Vitamin D supplementation and COVID-19 risk: a population-based, cohort study.

PURPOSE: To analyze the associations between cholecalciferol or calcifediol supplementation, serum 25-hydroxyvitamin D (25OHD) levels and COVID-19 outcomes in a large population. METHODS: All individuals ≥ 18 years old living in Barcelona-Central Catalonia (n = 4.6 million) supplemented with cholecalciferol or calcifediol from April 2019 to February 2020 were compared with propensity score-matched untreated controls. Outcome variables were SARS-CoV2 infection, severe COVID-19 and COVID-19 mortality occuring during the first wave of the pandemic. Demographical data, comorbidities, serum 25OHD levels and concomitant pharmacological treatments were collected as covariates. Associations between cholecalciferol or calcifediol use and outcome variables were analyzed using multivariate Cox proportional regression. RESULTS: Cholecalciferol supplementation (n = 108,343) was associated with slight protection from SARS-CoV2 infection (n = 4352 [4.0%] vs 9142/216,686 [4.2%] in controls; HR 0.95 [CI 95% 0.91-0.98], p = 0.004). Patients on cholecalciferol treatment achieving 25OHD levels ≥ 30 ng/ml had lower risk of SARS-CoV2 infection, lower risk of severe COVID-19 and lower COVID-19 mortality than unsupplemented 25OHD-deficient patients (56/9474 [0.6%] vs 96/7616 [1.3%]; HR 0.66 [CI 95% 0.46-0.93], p = 0.018). Calcifediol use (n = 134,703) was not associated with reduced risk of SARS-CoV2 infection or mortality in the whole cohort. However, patients on calcifediol treatment achieving serum 25OHD levels ≥ 30 ng/ml also had lower risk of SARS-CoV2 infection, lower risk of severe COVID-19, and lower COVID-19 mortality compared to 25OHD-deficient patients not receiving vitamin D supplements (88/16276 [0.5%] vs 96/7616 [1.3%]; HR 0.56 [CI 95% 0.42-0.76], p < 0.001). CONCLUSIONS: In this large, population-based study, we observed that patients supplemented with cholecalciferol or calcifediol achieving serum 25OHD levels ≥ 30 ng/ml were associated with better COVID-19 outcomes.

Corticosteroids and tocilizumab reduce in-hospital mortality in severe COVID-19 pneumonia: a retrospective study in a Spanish hospital.

BACKGROUND: There is an urgent need to reduce mortality of COVID-19. We examined if corticosteroids and tocilizumab reduce risk for death in patients with severe pneumonia caused by SARS-CoV-2. METHODS: A retrospective cohort study was performed in a single university hospital. All adult patients admitted with confirmed severe COVID-19 pneumonia from 9 March to 9 April 2020 were included. Severe pneumonia was defined as multi-lobar or bilateral pneumonia and a ratio of oxygen saturation by pulse oximetry to the fraction of inspired oxygen (SpFi)<315. All patients received antiviral and antibiotic treatment. From March 26, patients also received immunomodulatory treatment with corticosteroids (methylprednisolone 250 mg/day for 3 days), or tocilizumab or both. In-hospital mortality in the entire cohort and in a 1:1 matched cohort sub-analysis was evaluated. RESULTS: 255 patients were included, 118 received only antiviral and antibiotic treatment while 137, admitted after March 26, also received immunomodulators. In-hospital mortality of patients on immunomodulatory treatment was significantly lower than in those without [47/137(34.3%) vs. 69/118(58.5%), (p < .001)]. The risk of death was 0.44 (CI, 0.26-0.76) in patients receiving corticosteroids alone and 0.292 (CI, 0.18-0.47) in those treated with corticosteroids and tocilizumab. In the sub-analysis with 202 matched patients, the risk of death was 0.356 (CI 0.179-0.707) in patients receiving corticosteroids alone and 0.233 (0.124-0.436) in those treated with the combination. CONCLUSIONS: Combined treatment with corticosteroids and tocilizumab reduced mortality with about 25% in patients with severe COVID-19 pneumonia. Corticosteroids alone also resulted in lower in-hospital mortality rate compared to patients receiving only antiviral and antibiotic treatment. Corticosteroids alone or combined with tocilizumab may be considered in patients with severe COVID-19 pneumonia.

Relapse rate and renal prognosis in ANCA-associated vasculitis according to long-term ANCA patterns.

