Severe neurologic syndrome associated with Middle East respiratory syndrome corona virus (MERS-CoV).

BACKGROUND: Since the identification of the first case of infection with the Middle East respiratory syndrome corona virus (MERS-CoV) in Saudi Arabia in June 2012, the number of laboratory-confirmed cases has exceeded 941 cases globally, of which 347 died. The disease presents as severe respiratory infection often with shock, acute kidney injury, and coagulopathy. Recently, we observed three cases who presented with neurologic symptoms. These are so far the first reported cases of neurologic injury associated with MERS-CoV infection. METHODS: Data was retrospectively collected from three patients admitted with MERS-CoV infection to Intensive Care unit (ICU) at King Abdulaziz Medical City, Riyadh. They were managed separately in three different wards prior to their admission to ICU. FINDING: The three patients presented with severe neurologic syndrome which included altered level of consciousness ranging from confusion to coma, ataxia, and focal motor deficit. Brain MRI revealed striking changes characterized by widespread, bilateral hyperintense lesions on T2-weighted imaging within the white matter and subcortical areas of the frontal, temporal, and parietal lobes, the basal ganglia, and corpus callosum. None of the lesions showed gadolinium enhancement. INTERPRETATION: CNS involvement should be considered in patients with MERS-CoV and progressive neurological disease, and further elucidation of the pathophysiology of this virus is needed.

Inflammatory, hemostatic, and clinical changes in a baboon experimental model for heatstroke.

The mortality and neurological morbidity in heatstroke have been attributed to the host's inflammatory and hemostatic responses to heat stress, suggesting that immunomodulation may improve outcome. We postulated that an experimental baboon model of heatstroke will reproduce human responses and clinical outcome to allow testing of new therapeutic strategies. Eight anesthetized juvenile baboons (Papio hamadryas) were subjected to heat stress in an incubator maintained at 44-47 degrees C until rectal temperature attained 42.5 degrees C (moderate heatstroke; n = 4) or systolic arterial pressure fell to <90 mmHg (severe heatstroke; n = 4) and were allowed to recover at room temperature. Four sham-heated animals served as a control group. Rectal temperature at the end of heat stress was 42.5 +/- 0.0 and 43.3 +/- 0.1 degrees C, respectively. All heat-stressed animals had systemic inflammation and activated coagulation, indicated by increased plasma IL-6, prothrombin time, activated partial thromboplastin time, and D-dimer levels, and decreased platelet count. Biochemical markers and/or histology evidenced cellular injury/dysfunction: plasma levels of thrombomodulin, creatinine, creatine kinase, lactic dehydrogenase, and alanine aminotransferase were increased, and varying degrees of tissue damage were present in liver, brain, and gut. No baboon with severe heatstroke survived. Neurological morbidity but no mortality was observed in baboons with moderate heatstroke. Nonsurvivors displayed significantly greater coagulopathy, inflammatory activity, and tissue injury than survivors. Sham-heated animals had an uneventful course. Heat stress elicited distinct patterns of inflammatory and hemostatic responses associated with outcome. The baboon model of heatstroke appears suitable for testing whether immunomodulation of the host's responses can improve outcome.

Activation of coagulation and fibrinolysis in heatstroke.

Hemorrhagic diathesis and widespread microthrombosis are common in heatstroke. To assess the early stages of coagulopathy in heatstroke, thrombin-antithrombin III (TAT), fibrin monomers, plasmin-alpha 2-antiplasmin (PAP), plasminogen and D-Dimer were measured in 16 heatstroke patients (means +/- SE rectal temperature 42.3 +/- 0.2 degrees C) pre- and postcooling and compared with 8 heatstressed and 23 normal controls. Comparing heatstroke patients with normal controls, TAT, fibrin monomers, PAP and D-Dimer were elevated to (median (range)) 16.5 (4-1000) versus 3.5 (2-7.2) micrograms/l p < 0.001, 16 (4-113) versus 2 (2-9) nM p < 0.001; 3300 (1000-36500) versus 255 (136-462) micrograms/l p < 0.001 and 0.72 (0.22-64.8) versus 0.15 (0.05-0.25) microgram/ml p < 0.01 respectively. Plasminogen decreased to 81% (34-106); PAP, TAT and D-Dimer correlated significantly with hyperthermia (r = 0.577, p = 0.02; r = 0.635, p = 0.01; r = 0.76, p = 0.003). Postcooling PAP decreased to 545 (260-850) micrograms/l p < 0.005, TAT 10 (6-70) micrograms/l, and fibrin monomers 22 (18-86) nM remained unchanged. Heatstressed controls showed mild but significant increase in all markers. Activation of coagulation and fibrinolysis occurs early and is profound and sustained in heatstroke. Cooling seems to attenuate the activation of fibrinolysis only, however, this requires confirmation in a larger study population.

