Managing pulmonary embolism secondary to suppurative deep vein thrombophlebitis due to community-acquired Staphylococcus aureus in a resource-poor setting.

Deep vein thrombosis and pulmonary thromboembolism are rare and life threatening emergencies in children. We report an 11-year old female who presented with acute complaints of high grade fever, pain in the left thigh and inability to walk and breathlessness since 6 days. On physical examination, there was a diffuse tender swelling of the left thigh, tachypnea, tachycardia with hyperdynamic precordium and bilateral basal crepitations. Ultrasonography and venous doppler of lower limbs showed mild effusion of left hip joint and thrombus in the left common femoral vein and left external iliac vein suggesting a diagnosis of septic arthritis with thrombophlebitis. The tachypnea and tachycardia which was out of proportion to fever and crepitations on auscultation prompted suspicion of an embolic phenomenon. Radiograph of the chest revealed multiple wedge shaped opacities in the right middle zone and lower zone suggestive of pulmonary embolism and left lower zone consolidation. For corroboration, computed tomography pulmonary angiography and computed tomography of abdomen was performed which showed pulmonary thromboembolism and deep venous thrombosis extending up to infrarenal inferior vena cava. On further workup, magnetic resonance imaging of hips showed left femoral osteomyelitis and multiple intramuscular abscesses in the muscles around the hip joint. Blood culture grew methicillin resistant Staphylococcus aureus. Antibiotics were changed according to culture sensitivity and there was a dramatic response. After four weeks of anticoagulation and antibiotics the child became asymptomatic and thrombus resolved. Thus, it is crucial to consider methicillin resistant Staphylococcus aureus infection as an important infection when we encounter such a clinical scenario. This case report highlights an unusual and potentially life threatening presentation of a virulent strain of a common pathogen, which when diagnosed was completely amenable to treatment.

Case Details

Apreviously healthy 11-year-old female child of Asian Indian origin born of a non-consanguineous marriage presented with acute onset of high-grade fever and progressively worsening pain in the left thigh since 6 days and breathlessness since 3 days. Routine activities were restricted due to painful ambulation. Parents had not noticed swelling or redness of the affected limb and joints. On enquiry, there was no history of previous hospital admissions, local trauma or injection, bleeding diathesis, infective focus elsewhere in the body, underlying heart disease, diabetes mellitus, immunodeficiency, and tuberculosis or contact with a person affected by tuberculosis. There was no significant past or family history.

Question 1: What are the causes of unilateral limb pain causing severe limitation of movements?

Answer: Causes of unilateral limb pain with limitation of movement in childhood are enumerated in Table 1.[1]

Table 1

Differential diagnosis of unilateral limb pain in children

Pathology	Etiology
Infection/infection-related	Septic arthritis
	Osteomyelitis
	Reactive arthritis
	Toxic synovitis
	Lyme disease
Inflammatory	Rheumatic fever
	Juvenile idiopathic arthritis
	Systemic lupus erythematosus
	Henoch–Schonlein purpura
Malignancy	Leukemia
	Neuroblastoma
	Bone tumors (osteosarcoma, Ewing sarcoma)
Trauma/overuse	Fracture
	Soft tissue injury
	Osgood–Schlatter disease
	Hypermobility
Hematological	Hemophilia
	Sickle cell anemia
Orthopedic/mechanical	Slipped capital femoral epiphysis
	Legg–Calvé–Perthes disease

Case Details (Continued)

On examination, temperature was 40°C, pulse rate was 148/min, all peripheral pulses were well felt, respiratory rate was 44 breaths/min, and blood pressure was 108/70 mmHg. Personal hygiene was satisfactory. Respiratory distress was evident by subcostal and intercostal retractions. The weight and height were 38 kg and 146 cm, respectively, corresponding to the 50th centile (NCHS 2000 chart). There was pallor. Homan sign (deep pain in the calf muscle after dorsiflexion of ankle) and Moses sign (pain experienced by squeezing the calf muscle against tibia) were absent. On local examination, the left hip joint was flexed, abducted, and externally rotated. There was a diffuse, tender, circumferential swelling extending from the left hip joint to mid-thigh with erythema and edema of the overlying skin. A difference of 3 cm was noted in the limb girth at mid-thigh level (31 and 28 cm on left and right sides, respectively). Movements of the left hip and knee joint were painful but unrestricted. Examination of other joints was normal. Respiratory system examination revealed crepitations in bilateral infra-mammary areas. The only abnormality on cardiovascular system examination was a hyperdynamic precordium. Other systems were normal. On admission, arterial oxygen saturation by pulse oximetry on room air was 88%, which increased to 98% on supplementation of oxygen by face mask at 4 L/min.

