumatoid factor and and as were data were described as and and as 2 were made the for To data we performed the the was than the with was was defined as were performed with the January 1987 and December patients had episodes of clinically definite IE. Rheumatic manifestations were observed in of the episodes features of patients with definite IE and rheumatic manifestations The main characteristics of patients with IE rheumatic manifestations are in Rheumatic manifestations were in were recorded A valve disease was the most heart The most valve was the by the valve features of cases with definite infective endocarditis and rheumatic of rheumatic manifestations In most cases with rheumatic complications these manifestations were included the symptoms or of the However, as previously described, in patients rheumatic manifestations the manifestations of IE (11, was a found in of cases Arthralgia without was observed in cases This was more in joints and those of Peripheral was clinically evident in 15 cases and in 1 back pain was described in cases and pain were in 6 and 5 Septic was observed in 2 cases and cutaneous leukocytoclastic vasculitis was found in 4 cases Also, as previously 2 patients with IE bursitis by Staphylococcus and 1 patient had a condition polymyalgia rheumatica (19). Moreover, a patient was not considered in the group of cases with rheumatic manifestations had been diagnosed previously as having osteomyelitis in and 2 years IE. other patients from this series were diagnosed as having osteomyelitis before the diagnosis of IE or during Rheumatic manifestations in cases with definite infective data in patients with IE and rheumatic manifestations of the cases had hemoglobin values than 12 at the time of diagnosis higher than were found in almost of the higher than were was observed in more than of the However, although renal insufficiency was also 6 of the cases had elevated of plasma creatinine had a history of an renal disease before the onset of the symptoms of IE such as rheumatoid of and and were or normal findings in cases with definite infective endocarditis and rheumatic and patients of the cases had peripheral and 1 had sacroiliitis. the patients with peripheral in an was a positive culture in the synovial fluid was found in The of patients with IE and positive synovial fluid cultures is in Staphylococcus aureus was the most In 6 patients, cultures from synovial fluid were In 2 of these 6 patients with culture and without a previous history of rheumatic the study of the synovial fluid the presence of of in In the 4 patients with synovial fluid culture and in the other 2 in was not the following according to blood culture All patients with positive cultures and those 2 patients with a diagnosis of had However, in 2 of the other 6 patients with cultures from the synovial fluid and without and 2 patients in was not 3 joints was and data and the joints in these cases are in 4 and The only patient with a in had positive blood cultures for Enterococcus and following with and a of the sacroiliac pain. Patients with were years of in with in the first joint and features of patients with peripheral and definite infective endocarditis had positive synovial fluid features of 6 patients with peripheral synovitis and definite infective endocarditis had cultures and absence of in the synovial fluid 4) or in synovial fluid cultures were not performed spondylitis Septic was observed in 2 of had and the other involvement. Blood cultures were positive for Streptococcus and Streptococcus Clinical was observed following for features of 2 patients with septic leukocytoclastic vasculitis related to IE with definite IE presented with skin lesions. In all of a leukocytoclastic vasculitis was confirmed by of had conditions had before the onset of Although blood cultures were positive in all patients, tissue biopsy cultures were in 3 of 4 patients in they were The main clinical features of 3 patients have been reported previously Two of the 4 patients met the of criteria for vasculitis The other 2 patients were diagnosed as having mixed according to previously reported criteria features of 4 patients with cutaneous leukocytoclastic vasculitis (CV) related to infective endocarditis in patients with IE with or without rheumatic manifestations in the at onset of symptoms, and to the diagnosis were observed in patients with IE with or without rheumatic manifestations of the development of rheumatic manifestations, IE was in patients older than years with a heart To rheumatic manifestations were more observed in patients from rural in patients with infective endocarditis with or without rheumatic in patients with IE with or without rheumatic manifestations The presence of rheumatic manifestations not a characteristic to clinically patients with such manifestations from those without rheumatic features In patients with and without rheumatic manifestations, a history of asthenia, anorexia, and weight loss was at the time of of IE such as and were also in the of valvular was Clinical in patients with infective endocarditis with or without rheumatic