Acute pneumonitis with bilateral pleural effusion after talc pleurodesis.

We describe a patient who developed acute pulmonary distress with bilateral interstitial infiltrates and pleural effusion following talc pleurodesis. Talc particles, obtained by bronchoalveolar lavage, were identified by transmission electron microscopy and chemical analysis. The patient improved with corticosteroid therapy. Acute respiratory failure can be a potential hazard of talc pleurodesis.

Elevated pyrogenic cytokines in heatstroke.

STUDY OBJECTIVES: Heatstroke, characterized by hyperthermia and neurologic abnormalities, can cause shock, adult respiratory distress syndrome, and multiorgan failure culminating in death. The mediation of metabolic changes and tissue damage is not fully understood. Recent evidence suggests the involvement of endotoxin, tumor necrosis factor alpha (TNF-alpha), and interleukin 1 alpha (IL-1 alpha) and we hypothesized that other pyrogenic cytokines may be implicated. DESIGN: Prospective analysis. SETTING: Heatstroke Center in Makkah (Mecca), Saudi Arabia. MEASUREMENTS AND RESULTS: We measured plasma IL-1 beta, IL-6, and interferon gamma (INF-gamma) concentrations by enzyme-linked immunosorbent assay in 28 heatstroke patients at the time of hospital admission (precooling) and after complete cooling (postcooling), and in 10 normal control subjects. We measured C-reactive protein (CRP) as a marker of acute phase response and calculated severity of illness using the simplified acute physiology score. Twenty-five male and 3 female subjects had mean (+/- SEM) rectal temperature of 41.2 +/- 0.2 degrees C. IL-6, IL-1 beta, and INF-gamma concentrations were elevated in 100 percent, 39 percent, and 50 percent of patients to (mean +/- SEM) 220 +/- 44 pg/ml, 42 +/- 14 pg/ml, and 1,180 +/- 879 pg/ml, respectively (normal control values: < 3.5 pg/ml, < 4.5 pg/ml, < 20 pg/ml). The CRP value was elevated in 72 percent of patients to 152 +/- 40 mg/L (control value: 0 to 17 mg/L). The IL-6 concentrations correlated with severity of illness (r = 0.516, p = 0.03); two patients with the highest concentrations died. There was no significant correlation between circulating levels of IL-6, IL-1 beta, INF-gamma, and temperature, or between IL-6, IL-1 beta, and CRP. Postcooling, IL-6, and IL-1 beta were still above normal control values; INF-gamma could be detected in one patient only. CONCLUSION: Our findings of elevated circulating IL-6, IL-1 beta, and INF-gamma in the presence of acute phase response, and correlation with severity of illness, suggest that these cytokines have a role in the pathogenesis of heatstroke, which could lead to new therapeutic strategies.

CT-guided fine needle aspiration biopsy in the diagnosis of mediastinal tuberculosis.