Question 2: After examination, what was the likely differential diagnosis for the unilateral thigh swelling?

Answer: The likely differential diagnoses at this stage were cellulitis with septic arthritis or toxic synovitis of the left hip joint and osteomyelitis of the left femur.[12]

The preliminary investigations are summarized in Table 2. Since an infective etiology was suspected, intravenous ceftriaxone (100 mg/kg in two divided doses) and vancomycin (60 mg/kg in three divided doses) were started after sending blood culture within 1 h of admission.

Table 2

Preliminary investigations in our patient

Investigation	Result (normal range)
Hemoglobin	9.1 (12–15 g/dL)
Leukocyte count and differential count	21 × 109/L (4–10.5 × 109/L)
	80% neutrophils (54%–62%), 20% lymphocytes (25%–33%)
Platelet count	200 × 109/L (150–400 × 109/L)
C-reactive protein	128 (0.6-8.1 mg/L)
Erythrocyte sedimentation rate	35 mm at the end of 1 h (<30)
Serum electrolytes (Na+/K+/Cl−)	136/4/110 (135–145/3.5–4.5/106–110 mEq/L)
BUN, serum creatinine	12 (7–18 mg/dL), 0.6 (0.31–0.88 mg/dL)
Serum albumin, total bilirubin	4.2 (3.5-5.6 g/dL), 0.8 (<1 mg/dL)
AST/ALT	23/28 (10-40/5–45 U/L)
Random blood sugar	78 (60-100 mg/dL)
Prothrombin time/INR	14.3/1.1 (11-15/<1.2)
Arterial blood gas (on room air)	pH 7.38, PaCO2 41 mm Hg, PaO2 68 mm Hg,
On 4 L/min of oxygen	HCO3-21 mmol/L, SpO2 89%
	pH 7.41, PaCO2 38 mm Hg, PaO2 91mm Hg, HCO3-20.6 mmol/L, SpO2 99%
Ultrasonography of left thigh	Mild joint effusion in the left hip joint; no soft tissue changes, muscular plane normal
HIV ELISA test	Non-reactive
NBT	Normal
Lymphocyte subset assay	Normal

BUN: Blood urea nitrogen, AST: Aspartate aminotransferase, ALT: alanine aminotransferase, INR: International normalized ratio, HIV: Human immunodeficiency virus, ELISA: Enzyme-linked immunosorbent assay, NBT: Nitro blue tetrazolium test

Question 3: What is the explanation for respiratory involvement in this case? What would be the investigations of choice to determine the nature of respiratory involvement?

Answer: Our patient developed symptoms (breathlessness) and signs (tachypnea, crepitations, and hypoxia) suggestive of respiratory system involvement after the initial symptoms of fever and limb pain. This temporal association suggests that the respiratory system could be involved secondary to the original limb pathology. The usual etiology could be pneumonia due to hematogenous spread of infection from the limb or sepsis. Pulmonary embolism was another possibility, the source of emboli being vegetations from right side infective endocarditis (secondary to bacteremia from the infective focus in the limb). An exceptional occurrence is the development of pulmonary thromboembolism (PTE) secondary to suppurative deep vein thrombosis (DVT) following an infective process such as septic arthritis or osteomyelitis.[345] Whereas association of septic PTE has been reported earlier with Lemierre's syndrome and right side infective endocarditis due to intravenous drug use, vascular catheters, or implantable devices[6]; recent papers have highlighted a change in the epidemiology of septic PTE. Septic PTE is now reported to occur secondary to septic thrombophlebitis as a result of deep soft tissue or bone infections of the extremities.[67]

Further investigations planned were chest radiograph, lower limb venous Doppler examination, electrocardiogram (ECG), and two-dimensional echocardiography.

Chest radiograph showed wedge-shaped opacities in the right middle and lower zones suggestive of pulmonary embolism and left lower zone consolidation [Figure 1]. On Day 2 of admission, venous Doppler of both the lower limbs showed left common femoral vein and external iliac vein thrombosis. ECG and two-dimensional echocardiography were normal. Anticoagulation with subcutaneous administration of injection enoxaparin in a dose of 1 mg/kg in two divided doses was started. Computed tomography (CT) pulmonary angiography, which is the definitive diagnostic modality for PTE, showed multiple hemorrhagic infarcts in bilateral lung parenchyma involving the middle and lower zones in our patient [Figure 2]. CT abdomen was done to delineate the extent of thrombosis, which revealed that the thrombus was extending inferiorly from the infrarenal segment of the inferior vena cava to involve the left common femoral vein, external iliac vein, and common iliac vein. Thus, the diagnosis of extensive DVT with PTE was confirmed.[8]