Long-term observation of patients with ANCA-associated vasculitis (AAV) allows the identification of different longitudinal patterns of ANCA levels during follow-up. This study aimed to characterize these patterns and to determine their prognostic significance. All ANCA determinations performed in two university hospitals during a 2-year period were retrospectively reviewed. Patients were included in the analysis if they had high titers of anti-myeloperoxidase (anti-MPO) or anti-proteinase 3 (anti-PR3) antibodies at least once, ≥ 5 serial ANCA determinations and AAV diagnosed by biopsy or American College of Rheumatology (ACR) classification criteria. Patients' time-course ANCA patterns were classified as monophasic, remitting, recurrent or persistent. Associations between ANCA patterns and prognostic variables (relapse rate and renal outcome) were analysed by univariate and multivariate statistics. A total of 99 patients [55 with microscopic polyangiitis (MPA), 36 with granulomatosis with polyangiitis (GPA) and eight with eosinophilic granulomatosis with polyangiitis (EGPA)] were included. Median follow-up was 9 years. Among patients diagnosed with MPA or GPA, recurrent or persistent ANCA patterns were associated with a higher risk of clinical relapse [hazard ratio (HR) = 3·7, 95% confidence interval (CI) = 1·5-9·1 and HR = 2·9, 95% CI = 1·1-8·0, respectively], independently of clinical diagnosis or ANCA specificity. In patients with anti-MPO antibodies, the recurrent ANCA pattern was associated with worsening renal function [odds ratio (OR) = 5·7, 95% CI = 1·2-26·0]. Recurrent or persistent ANCA patterns are associated with a higher risk of clinical relapse. A recurrent ANCA pattern was associated with worsening renal function in anti-MPO-associated vasculitis.

Safety and effectiveness of home intravenous antibiotic therapy for multidrug-resistant bacterial infections.

Home intravenous antibiotic therapy is an alternative to hospital admission for moderately severe infections. However, few studies have analyzed its safety and effectiveness in the treatment of infections caused by multidrug-resistant bacteria. The purpose of this study is to analyze the safety and effectiveness of home intravenous antibiotic therapy in multidrug-resistant bacterial infections. We analyzed prospectively all patients admitted to our service who underwent home intravenous antibiotic therapy during the period 2008-2012. All the treatments were administered by caretakers or self-administered by patients, through elastomeric infusion devices. Effectiveness was evaluated by analyzing the readmission rate for poor infection control. Safety was evaluated by analyzing adverse events, catheter-related complications, and readmissions not related to poor infection control. There were 433 admissions (in 355 patients) for home intravenous antibiotic therapy during the study period. There were 226 (52.2 %) admissions due to multidrug-resistant bacterial infections and 207 (47.8 %) due to non-multidrug-resistant infections. Hospital readmissions in patients with multidrug-resistant infections were uncommon. Multidrug-resistant enterococcal infections, healthcare-associated infections, and carbapenem therapy were independent variables associated with increased readmissions due to poor infection control. Readmissions not related to poor infection control, adverse events, and catheter-related complications were similar in multidrug-resistant compared to non-multidrug-resistant bacterial infections. Home intravenous therapy, administered by patients or their caretakers using elastomeric infusion pumps, was safe and effective for the treatment of most multidrug-resistant bacterial infections.

The Computer Book of the Internal Medicine Resident: competence acquisition and achievement of learning objectives.

BACKGROUND: The Computer Book of the Internal Medicine resident (CBIMR) is a computer program that was validated to analyze the acquisition of competences in teams of Internal Medicine residents. OBJECTIVES: To analyze the characteristics of the rotations during the Internal Medicine residency and to identify the variables associated with the acquisition of clinical and communication skills, the achievement of learning objectives and resident satisfaction. METHODS: All residents of our service (n=20) participated in the study during a period of 40 months. The CBIMR consisted of 22 self-assessment questionnaires specific for each rotation, with items on services (clinical workload, disease protocolization, resident responsibilities, learning environment, service organization and teamwork) and items on educational outcomes (acquisition of clinical and communication skills, achievement of learning objectives, overall satisfaction). Associations between services features and learning outcomes were analyzed using bivariate and multivariate analysis. RESULTS: An intense clinical workload, high resident responsibilities and disease protocolization were associated with the acquisition of clinical skills. High clinical competence and teamwork were both associated with better communication skills. Finally, an adequate learning environment was associated with increased clinical competence, the achievement of educational goals and resident satisfaction. CONCLUSIONS: Potentially modifiable variables related with the operation of clinical services had a significant impact on the acquisition of clinical and communication skills, the achievement of educational goals, and resident satisfaction during the specialized training in Internal Medicine.