Twenty-two patients with mediastinal tuberculosis were reviewed. The most common symptoms were chest pain, cough, fever, and weight loss. Results of the physical examination were unremarkable. The chest radiographs of all 22 patients showed abnormal mediastinum with no evidence of extramediastinal disease. Most (62%) had right-sided paratracheal lymphadenopathy. Mantoux skin test was positive (> 15 mm) in all patients, whereas sputum smears and cultures for acid-fast bacilli were negative. Computed tomographic (CT) guided fine needle aspiration biopsies (FNAB) were performed in 12 patients using 22- to 25-gauge needles. Ten patients had fiberoptic bronchoscopic (FOB) examination with brushings and biopsies. Mediastinoscopy (n = 8) or thoracotomy (n = 6) was performed in patients where either FNAB or FOB was not diagnostic or where lymphoma was suspected clinically. The rates of true-positive diagnoses were 20%, 66%, 75%, and 100% for FOB, FNAB, mediastinoscopy, and thoracotomy, respectively. The rate of false-negative for FNAB was 34%. Only one patient developed nonsignificant pneumothorax after FNAB. These findings suggest that CT-guided FNAB is a useful and safe procedure and should be considered in the initial evaluation of patients suspected of having mediastinal tuberculosis.

Acid-base alterations in heatstroke.

OBJECTIVE: To analyze the acid-base balance during heatstroke. DESIGN: Retrospective study. SETTING: Heatstroke Center, Makkah, Saudi Arabia. PATIENTS: Hundred nine consecutive heatstroke patients (mean age 55 +/- 12 years) with rectal temperature from 40 to 43.4 degrees C following exposure to hot weather. INTERVENTION: Arterial blood gases collected prospectively and analyzed using 95% confidence limits established by controlled experimental studies. Severity of heatstroke on admission assessed by Simplified Acute Physiology Score and Organ System Failure score. RESULTS: Metabolic acidosis was the predominant acid-base change followed by respiratory alkalosis (81 and 55% of the patients, respectively). The prevalence of metabolic acidosis (but not respiratory alkalosis) was significantly associated with the degree of hyperthermia: 63, 95 and 100% at 41, 42 and 43 degrees C, respectively (p < 0.0001). Patients with metabolic acidosis had a large anion gap (24 +/- 5). Arterial partial pressure of oxygen (PaO2), systolic blood pressure and Organ System Failure score were similar with or without metabolic acidosis. Although the acute physiology score was higher in patients with, than without, metabolic acidosis (15.7 +/- 3.7 vs 9.8 +/- 4.4, p < 0.001), there was no significant difference in neurologic morbidity and mortality (7.9 vs 1.1%, 5.6 vs 0%, p = 0.776 and 0.581, respectively). CONCLUSION: We conclude that metabolic acidosis is the predominant response in heatstroke.

Hematopoietic colony-stimulating factors for neutropenic patients in the ICU.

OBJECTIVE: To assess whether adjunct hematopoietic colony-stimulating factor (H-CSF) accelerates neutrophil recovery and improves survival. DESIGN: A retrospective study. SETTING: Medical/surgical intensive care unit (ICU). PATIENTS: 30 neutropenic patients admitted to the ICU and treated with H-CSF. Controls were the preceding 30 neutropenic patients not treated with H-CSF. MEASUREMENTS AND RESULTS: Patient admission characteristics were reviewed. Endpoints were neutrophil recovery ( > 1.0 x 10(9)/l), length of ICU stay and survival. Depth and duration of neutropenia (0.267 +/- 0.04 x 10(9)/l for 12 +/- 1.7 days vs 0.293 +/- 0.05 x 10(9)/l for 15 +/- 1.9 days; p = 0.67 and 0.21), and the Acute Physiology and Chronic Health Evaluation II and organ system failure scores were similar. Systemic candidiasis was lower in the H-CSF group (20 vs 3 %; p > 0.05). In 11 (36.6 %) and 10 (33.3 %) patients neutrophil count recovered ( > 1.0 x 10(9)/l); H-CSF did not reduce the duration of neutropenia (7.8 +/- 1.4 vs 5.7 +/- 1.3 days; p = 0. 28), the length of ICU stay (7.8 +/- 1.1 vs 8.9 +/- 1.5 days; p = 0. 55) or improve survival (23 vs 10 %; p = 0.168). CONCLUSION: H-CSF for treatment of neutropenia in patients admitted to the ICU did not accelerate neutrophil recovery or improve survival.

Differential effects of in vitro and in vivo hyperthermia on the production of interleukin-10.