in patients with IE with or without rheumatic manifestations in blood were found 10). However, patients with rheumatic manifestations more had or low of that might the presence of an in patients with infective endocarditis with or without rheumatic manifestations blood culture and patients with IE with or without rheumatic manifestations Microbiologic in blood cultures cases with or without rheumatic manifestations are described in Staphylococcus aureus was more from blood cultures in patients with rheumatic In Streptococcus and Streptococcus were found more in patients without rheumatic However, the presence of rheumatic manifestations was not associated with a of as in patients with rheumatic manifestations were not different from those in the group without rheumatic manifestations Microbiologic blood culture and cases with infective endocarditis with or without rheumatic manifestations in clinical complications and outcome in patients with IE with or without rheumatic manifestations complications were in However, embolic complications were present more in patients with rheumatic the embolic the mortality rate in cases with rheumatic manifestations was not different from that found in the other in clinical complications and mortality rate in patients with infective endocarditis with or without rheumatic In this study we to the frequency of rheumatic manifestations in an unselected and population of patients with IE. We also previous on musculoskeletal manifestations of this condition and the first data on the spectrum of rheumatic manifestations from a of patients over a 12-year in Moreover, we the and patients with IE rheumatic manifestations and those not during a of the present study the first of rheumatic manifestations in IE the Duke criteria. The use of these criteria to such complications in those patients definite clinical criteria for IE. the of the and the of the Osler described IE as a disease that may present variable symptoms and clinical findings However, in most studies of IE performed during the rheumatic manifestations in IE were not documented and were it was not the that to the of musculoskeletal manifestations in IE. in the and in and the group of and at the reported the presence of rheumatic manifestations in 50 of patients and in of cases with IE, musculoskeletal manifestations of IE have also been reported in a series from different and such as and 35, 38). A of for the patients with IE is that in most of the series previously were not for the diagnosis of IE, which in a might the actual frequency of rheumatic in IE. To avoid of IE and its associated rheumatic manifestations, we have used the Duke criteria, in which evidence of endocardial involvement a major In addition, in series either evidence of endocardial involvement as a major criterion or an consistent with IE but not fulfilling the major criterion described above was found in all In most studies the frequency of rheumatic manifestations of IE has 25% and 29, 35, 38). In series we observed a frequency of The higher incidence in the patients in Lugo may be due to the absence of previous of patients the hospital and to the of other rheumatic that had been documented in studies of IE 29, 35, 38). In this regard, although polymyalgia rheumatica manifestations have been described in patients with IE the presence of this syndrome has not been documented in cutaneous leukocytoclastic vasculitis has been reported to be associated with (11, but no well-defined cases of leukocytoclastic CV in IE have been described in those series reported the frequency of rheumatic manifestations in Lugo patients with IE was to that reported from the A for this might be the by in of cases where rheumatic manifestations were by the incidence of musculoskeletal manifestations in patients with IE from the data reported by the group of at the it is evident that the frequency of peripheral low back and septic is in and Spain. In this regard, in patients from arthralgia and myalgia were found in and patients from the group of patients with IE in Lugo the of arthralgia and myalgia was in peripheral septic and low back pain in the study in and of the patients with IE, In the present series from peripheral was found in 15 of cases disc infection in and low back pain in We the and clinical findings of IE cases with rheumatic manifestations in the present study with other studies from other regions We found that rheumatic manifestations in patients with IE from are more in aged in the or in and the the rheumatic manifestations of IE in people without a in (6, 24, 29, 35, 38). Peripheral synovitis and low back pain may be for the presence of IE, as they were observed in and of the and clinical findings in infective endocarditis cases with rheumatic manifestations, present and previous studies the present study and those previously reported is the data we present on from the synovial fluid in all but 2 of the 15 patients with IE and peripheral In the present series from the in patients with IE and positive synovial fluid cultures was In addition, in with the data from the group of