[The Computer Book of the Internal Medicine resident: validity and reliability of a questionnaire for self-assessment of competences in internal medicine residents]. / El Libro Informático del residente de Medicina Interna: validez y fiabilidad de un cuestionario para la autoevalución de competencias en residentes de Medicina Interna.

BACKGROUND: There are no simple and validated instruments for evaluating the training of specialists. OBJECTIVES: To analyze the reliability and validity of a computerized self-assessment method to quantify the acquisition of medical competences during the Internal Medicine residency program. METHODS: All residents of our department participated in the study during a period of 28 months. Twenty-two questionnaires specific for each rotation (the Computer-Book of the Internal Medicine Resident) were constructed with items (questions) corresponding to three competence domains: clinical skills competence, communication skills and teamwork. Reliability was analyzed by measuring the internal consistency of items in each competence domain using Cronbach's alpha index. Validation was performed by comparing mean scores in each competence domain between senior and junior residents. Cut-off levels of competence scores were established in order to identify the strengths and weaknesses of our training program. Finally, self-assessment values were correlated with the evaluations of the medical staff. RESULTS: There was a high internal consistency of the items of clinical skills competences, communication skills and teamwork. Higher scores of clinical skills competence and communication skills, but not in those of teamwork were observed in senior residents than in junior residents. The Computer-Book of the Internal Medicine Resident identified the strengths and weaknesses of our training program. We did not observe any correlation between the results of the self- evaluations and the evaluations made by staff physicians. CONCLUSIONS: The items of Computer-Book of the Internal Medicine Resident showed high internal consistency and made it possible to measure the acquisition of medical competences in a team of Internal Medicine residents. This self-assessment method should be complemented with other evaluation methods in order to assess the acquisition of medical competences by an individual resident.

Off-label use of rituximab in 196 patients with severe, refractory systemic autoimmune diseases.

OBJECTIVES: To analyse the safety and efficacy of the off-label use of rituximab in patients with severe, refractory systemic autoimmune diseases. METHODS: In 2006, the Study Group on Autoimmune Diseases of the Spanish Society of Internal Medicine created the BIOGEAS project, a multicenter study devoted to collecting data on the use of biological agents in adult patients with systemic autoimmune diseases refractory to standard therapies (failure of at least two immunosuppressive agents). RESULTS: One hundred and ninety-six patients with systemic autoimmune diseases treated with rituximab have been included in the Registry (158 women and 38 men, mean age 43 years). Systemic autoimmune diseases included systemic lupus erythematosus (107 cases), inflammatory myopathies (20 cases), ANCA-related vasculitides (19 cases), Sjögren's syndrome (15 cases) and other diseases (35 cases). A therapeutic response was evaluable in 194 cases: 99 (51%) achieved a complete response, 51 (26%) a partial response and 44 (23%) were classified as non-responders. After a mean follow-up of 27.56+/-1.32 months, 44 (29%) out of the 150 responders patients relapsed. There were 40 adverse events reported in 33 (16%) of the 196 patients. The most frequent adverse events were infections, with 24 episodes being described in 19 patients. Thirteen (7%) patients died, mainly due to disease progression (7 cases) and infection (3 cases). CONCLUSIONS: Although not yet licensed for this use, rituximab is currently used to treat severe, refractory systemic autoimmune diseases, with the most favourable results being observed in Sjögren's syndrome, inflammatory myopathies, systemic lupus erythematosus and cryoglobulinemia.

Analysis of temporal artery biopsies in an 18-year period at a community hospital.

