Banani Poddar, Jyoti Narayan Sahoo, Mohan Gurjar, Ratender Singh, Afzal Azim

Transcription

1 Case Report Deep-vein thrombosis and septic pulmonary emboli in methicillin-sensitive Staphylococcus aureus infection Banani Poddar, Jyoti Narayan Sahoo, Mohan Gurjar, Ratender Singh, Afzal Azim Department of Critical Care Medicine, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India Deep-vein thrombosis (DVT) in children is most often secondary to a predisposing cause. DVT and septic pulmonary emboli in staphylococcal sepsis has been described most often with methicillin-resistant Staphylococcus aureus. The clinical features of four previously healthy children with community-acquired, methicillin-sensitive Staphylococcus aureus sepsis associated with DVT are described. Keywords: Pneumonia, Staphylococcal, Intensive care unit, Paediatric, Venous thrombo-embolism, Embolism, Pulmonary Introduction Staphylococcus aureus, a gram-positive, coagulasepositive bacterium, is an important human pathogen. Invasive infection with community-acquired, methicillin-resistant Staphylococcus aureus (MRSA) is reported increasingly from industrialised countries, often associated with genes encoding for Panton- Valentine leucocidin (PVL). 1 Severe communityacquired staphylococcal infections, many requiring intensive care, have been reported in India. 2 4 Contrary to the situation in industrialised countries, almost all these infections are methicillin-sensitive S. aureus (MSSA). The manifestations are myriad and include pleuro-pulmonary disease, pyopericardium, musculoskeletal involvement, meningitis and, occasionally, endocarditis. However, deep-vein thrombosis (DVT) has been reported infrequently 4 6 and association with septic pulmonary emboli in MSSA infections is rare. 5 8 Four successfully managed cases of invasive staphylococcal infection, all MSSA, presenting with DVT are presented. Subjects and Methods The medical charts and radiological and laboratory findings in four consecutive children with S. aureus infection and DVT (including the details of one previously published 7 ) admitted to the intensive care unit (ICU) of Sanjay Gandhi Postgraduate Institute Correspondence to: B Poddar, Department of Critical Care Medicine, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India Fax: z ; bananip@sgpgi.ac.in of Medical Sciences, Lucknow were retrospectively reviewed. All were infected by methicillin-sensitive S. aureus and had DVT, and three of them had septic pulmonary embolism. Details of the presenting histories and sites of involvement are shown in Table 1. All were males aged between 8 and 14 years and presented with a history of limb pain and swelling, fever and respiratory distress for 5 8 days (median 6.5). Their admission laboratory profiles are shown in Table 2. Qualitative assay of D-dimer was positive in all, with normal to raised fibrinogen level (range mmol/l). There was no family history of thrombotic tendency and work-up for hypercoagulability was negative in all patients. All four patients had clinical features suggestive of bronchopneumonia with abnormal chest radiographs (Table 3). CT of the chest undertaken in three children showed multiple pleural-based, ill defined densities of varying sizes with central cavitation and a feeding vessel, consistent with septic pulmonary emboli (Figure 1), and one had hydropneumothorax. Doppler flow study identified DVT of lower limb veins in three and an upper limb vein in one. Echocardiography was normal in all patients. MRI of affected limbs was undertaken and showed effusion of the hip joint in one patient with osteomyelitis of the right femur neck, and shoulder joint effusion in another. Myositis was detected around the corresponding joints. Supportive therapies given in the ICU are detailed in Table 3. Two children required mechanical ventilation ß W. S. Maney & Son Ltd 2013 DOI / Y Paediatrics and International Child Health 2013 VOL. 33 NO. 1 49