Figure 1

Chest radiograph (frontal view) at presentation showing multiple wedge-shaped opacities suggestive of pulmonary infarcts in the right middle and lower zones with left lower zone consolidation

Figure 2

Computerized tomography pulmonary angiography (axial section) lung window showing nodular opacities (open arrows) scattered through bilateral lung fields with peripheral pleural based wedge opacities suggestive of embolic infarcts with left lower zone consolidation (solid arrow)

Despite 5 days of empirical antibiotic therapy (ceftriaxone + vancomycin), fever and local signs of inflammation persisted, along with worsening of the respiratory status requiring bilevel positive airway pressure (BiPAP) ventilation. Magnetic resonance imaging (MRI) of the hip joint along with diagnostic and therapeutic aspiration of the joint fluid was planned. The critical condition of the child did not permit immediate imaging and aspiration. Meanwhile, the blood culture report was available and it revealed growth of methicillin-resistant Staphylococcus aureus (MRSA). Initial antibiotics were substituted by intravenous linezolid (30 mg/kg in three divided doses) according to the sensitivity pattern showing minimum inhibitory concentration of 0.4–3 μg/mL for linezolid. Vancomycin discs for sensitivity testing were not available in our institute while our patient was being treated. Within 48 h of commencing linezolid, there was a dramatic clinical response with resolution of fever, reduction of limb swelling and pain, and gradual reduction in oxygen requirement. BiPAP ventilation was discontinued after 2 days and oxygen support could be withdrawn after 5 days. Limb MRI could be performed after 16 days of admission (22 days after onset of symptoms). Abnormal hyperintense signals were noted on the MRI involving the left femoral proximal metaphysis and epiphysis, lesser trochanter and greater trochanter, and effusion of left hip joint [Figure 3]. In addition, there were multiple abscesses in the left vastus medialis, vastus lateralis, iliacus, and quadrates lumborum muscles (the largest abscess measured 3 × 1.5cm) and mild effusion of the right hip joint. Thus, our patient had an unusual complication of septic PTE due to suppurative deep vein thrombophlebitis with primary infective focus being left femoral osteomyelitis, septic arthritis, pyomyositis, and cellulitis [Figure 3]. The effusion of the right hip joint could be an early stage of infective arthritis as a part of the disseminated Staphylococcus infection.

Figure 3

Magnetic resonance imaging of hip (STIR) coronal image showing abnormal T2 hyperintensity in the marrow (arrow) of the left proximal femur involving the epiphysis, metaphysis, lesser trochanter, and greater trochanter suggestive of osteomyelitis with bilateral hip joint effusion

Question 4: What could be the reason for multifocal infection with CA-MRSA in a previously healthy girl?

Answer: Our patient was previously healthy, had no prior hospitalization, and the parents did not recall any obvious trauma. The infection was most likely due to community-acquired MRSA (CA-MRSA) causing septicemia and complications due to widespread local infection. The spectrum of infections due to CA-MRSA includes severe multifocal disease manifesting as necrotic skin lesions, abscesses, arthritis, and osteomyelitis complicated by deep vein thrombosis and severe necrotising pneumonia.[910] High virulence of S. aureus, including CA-MRSA has been attributed to Panton–Valentine leukocidin (PVL)[10] which is a cytotoxin causing leukocyte destruction and tissue necrosis.[11] A polymerase chain reaction (PCR) test for PVL genes (lukS-PV and lukF-PV) and simultaneous discrimination of MRSA from methicillin-sensitive strains of S. aureus has recently been developed.[12] Detection of PVL carrying S. aureus has been performed in India for research purposes.[13] However currently, PCR for PVL and identification of MRSA genes and immunological tests for PVL are neither available commercially nor for research basis locally or at other centers in India. Therefore, these tests, although indicated, could not be performed in our patient.

Question 5: What is the antibiotic of choice for treatment of severe CA-MRSA infection?

Vancomycin is the antibiotic of choice for treatment of bone and joint infection and/or severe sepsis due to CA-MRSA infection in children.[14] However, it is critical to recognize and treat persistent methicillin-resistant S. aureus bacteremia (MRSAB) as it is both limb and life-threatening.[15] Alternative approaches to treat MRSAB should be considered within 3–4 days of persistent MRSAB.[16] As our patient was clinically deteriorating despite 5 days of therapy with vancomycin, we substituted vancomycin + ceftriaxone with intravenous linezolid according to published recommendations.[16] Linezolid is considered appropriate for the treatment of complicated MRSA skin and soft tissue infections, including the treatment of lower extremity infections as it achieves high penetration into skin and soft tissues.[17]

Question 6: Since DVT in our patient is a known complication of osteomyelitis and arthritis caused by MRSA, are additional investigations required to determine other risk factors predisposing to DVT?