OBJECTIVE: To identify analytical and clinical variables that may improve the effectiveness of temporal artery biopsy (TAB) for the diagnosis of giant cell arteritis (GCA). MATERIALS AND METHODS: A retrospective study of TABs conducted between 1989 and 2007 at the 450-bed Hospital Parc Taulí, Sabadell. Demographic data, clinical manifestations, analytical data prior to the biopsy and final diagnoses were recorded, including only those cases in which these data were reflected in the clinical history. RESULTS: In this period, 278 TABs were conducted in 181 women (65.1%) and 97 men (mean age 74 years). Seventy-nine (28.4%) were positive (GCA+) and 199 (71.5%) negative (TAB-). The most frequent final diagnoses in the TAB- group were: polymyalgia rheumatica (PMR) (18.6%), giant cell arteritis plus negative TAB (GCA-) (13.6%), tension headache (7.5%), infection (7.5%), other vasculitis (7.5%), and neoplasm (6.0%). The GCA+ group was compared with the TAB- group, the GCA- group and the PMR group. In the multivariate analysis only headache (RR 3.6), jaw claudication (RR 2.9) and abnormal temporal artery on palpation (RR 2.5) revealed statistical differences between the GCA+ and TAB- groups. CONCLUSION: One third of the biopsies performed at our centre were positive for GCA. The clinical variables that best predicted a positive TAB in our series were headache, jaw claudication, and abnormal temporal artery on palpation.

[Type II essential mixed cryoglobulinemia and renal disease. Hepatitis C virus association]. / Afectación renal en la crioglobulinemia mixta tipo II.

UNLABELLED: Recently a number of studies have implicated C virus as a major cause of mixed cryoglobulinemia. Several authors described that up to 95% of "essential" mixed cryoglobulinemia could be attributed to this viral infection. Nevertheless, its prevalence and clinical significance are not well known. We review our experience in relation with the clinical, biological and evolutive characteristics of patients diagnosed of type II mixed cryoglobulinemia. METHODS: Descriptive and protocolized study of all cases found to have type II mixed cryoglobulinemia over a period of 8 years. Secondary cryoglobulinemic nephropathy was defined in a restrictive way: a plasma creatinine > 1.5 mg/dl and/or proteinuria > 500 mg/24 h and/or hematuria (> 15 red blood cells) need to be present in the absence of any other pathological conditions that could justify these alterations. Furthermore, the information obtained from available kidney biopsies was considered. RESULTS: 62 patients have been detected. C virus infection was demonstrated in 44 (72%). 52% had clinical symptoms related with cryoglobulinemia. 56% had alteration of renal tests, and 17 (27%) fulfil the conditions for the diagnosis of cryoglobulinemic nephropathy (nearly all with persistent microhematuria, median proteinuria 4.2 +/- 3.9 g/24 h; median plasma creatinine 2.8 +/- 1.8 mg/dl). Nine patients had been histologically examined, showing 6 cases a membranoproliferative glomerulonephritis pattern, one with associated extraglomerular vasculitis; two with mesangial proliferative pattern and one with membranous glomerulonephritis. The most striking differences between cryoglobulinemic nephropathy patients and the rest has been: higher amount of cryoglobulins (49 +/- 28 vs 20 +/- 22); more frequent hypocomplementemia, especially C4 (93% vs 59%) and recurrent purpura (75% vs 32%). No differences in the presence of C virus infection could be observed (75% vs 71%). IN CONCLUSION: 72% of patients with type II mixed cryoglobulinemia are infected by C virus (so 28% in our serie are "essential"); 52% have symptoms related with the presence of cryoglobulins, half of them with cryoglobulinemic nephropathy.

Circulating soluble adhesion molecules in patients with giant cell arteritis. Correlation between soluble intercellular adhesion molecule-1 (sICAM-1) concentrations and disease activity.

OBJECTIVE: To evaluate whether changes in concentrations of circulating adhesion molecules are related to disease activity in patients with giant cell arteritis (GCA). METHODS: A sandwich ELISA was used to measure soluble intercellular adhesion molecule-1 (sICAM-1), sICAM-3, vascular cell adhesion molecule-1 (sVCAM-1), E-selectin (sE-selectin), and L-selectin (sL-selectin) in serum and plasma samples from patients with GCA. A cross sectional study was performed on 64 GCA patients at different activity stages and on 35 age and sex matched healthy donors. Thirteen of these patients were evaluated at the time of diagnosis and serially during follow up. RESULTS: At the time of diagnosis, sICAM-1 concentrations were significantly higher in active GCA patients than in controls (mean (SD) 360.55 (129.78) ng/ml versus 243.25 (47.43) ng/ml, p < 0.001). In contrast, sICAM-3, sVCAM-1, sE-selectin, and sL-selectin values did not differ from those obtained in normal donors. With corticosteroid administration, a decrease in sICAM-1 concentrations was observed, reaching normal values when clinical remission was achieved (263.18 (92.7) ng/ml globally, 293.59 (108.39) ng/ml in the group of patients in recent remission, and 236.83 (70.02) ng/ml in those in long term remission). In the 13 patients followed up longitudinally, sICAM-1 values also normalised with clinical remission (225.87 (64.25) ng/ml in patients in recent remission, and 256.29 (75.15) ng/ml in those in long term remission). CONCLUSIONS: Circulating sICAM-1 concentrations clearly correlate with clinically apparent disease activity in GCA patients. Differences with results previously found in patients with other vasculitides may indicate that different pathogenic mechanisms contribute to vascular inflammation in different disorders.