OBJECTIVE: To determine whether hyperthermia activates an anti-inflammatory response. DESIGN: A prospective study. SETTING: Heatstroke Center, Makkah, and King Faisal Specialist Hospital, Riyadh, Saudi Arabia. PATIENTS: Twenty-five heatstroke patients pre-cooling (rectal temperature 42.4 +/- 0.8 degrees C) (group 1) and 13 normothermic heat-stressed subjects were studied (group 2). Twelve of the 25 heatstroke patients were also studied post-cooling (group 3). Mononuclear cells from six healthy blood donors resting at 24 degrees C were used for in vitro study. INTERVENTIONS: Mononuclear cells were cultured at a concentration of 1 x 10(6)/ml without and with lipopolysaccharide (LPS) added at concentration of 10, 100, and 1000 ng/ml. The cells were incubated for 24 h at 37, 39, 41, and 43 degrees C. ELISA was used to measure IL-10 in the supernatant and plasma from heatstroke and heat-stressed subjects. RESULTS: All patients in group 1, 40% of group 2, and 37% of group 3, showed elevation of IL-10 (1289 +/- 2519, 248 +/- 393, and 172 +/- 226 pg/ml, respectively) compared with normal control levels, (< 100 pg/ml) P < 0.05. IL-10 level on admission did not correlate with degree of hyperthermia. During 24 h incubation at 37 degrees C without LPS, no IL-10 was detected, whereas with 10 ng/ml LPS, monocytes released 658 +/- 291 pg IL-10/10(6) cells. At 39 degrees C and 41 degrees C IL-10 release was decreased to 225 +/- 114, and 245 +/- 90 pg/10(6) cells, respectively; and was completely inhibited at 43 degrees C (67 +/- 10 pg/10(6) cells), P < 0.0001. CONCLUSION: Heat-stress with and without hyperthermia is associated with anti-inflammatory response in vivo. However, it does not seem to be the direct effect of heat on monocytes, suggesting that other environmental or genetic factors may be involved.

Endotoxemia and release of tumor necrosis factor and interleukin 1 alpha in acute heatstroke.

To determine whether endotoxemia and release of tumor necrosis factor (TNF-alpha) and/or interleukin 1 alpha (IL-1 alpha) are involved in the pathogenesis of heatstroke, 17 adult patients with a mean rectal temperature of 42.1 +/- 0.2 degrees C were studied. Blood samples were taken on admission and after cooling was completed. TNF-alpha and IL-1 alpha levels were measured by enzyme-linked immunosorbent assay, and lipopolysaccharide (LPS) content was measured by the chromogenic substrate modification of the Limulus amebocyte lysate. TNF-alpha, IL-1 alpha, and LPS were elevated in all patients [199 +/- 25 (SE) pg/ml, 480.5 +/- 68.3 pg/ml, and 8.60 +/- 1.19 ng/ml, respectively, compared with normal control values of 31.4 +/- 8.4 pg/ml, 53.7 +/- 5.32 pg/ml, and less than 9 pg/ml]. There was no significant correlation between temperature and the circulating concentration of TNF-alpha, IL-1 alpha, and LPS. Postcooling TNF-alpha, IL-1 alpha, and LPS concentrations were significantly decreased but still above normal control values. The findings suggest that these mediators may have a role in the pathogenesis of heatstroke that could change the strategy of management.

Mechanisms of hypophosphatemia in humans with heatstroke.

Hypophosphatemia is common in heatstroke, but little is known about its mechanism. We investigated 10 consecutive patients with heatstroke (mean age 58 +/- 2 yr) whose mean rectal temperature at admission was 42.3 +/- 0.2 degrees C. Eight patients presented with hypophosphatemia [0.48 +/- 0.08 mmol/l, normal range (NR) 0.8-1.4 mmol/l], associated with increased fractional excretion of phosphate (19.8 +/- 6.4%, NR 6-20%) relative to plasma phosphate levels and reduced renal threshold for phosphate (0.55 +/- 0.08 mmol/l glomerular filtrate, NR 0.8-1.4 mmol/l). Plasma parathyroid hormone (75.0 +/- 5 pmol/l) and calcium (2.24 +/- 0.02 mmol/l) levels and fractional excretion of calcium were normal (1.66 +/- 0.27%). There was no evidence of uricosuria or aminoaciduria, and only one patient had glucosuria. Arterial carbon dioxide was decreased in eight patients (28 +/- 1.1 Torr); however, none had elevated blood pH (7.35 +/- 0.02). The results suggest that heatstroke-related hypophosphatemia is associated with abnormal phosphaturia independent of the parathyroid hormone level, and there is no evidence of tubular dysfunction.