Answer: Our previously healthy patient did not have risk factors for thromboembolism at the time of initial presentation. Knowing that DVT with PTE is a well-documented complication of bone and joint infection and severe sepsis caused by MRSA, investigations for thrombophilia in such a patient can be avoided in a resource-limited setting. Though we could not test for PVL, it seemed prudent to rule out an underlying thrombophilia in presence of extensive DVT and PTE as coexisting inherited thrombophilia would determine requirement for long-term anticoagulation therapy.[18]

Laboratory work-up for thrombophilia [serum homocysteine, factor V Leiden mutation (G1691A mutation of F5 gene), prothrombin G20210A mutation, and measuring levels of protein C, protein S, and antithrombin III] was sent before starting enoxaparin on day 2 of admission which showed low protein C value of 32%, suggestive of protein C deficiency (normal range of 60%–150% for age and sex).[1819] The results of investigations for thrombophilia are shown in Table 3.

Table 3

Results of investigations for thrombophilia

Tests	Patients’ value	Normal range
Antithrombin III	86%	70%-140%
Factor V leiden mutation	Not detected
Prothrombin gene (20210 A) mutation	Not detected
Serum homocysteine	1.9 µmol/L	<2.5 µmol/L
Protein C level	32%	60%-150%
Protein S level	80%	60%-150%

Question 7: What is the interpretation for low protein C activity in our patient?

Answer: Protein C deficiency is tested by measuring protein C antigen level (quantitative) via enzyme-linked immunosorbent assay (ELISA). Protein C deficiency is a rare inherited autosomal recessive disorder.[19] Patients with homozygous deficiency manifest symptoms in early life in the form of purpura fulminans, cerebral thrombosis, ophthalmic thrombosis, disseminated intravascular coagulation, and large vessel thrombosis.[18] Heterozygous deficiency occurs in 0.2% of the population, and among these, 3% present with venous thromboembolism.[19] In our patient, the presentation was late, without any past history or family history of thromboembolism, and therefore, homozygous protein C deficiency would be less likely.

Low values of protein C are also encountered as an acute phase reaction or secondary to acute thrombosis, infection, inflammation, hepatic dysfunction, and vitamin K antagonist (protamine sulfate) use.[19] Therefore, in our patient, the low protein C activity was attributable to an acute thrombotic state secondary to infection.

After 4 weeks of treatment with anticoagulants, repeat lower limb venous Doppler revealed complete recanalization of left common femoral vein, external iliac vein, common iliac vein, and infrarenal inferior venous cava with no residual thrombus.

Question 8: What was the long-term monitoring plan for this patient?

Answer: Antibiotic therapy is recommended for 4–6 weeks in such cases.[20] Our patient received intravenous linezolid for 3 weeks, after which the patient improved clinically and was transitioned to oral linezolid (10 mg/kg/dose thrice a day) for 3 weeks (total duration of 6 weeks).[20] Enoxaparin was continued for 3 months and then stopped.[18] Documentation of normal protein C level by repeat testing after resolution of the acute thrombotic episode and discontinuation of anticoagulation therapy ruled out primary inherited protein C deficiency. Due to the dynamic state of growth in children, sequelae of skeletal infections might not become apparent for months or years, and therefore long-term follow-up is necessary with close attention to range of motions and bone length in the affected limb.[20]

Conclusion

Multifocal, deep-seated, fulminant infection complicated by severe sepsis and/or DVT in a previously healthy immunocompetent child should arouse suspicion of infection due to an organism like highly virulent CA-MRSA. Early, aggressive, and pragmatic treatment is necessary to successfully treat a child who is critically ill due to CA-MRSA infection. Vancomycin is the drug of first choice in the treatment of CA-MRSA. However, in the absence of sensitivity testing for vancomycin and especially when there is persistent MRSAB beyond 3–4 days, it is prudent to consider alternative approaches to treating this life-threatening infection. The present case amply demonstrates that in a resource-poor setting wherein optimal antibiotic sensitivity testing facility may not be available, a prudent and pragmatic decision has to be taken in deciding not only the first-line antibiotics (vancomycin + ceftriaxone) but also knowing when to change the antibiotics (to linezolid) while treating persistent CA-MRSAB (CA-MRSA bacteremia).

Declaration of patient consent

The authors certify that appropriate patient consent was obtained.

Financial support and sponsorship

Nil.

Conflicts of interest

Dr. Sunil Karande is the editor of the Journal of Postgraduate Medicine.