2 Table 1 Presenting complaints and sites of involvement Case 1* Case 2 Case 3 Case 4 Age, yrs Gender M M M M History of boils Yes No No No History of trauma No No No Yes Onset of illness to hospital admission, days Symptoms, days Left lower limb pain and swelling (8) Right lower limb pain and swelling (5) Left upper limb pain and swelling (8) Right lower limb pain and swelling (6) Fever (7) Fever (3) Fever (7) Fever (1) Resp. distress (1) Resp. distress (2) Resp. distress (2) Resp. distress (1) Primary site of infection Left thigh Right thigh Left upper limb Right foot ulcer Bone or joint involvement No Right hip, left elbow, Osteomyelitis right femur * Details published previously 7 Myositis around left shoulder joint No and vasopressor infusions. All patients were treated with antibiotics for 4 6 weeks. The patients were anticoagulated with heparin and this was changed to vitamin K antagonists once they stabilised. The international normalised ratio (INR) was maintained at between 2 and 3. This was continued for 3 months and then discontinued as no prothrombotic state was found in any of the patients. The median ICU stay was 20 days (range 6 30); the two boys on vasopressors and mechanical ventilation had a prolonged stay in the ICU. Three children are on follow-up and are well. One boy with osteomyelitis of the right femur neck was referred to another hospital for orthopaedic intervention and is lost to follow-up. Discussion S. aureus is a well recognised pathogen and disseminated disease in previously healthy children is well described. 2,3 However, in a review of 50 children with disseminated staphylococcal disease requiring ICU care in Chandigarh, India, none was reported to have deep-vein thrombosis. 2 In many countries since the late 1990s, the epidemiology of community-acquired S. aureus has changed from MSSA to virulent MRSA strains. 1,9 Strains of S. aureus with genes encoding PVL were implicated in this serious invasive disease. 1,5,9 However, recent literature has questioned the role of PVL in the virulence of staphylococcal disease; 1 other factors which promote necrosis such as a-toxin and novel cytolytic peptides (e.g. phenol-soluble modulinlike peptides or PSMs) might play a more important role. Furthermore, the expression of these virulence factors is influenced by differential gene expression, thus affecting virulence of the organism. Venous thrombo-embolism is rare in childhood and is typically associated with the presence of central venous catheters, trauma, sepsis, malignancies and preexisting coagulation disorders. 5 They occur in 0.07/ 10,000 children, with neonates and adolescents being at highest risk. 10 The incidence of pulmonary embolism in children is low; however, mortality rates may be as high as 30%. Various genetic prothrombotic defects affecting the physiological anticoagulant system have been identified as risk factors for thrombotic events. In 2000, three Israeli children were reported with a triad of DVT, septic pulmonary embolism and acute osteomyelitis associated with staphylococcal disease, and the authors proposed that the venous thrombus acts as a focus of infection and leads to disseminated disease. 8 Subsequent studies from Houston, Texas 5 and Taiwan 6 also found the same association. Septic DVT occurs following the release of various exotoxins, a-toxin and coagulase being the most important. a-toxin acts on cell membranes and produces aggregation of platelets and vascular spasm, while Table 2 Laboratory investigations on admission Case 1 Case 2 Case 3 Case 4 Total leukocyte count /L Platelet count /L Haemoglobin, g/dl PT patient/control, sec 17.1/ / / /11.6 APTT patient/control, sec 42.1/ / / /27.2 APLA Absent Absent Absent Absent Protein C, protein S assay Normal Not done Borderline low Normal Factor V Leiden mutation Absent Absent Absent Absent Homocysteine level Normal Not done Normal Not done Cultures showing growth of S. aureus (methicillin-sensitive) Blood Blood Blood Wound swab Pus from hip joint Tracheal aspirate Pleural aspirate PT, prothrombin time; APTT, activated partial thromboplastin time; APLA, anti-phospholipid antibodies. 50 Paediatrics and International Child Health 2013 VOL. 33 NO. 1