Distribution of peripheral blood leukocytes in acute heatstroke.

We examined 11 heatstroke patients (mean rectal temperature 41.4 +/- 0.3 degrees C) and 40 healthy subjects to determine the effects of hyperthermia on peripheral blood leukocyte distribution. Precooling samples were taken on admission. Whole blood was incubated with conjugated monoclonal antibodies, and erythrocytes were eliminated by FACS lysing solution. Lymphocyte subsets were detected by specific mouse monoclonal antibodies: Leu-4/CD3+ (T-cells), Leu-3a/CD4+ (T-helper cells), Leu-2a/CD8+ (T-suppressor-cytotoxic cells), Leu-11/19/CD16+/CD56+ (natural killer cells), and Leu-12/CD19+ (B-cells). Immunofluorescence was measured with a flow cytometer. The number of circulating leukocytes and lymphocytes was significantly increased in heatstroke patients. This lymphocytosis was mainly due to an increase in T-suppressor-cytotoxic cells and natural killer cells. The absolute number of lymphocytes and T-suppressor-cytotoxic cells significantly correlated with the degree of hyperthermia (r = 0.62, P = 0.04; r = 0.751, P = 0.007, respectively). There was a significant decrease in the percentages of T-, B-, and T-helper cells and increase in T-suppressor-cytotoxic and natural killer cells, giving a marked decrease in the ratio of T-helper to T-suppressor-cytotoxic cells. We conclude that heatstroke is associated with leukocytosis and significant alteration in absolute number and percentage of circulating lymphocyte subpopulations.

Lymphocyte subsets and adhesion molecules expression in heatstroke and heat stress.

We examined the specificity of the recently reported alterations in circulating lymphocytes in heatstroke by determining lymphocyte subsets in 14 consecutive heatstroke patients before and after cooling and in 7 heat-stressed controls using single- or two-color immunofluorescence flow cytometry. The relationship with catecholamine levels was also studied. In heatstroke, percentages of T (CD3(+)/CD19(-)), T-helper (CD4(+)/CD8(-)), T-inactive [CD3(+)/human leukocyte antigen-DR-], CD11a+, CD11c+, and CD44(+) lymphocytes were significantly decreased, whereas percentages of T-suppressor-cytotoxic (CD8(+)/CD4(-)), natural killer (NK; CD3(-)/CD16(+) or CD56(+)), CD3(+)/CD16(+) or CD56(+), and CD54(+) lymphocytes were significantly increased, compared with 11 normal controls. The changes in the absolute numbers of lymphocyte subsets were in the same direction and were significant for T-helper, T-suppressor-cytotoxic, NK, CD3(+)/CD16(+) or CD56(+), and CD11c+ lymphocytes. Milder but significant changes in percentages of T-helper, T-suppressor-cytotoxic, CD11c+, and CD44(+) lymphocytes were seen in heat stress. Cooling was associated with partial or complete normalization, further derangement (CD11a+, CD11c+), or overcorrection (NK, T-suppressor-cytotoxic, CD11b+) of abnormal percentages of lymphocyte subsets. Norepinephrine levels were significantly elevated in heatstroke (4.7-fold) and heat stress (3.2-fold), but did not significantly correlate with lymphocyte subsets. We conclude that heatstroke is associated with significant changes in percentages and in absolute numbers of a wide range of circulating lymphocyte subsets that are not related to elevated catecholamine levels or totally normalized by cooling. Similar, albeit milder, changes are seen in heat stress, suggesting that the two syndromes represent a continuum.

Impaired elimination of atenolol in a nephropathic patient with self-medication overdose.