the and from in patients from Lugo with peripheral without positive cultures in the synovial the peripheral was to a single and the and the were the most joints in the present study we were not to symptoms or clinical that might to clinically patients with rheumatic manifestations from those without However, with to the we observed that was more in patients with rheumatic complications 10). the other there was a to in patients with rheumatic in the may be due to an by of the for the IE, or may from related to the This may be more evident in those cases with IE and leukocytoclastic In this study the incidence of positive rheumatoid factor was to that reported in (6, However, we not in the incidence of positive rheumatoid factor patients with or without rheumatic In this regard, the presence of positive rheumatoid factor in has been with a of disease symptoms than 6 (6, to we examined the disease in those patients from Lugo in rheumatoid factor had been In with and of the development of rheumatic manifestations, patients with IE had a positive rheumatoid factor had a disease This was in those patients with rheumatic manifestations with positive rheumatoid in those with rheumatoid that described positive in a patients with IE (6, of the 15 patients with rheumatic manifestations in were had positive of in the present study was the for a of infection in those patients with rheumatic However, the of blood culture not patients with or without rheumatic manifestations were observed by pathogens and found no for Streptococcus which was more from blood cultures in patients with rheumatic Also, the spectrum of bacterial organisms from the blood cultures in Lugo patients was to that described in (6, 38). In this regard, and staphylococci were the most bacterial pathogens of IE. In series 2 patients had septic and in 1 of disc involvement in more than 1 This is but it has been described previously in a cases of septic in the setting of IE 38). was to the presence of rheumatic manifestations was associated with a different spectrum of clinical complications and these patients had a different outcome from the of IE patients without rheumatic complications. The of complications not in the cardiac complications patients with and without rheumatic manifestations However, septic were more in the cases with rheumatic is also known that renal is not during the of IE, and may the of the disease However, although in the present series was more in patients with rheumatic manifestations no in the clinical outcome were and the mortality rate in patients with rheumatic manifestations was not different from that of patients without these manifestations In the present study the that rheumatic complications are in patients with clinically definite IE from The presence of musculoskeletal or manifestations may be of as signs, for the of patients with severe disease a diagnosis and Infective endocarditis (IE) is due to a microbial infection of the heart valves or of the endocardium in close proximity to either congenital or acquired cardiac defects. This infection is associated with a high risk of complications. Rheumatic manifestations are known to be complications of IE. exists about the actual incidence of these complications. This may be due to the small number of series describing the frequency and type of rheumatic manifestations, the absence of uniform criteria used for the diagnosis of IE, and the that studies on rheumatic manifestations in IE have been described from tertiary referral centers, which implicates associated problems of referral bias and uncertainty of denominator population. To investigate further the clinical and outcome of patients with IE and rheumatic manifestations, we examined the features of patients diagnosed with clinically definite IE according to the Duke criteria at the single reference hospital for a defined population in northwestern Spain during a 12-year period. 1987 and patients had episodes of clinically definite IE. Rheumatic manifestations were observed in of the episodes As in other they more in aged in The most valve was the by the valve was a Peripheral as was clinically evident in 15 cases and in 1 back pain was described in cases Septic was observed in 2 and cutaneous leukocytoclastic vasculitis was found in 4 conditions such as bursitis and polymyalgia were observed in 2 and 1 from a higher frequency of hematuria and a to in patients with rheumatic complications, no in clinical or blood culture were found cases with IE with or without rheumatic Also, although patients with rheumatic manifestations had more embolic complications, the mortality rate in patients with rheumatic manifestations was not different from that of the of the The present study the that rheumatic complications are in patients with clinically definite IE from The presence of musculoskeletal or manifestations may be of as signs, for the of patients with severe disease diagnosis and We are to the members of the Department and the of the Infectious of the Hospital Also, the the by and from the Department of the Hospital We also and from the for in the