3 Table 3 Radiology and interventions Case 1 Case 2 Case 3 Case 4 Chest radiograph Nodular opacity Nodular opacity Left pleural effusion Consolidation, right lung, pleural effusion Right superficial and deep femoral vein thrombosis Left axillary and brachial vein thrombosis Distal part of right common iliac vein, upper 3rd of superficial femoral vein thrombosis Doppler Left common iliac vein, superficial & deep femoral vein thrombosis Minimal effusion left shoulder joint Oedema & inflammation of muscles of Inflammation, oedema & small fluid adductor compartment of right thigh Osteomyelitis right femur neck, effusion right hip joint MRI soft tissue and bone Oedema & inflammation of left thigh muscles. collections in the surrounding muscles Echo Normal Normal Normal Normal CT chest SPE SPE SPE, hydropneumothorax Not done Antibiotic therapy Vancomycin initially, later cloxacillin z Cloxacillin z amikacin Cloxacillin z amikacin Cloxacillin z amikacin (amikacin 61 wk) amikacin Oxygen therapy Yes Yes Yes Yes Mechanical ventilation, days 3 No 10 No Vasopressor, days 2 No 6 No Short-term anticoagulant Unfractionated heparin Low-molecular-weight heparin Unfractionated heparin Low-molecular-weight heparin Not done Thrombosis resolved in 13 days Thrombosis resolved in 5 days Follow-up doppler Thrombosis resolved several months later Long-term DVT prophylaxis Vit. K antagonist Not known Vit K antagonist Vit. K antagonist ICU stay, days Discharged Discharged Outcome Discharged Referred for orthopaedic intervention (lost to follow-up) MRI, magnetic resonance imaging; SPE, septic pulmonary emboli; CT, computed tomography; DVT, deep-vein thrombosis Figure 1 (arrows) CT chest: multiple septic pulmonary emboli coagulase interacts with fibrinogen and causes plasma to clot. These predispose to the development of DVT adjacent to deep-seated foci of infection. 5,8 In a recent study of DVT associated with staphylococcal disease, transient prothrombotic abnormalities were present which normalised on follow-up. 5 We found no underlying prothrombotic state in any of our patients. In a study of ten children with septic pulmonary emboli (SPE), nine were owing to S. aureus, seven of which were community-acquired. 6 All but one of the isolates were MRSA. In another study in Houston, Texas, of nine children with DVT related to invasive staphylococcal disease, seven isolates were MRSA and septic pulmonary emboli were found in four. 5 In our study, the invasive staphylococcal disease was MSSA in all four patients. Considering the magnitude of invasive staphylococcal disease in developing countries, it is likely that many cases of venous thrombosis and pulmonary emboli are being missed, contributing to the high mortality of this disease. This might be partly because of a lack of appropriate haematological investigations and chest imaging. Furthermore, we speculate that the virulence of community-acquired staphylococcal disease, albeit methicillin-sensitive, has increased to a level approaching that seen in industrialised countries. In the absence of molecular analysis, the presence of genes encoding for PVL or PSMs remains speculative. Hence, molecular analysis of community-acquired S. aureus strains is warranted in India and other developing countries. The diagnosis of invasive S. aureus infection with pulmonary lesions should prompt the physician to search for DVT as a source for septic emboli. Doppler ultrasonography is a good tool for detecting DVT in the thigh and popliteal areas with a sensitivity of % and a specificity of %. 11 Paediatrics and International Child Health 2013 VOL. 33 NO. 1 51

4 Aggressive treatment with appropriate antibiotics, anticoagulation, surgical drainage, and assisted ventilation, when indicated, are the cornerstones for treatment of this life-threatening triad of staphylococcal infection, DVT and septic emboli. 7,8 Antibiotics should be continued for 4 6 weeks as the DVT acts as a deep-seated source of infection. Screening for prothrombotic conditions is necessary to decide the duration of anticoagulation. Therapeutic anticoagulation with heparin (unfractionated or low molecular weight) is recommended, followed by oral vitamin K antagonists (with INR monitoring); these may be discontinued after 3 months if no prothrombotic condition is found. 12 References 1 DeLeo FR, Diep B A, Otto M. Host defense and pathogenesis in Staphylococcus aureus infections. Infect Dis Clin North Am. 2009;23: Baranwal AK, Singhi SC, Jayashree M. A 5-year PICU experience of disseminated staphylococcal disease, part 2: management, critical care needs and outcome. J Trop Pediatr. 2007;53: Kabra SK, Jain Y, Kataria A, John S, Chatterjee A, Seth V. Disseminated staphylococcal disease. Indian Pediatr. 1996;33: Prasad R, Mishra OP, Pant P. Deep vein thrombosis with Staphylococcus aureus infection. Indian Pediatr. 2007;44: Gonzales BE, Teruya J, Mahoney DH, Hulten KG, Edwards R, Lamberth LB, et al. Venous thrombosis associated with staphylococcal osteomyelitis in children. Pediatrics. 2006;117: Wong KS, Lin TY, Huang YC, Hsia SH, Yang PH, Chu SM. Clinical and radiographic spectrum of septic pulmonary embolism. Arch Dis Child. 2002;87: Joshi MC, Baronia AK, Singh RK, Poddar B. Staphylococcal sepsis presenting with septic pulmonary embolism. Indian J Pediatr. 2010;77: Gorenstein A, Gross E, Houri S, Gewirts G, Katz S. The pivotal role of deep vein thromphlebitis in the development of acute disseminated staphylococcal disease in children. Pediatrics. 2000;106:E87. 9 Miller LG, Kaplan SL. Staphylococcus aureus: a community pathogen. Infect Dis Clin North Am. 2009;23: Nowak-Gottl U, Kosch A. Factor VIII, D-dimer, and thromboembolism in children. N Engl J Med. 2004;351: Elliott CG, Lovelace TD, Brown LM, Adams D. Diagnosis: imaging techniques. Clin Chest Med. 2010;31: Monagle P, Chalmers E, Chan A, de Veber G, Kirkham F, Massicotte P, Michelson AD. Antithrombotic therapy in neonates and children. Chest. 2008;133: S. 52 Paediatrics and International Child Health 2013 VOL. 33 NO. 1

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