A case of intoxication with atenolol (plasma concentration of 2.71 mg/L) caused by an improper self-medication combined with impaired renal function is presented. The patient was supported with atropine, isoproterenol, dopamine, and dobutamine, and a thorough pharmacokinetic monitoring of atenolol was conducted. As the serum creatinine concentration returned slowly to baseline with good diuresis, the concentration of atenolol decreased (biologic half-life = 2.95 days) and the blood pressure gradually recovered. The patient improved and was subsequently discharged in good health. Had pharmacokinetic monitoring of atenolol not been performed, hemodialysis would have been indicated.

Brain biopsy in tuberculoma: the risks and benefits.

In developing countries, 5 to 8% of the space-occupying lesions of the central nervous system are tuberculomas. Diagnosis can be difficult in the absence of extracranial tuberculosis; computed tomography is suggestive only. To assess the value of brain biopsies in tuberculomas, the records of 15 patients aged 6 to 80 years were reviewed. Histological confirmation was obtained in 15 patients, and acid-fast bacilli were cultured from 12 patients. Intracranial hypertension was the principal sign in 11 patients; other neurological signs were related to the location of the tuberculoma. One patient had evidence of extracranial tuberculosis. Biopsy-related complications consisted of an epidural hematoma in 1 patient and hydrocephalus in another; both required additional surgery. One case of tuberculous meningitis was probably related to surgery and poor drug compliance. There was no postoperative mortality. Thirteen patients (2 were lost to follow-up) were cured after an average of 16 months of antituberculous therapy. It was concluded that the brain biopsy is useful in diagnosing tuberculoma but that there is some associated risk.

[Pulmonary thromboembolic complications of catheterization using the Swan-Ganz catheter]. / Complications thrombo-emboliques pulmonaires des cathétérismes par sonde de Swan-Ganz.

Twenty-two adult patients who had required catheterization with a Swan-Ganz catheter and had thrombosis of the internal jugular vein were investigated for pulmonary embolism. In 4 of these, pulmonary embolism was detected by angiography, and 2 patients who died with the catheter in situ had also pulmonary embolism. In 5 out of these 6 patients prophylactic heparin treatment failed to prevent this complication. This study suggests that the Swan-Ganz catheter placement is indicated only when the value of the information to be gained exceeds the potential risk.

[Urinary tract obstruction by Candida bezoars, or fungus balls]. / Obstruction des voies urinaires par des bézoars candidosiques, ou "fungus balls".

Two patients admitted to an intensive care unit for severe bacterial infection develops Candida albicans superinfection with obstruction of the urinary canals by "fungus balls". The development of medico-surgical techniques using antibiotics and immunosuppressive drugs accounts for the increasing incidence of disseminated candidiasis. The kidneys are particularly sensitive to Candida infections. Fungus balls are conglomerates of mycelium which may result in obstruction of the urinary tract. Their clinical, radiological and ultrasonic features, as well as the microbiological and serological diagnostic problems they raise are described. Ultrasonically guided percutaneous nephrostomy is a very interesting technique for the diagnosis of the condition and its local treatment by drainage and lavage with amphotericin B. This antifungal, combined with flucytosine is still used for the systemic treatment of candidiasis.

[Breast hypertrophy: preliminary study in Dakar]. / Les Hypertrophies Mammaires : Etude Preliminaire A Dakar.

The management of breast hypertrophy has become a new and increasing need in Senegal. The files of 47 patients presenting with breast hypertrophy were collated over twelve years. The mean age was 33,9 years. Three surgical techniques were used. The average sternal notch to nipple measurement was 33 cm. Surgery was performed on twenty-two patients, or 42 breast. The surgical technique of Mac Kissock was used in 50% of the cases, the inferior pedicle technique in 13.6% of the cases and the technique of Thorek in 36.4% of the cases. The average weight of tissue removed was 1.3 kg per breast. Our rate of post-operative complications was 9.5% , mostly suppurations. Close to 91% of the patients expressed being satisfied with the aesthetic result obtained. The surgery of breast hypertrophy is increasing in our activity.