Association between strong inflammatory response and low risk of developing visual loss and other cranial ischemic complications in giant cell (temporal) arteritis.

OBJECTIVE: To identify clinical and biochemical parameters that have good predictive value for identifying giant cell (temporal) arteritis (GCA) patients who are at high or low risk of developing cranial ischemic events. METHODS: In this multicenter study, records of patients at 3 university hospitals in Barcelona were reviewed retrospectively. Two hundred consecutive patients with biopsy-proven GCA were studied. RESULTS: Thirty-two patients developed irreversible cranial ischemic complications. The duration of clinical symptoms before diagnosis was similar in patients with and those without ischemic events. Patients with ischemic complications less frequently had fever (18.8% versus 56.9%) and weight loss (21.9% versus 62%) and more frequently had amaurosis fugax (32.3% versus 6%) and transient diplopia (15.6% versus 3.6%). Patients with ischemic events had lower erythrocyte sedimentation rates (ESR) (82.7 mm/hour versus 104.4 mm/hour) and higher concentrations of hemoglobin (12.2 gm/dl versus 10.9 gm/dl) and albumin (37.4 gm/liter versus 32.7 gm/liter). Clinical inflammatory status and biologic inflammatory status were defined empirically (clinical: fever and weight loss; biologic: ESR > or =85 mm/hour and hemoglobin < 11.0 gm/dl). Patients not showing a clinical and biologic inflammatory response were at high risk of developing ischemic events (odds ratio [OR] 5, 95% confidence interval [95% CI] 2.05-12.2). The risk was greatly reduced among patients with either a clinical (OR 0.177, 95% CI 0.052-0.605) or a biologic (OR 0.226, 95% CI 0.076-0.675) inflammatory reaction. No patient with both a clinical and a biologic response developed ischemic events. CONCLUSION: The presence of a strong acute-phase response defines a subgroup of patients at very low risk of developing cranial ischemic complications. Our findings provide a rationale for testing less aggressive treatment schedules in these individuals. Conversely, a low inflammatory response and the presence of transient cranial ischemic events provide a high risk of developing irreversible ischemic complications and require a prompt therapeutic intervention.

Circulating soluble adhesion molecules in patients with classical polyarteritis nodosa.

The objective was to evaluate whether changes in circulating soluble adhesion molecule levels reflect disease activity in patients with systemic polyarteritis nodosa (PAN). A sandwich ELISA was used to measure soluble (s) intercellular adhesion molecule 1 (sICAM-1), vascular cell adhesion molecule 1 (sVCAM-1), E-selectin, L-selectin and P-selectin in sera and plasma from 22 patients with active PAN, in sera from 13 of these patients taken serially during follow-up, and in sera from 13 healthy controls. At the time of diagnosis, sICAM-1, sVCAM-1 and sE-selectin levels (488.5 +/- 201.3, 1176.5 +/- 514.1 and 60.6 +/- 27 ng/ml, respectively) were significantly higher in patients than in controls (P < 0.0001, P = 0.001 and P = 0.003, respectively). In contrast, sL-selectin levels tended to be lower in patients than in controls. Within the first 7 days after starting treatment, there was a significant increase in sICAM-1 concentrations, which fell thereafter, but did not completely reach normal levels when patients achieved clinical remission. sE-selectin also remained elevated during follow-up. Only sVCAM-1 decreased, tending to reach normal values in inactive disease. Increased levels of sICAM-1, sVCAM-1 and sE-selectin, and decreased levels of sL-selectin, in active PAN suggest immune and endothelial stimulation during disease activity. Abnormal levels of soluble adhesion molecules in clinically inactive patients might reflect persistence of immune activation and/or endothelial cell exposure to a remaining inflammatory microenvironment.

Giant cell (temporal) arteritis and secondary renal amyloidosis: report of 2 cases.

Renal involvement is unusual in giant cell (temporal) arteritis (GCA). Microscopic hematuria and minimal proteinuria responsive to steroid therapy have been described as the most frequent renal alterations. The nephrotic syndrome in GCA has been rarely reported. We describe 2 cases of GCA with nephrotic syndrome, one at the time of diagnosis, the other 2 years after treatment. Percutaneous renal biopsy in both cases disclosed secondary renal amyloidosis confirmed by permanganate sensitivity and immunohistochemical analysis. To our knowledge, cases of GCA and secondary amyloidosis have not been reported.

Von Willebrand factor in the outcome of temporal arteritis.

OBJECTIVE: To determine fluctuation in circulating von Willebrand factor (vWF) in the outcome of patients with temporal arteritis. METHODS: Plasma vWF antigen concentrations were measured in 65 patients with biopsy proven temporal arteritis at different disease activity stages, in 12 with isolated polymyalgia rheumatica, and in 16 controls. Fourteen temporal arteritis patients underwent serial determinations during the course of their disease. RESULTS: vWF concentrations were significantly raised in temporal arteritis (mean 220 [arbitrary units], range 96 to 720) and in polymyalgia rheumatica (mean 196, range 103 to 266) compared with healthy controls (mean 98, range 75 to 137) (P < 0.05). Although vWF values tended to be higher in temporal arteritis, no significant differences were found between temporal arteritis and polymyalgia rheumatica patients nor between temporal arteritis patients with ischaemic complications (mean 269, range 130 to 720) and those who presented with polymyalgia rheumatica or constitutional symptoms only (mean 179, range 140 to 220). The highest levels were obtained in patients with associated, mainly infectious, diseases (mean 631, range 240 to 1680). Raised vWF values found in active temporal arteritis patients (mean 220, range 96 to 720) persisted within the first two years after the beginning of treatment (mean 244, range 102 to 510) but tended to normalise in patients in long term remission (mean 143, range 50 to 260). CONCLUSIONS: Persistent elevation of vWF during early remission of temporal arteritis might represent an endothelial activation status induced by a remaining inflammatory microenvironment rather than a marker of endothelial cell injury. In long term remission, decreasing vWF concentrations might reflect progression of inflammatory lesions to a healing stage.

Release of soluble tumor necrosis factor receptors in Mediterranean spotted fever rickettsiosis.

Tumor necrosis factor alpha (TNF) is a key cytokine in the defense against many intracellular pathogens, including Rickettsia conorii, the causative agent of Mediterranean spotted fever (MSF). The levels of two soluble TNF receptors (sTNFR-p55 and sTNFR-p75), the extracellular domains of the two cell surface receptors for TNF, were elevated in the acute-stage plasma samples from 20 patients with serologically confirmed MSF. The median values were 3.1 and 7.8 ng/ml for sTNFR-p55 and sTNFR-p75, respectively. sTNFR values correlated significantly with plasma TNF concentrations. Patients with severe MSF had higher values for both receptor fragments than patients with nonsevere disease. The differences were statistically significant for sTNFR-p55 (median, 5.8 versus 2.0 ng/ml; P = 0.008). Given the proportionately higher values for both TNF and sTNFR-p55 in patients with severe MSF, the sTNFR-p55/TNF ratios for the two patient subgroups did not differ (P = 0.5), while the sTNFR-p75/TNF ratios were significantly different (P = 0.01), with disproportionately lower values in patients with severe disease.

Plasma levels of tumor necrosis factor alpha in patients with Mediterranean spotted fever: clinical and analytical correlations.

Twenty consecutive patients with serologically confirmed Mediterranean spotted fever were analyzed for determination of plasma levels of tumor necrosis factor alpha (TNF-alpha) by means of an ELISA. Increased levels of TNF-alpha in plasma were found during the acute phase of the disease (52.3 +/- 49.8 pg/mL) compared to levels in the convalescent phase (9.0 +/- 9.3 pg/mL; P < .001) or in healthy controls (6.5 +/- 3.2 pg/mL; P < .001). Plasma TNF-alpha levels were significantly higher in patients with severe Mediterranean spotted fever. Levels of TNF-alpha correlated significantly with serum levels of C-reactive protein and triglycerides and inversely with serum levels of sodium.