Recurrent pulmonary embolism in a boy with antiphospholipid syndrome

doi:10.4236/crcm.2013.25083

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Vol.2, No.5, 310-314 (2013) Case Reports in Clinical Medicine

http://dx.doi.org/10.4236/crcm.2013.25083

Recurrent pulmonary embolism in a boy with

antiphospholipid syndrome

Christian Müller1*, Christian Willaschek1, Mathias Borst2, Reiner Buchhorn1

1Department of Pediatrics, Caritas Krankenhaus, Bad Mergentheim, Germany; *Corresponding Author: [email protected]

2Department of Medicine, Caritas Krankenhaus, Bad Mergentheim, Germany

Received 2 October 2012; revised 16 November 2012; accepted 8 December 2012

which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

ABSTRACT

We report a 14-year-old patient with recurrent

pulmonary embolism due to catastrophic anti-

phospholipid syndrome (APS) with severe pul-

monary inflammation. We considered elevated

antibodies against cardiolipin and anti-beta2-

glycoprotein-1, but no clinical nor laboratory

manifest atio ns of syst emic lupus erythem atosus

(SLE). Pulmonary embolism had been the first

manifestation of catastrophic APS in this patient.

We prescribed warfarin and systemic corticos-

teroids. A second embolism appeared during

anticoagulation with warfarin. This event led to a

marked decrease of his physical performance

due to his obstructive and restrictive lung dis-

ease. Anticoagulation was changed from enteral

warfarin to subcutaneous enoxaparine. We also

prescribed inhaled corticosteroid which led to

an improvement of his respiratory symptoms

and overall poor physical condition.

Keywords: Pulmonary Embolism; Antiphospholipid

Syndrome; APS; Inhaled Corticosteroid

1. INTRODUCTION

APS is a rare disease, especially in children [1]. As

opposed to the secondary form of APS occurring in pa-

tients with autoimmune disorders, predominately SLE.

APS is said to be primary if there are no features of SLE

or other autoimmune disorders [1,2].

Clinical manifestations of primary APS are variable

[3]: one feature is pulmonary embolism [4] which in one

case study occurred in 2.1% of patients with APS [5].

Especially in children, pulmonary embolism associ-

ated with APS is rare [6], but may be its first manifesta-

tion [2].

Chronic thromboembolic pulmonary hypertension (CTE-

PH) due to APS is a severe disease with high morbidity

and mortality [2,7]. Histopathologically, there may be

signs of catastrophic APS such as alveolar hemorrhage,

microvascular thrombosis and pulmonary capillaritis, which

is the most severe course of high mortality due to multi-

ple vascular occlusive events [8]. Pulmonary embolism

in APS associated with fever and elevated autoantibodies

are usually caused by SLE. Diagnosis of SLE is based on

clinical and laboratory features according to the classifi-

cation criteria [9-12]. Because there was no evidence of

autoimmune disorders the present case was classified to

primary APS.

2. CASE REPORT

We report a 14-year-old male in good overall physical

condition (BMI: 19.6 kg/m2) with no history of severe

diseases. He did not consume any medication, nicotine,

alcohol, or other drugs. The familial history was unre-

markable. He presented with acute chest pain and fever

up to 40˚C having lasted for one week. There was no

trauma recalled by the patient or his family. He presented

with pain, which was located in the right hemithorax and

increased in intensity when in supine position. During

physical examination a reduced respiratory sound over

his right lower pulmonary lobe was found.

Chest x-ray showed a consolidation in the right lower

pulmonary lobe. C-reactive protein (CRP) was elevated

to 9.37 mg/dL. An initial diagnosis of pneumonia was

made and antibiotic therapy (Cefuroxim, Doxycycline,

Gentamicin) was initiated.

Five days later there was no clinical improvement. A

computed tomography (CT) scan of the thorax (Figure 1)

showed signs of past pulmonary embolism in the right

lower lobe. We started effective anticoagulation with

intravenous heparin and enhanced the antibiotic therapy

(Cefuroxim, Doxycycline, Gentamicin and Vancomycin).

An ultrasound examination showed a deep venous throm-

bosis of the left lower extremity. The patient’s clinical

C. Müller et al. / Case Reports in Clinical Medicine 2 (2013) 310-314 311

Figure 1. Primary thoracic computerized tomography.

conditions deteriorated and because of respiratory failure

with tachypnea he needed supplemental oxygen.

A CT-guided lung biopsy demonstrated changes sug-

gesting a hemorrhagic pulmonary infarct. Moreover, fea-

tures of catastrophic APS such as capillary inflammation,

microvascular thrombosis and alveolar haemorrhage were

found [4,13]. A malignant transformation was excluded

by means of a bone marrow biopsy.

Laboratory analyses demonstrated elevated autoanti-

bodies directed against cardiolipin and anti-beta2-glyco-

protein-1 on several occasions. Antinuclear antibodies,

dsDNA-antibodies, anti-SM-antigen and SSA-antigen were

negative. Based on the laboratory results and the histo-

logical findings the diagnosis of catastrophic APS was

made.

Intravenous glucocorticosteroid therapy (methyl pred-

nisolone 150 mg/d) was begun. Body temperature de-

creased from 39.8˚C to 37.0˚C within twelve hours and

the clinical condition improved. Anticoagulation therapy

was changed from heparin to warfarin [14,15] with a

target INR of 2.0 - 3.0. The patient was equipped with an

INR home monitoring system. Compression stockings

were prescribed.

Two weeks later the patient suddenly felt acute chest

pain in the left hemithorax, consistent with pleuritic pain.

He reported shortness of breath and dyspnea. His body

temperature was normal. The INR was 2.18. A second

CT scan of the thorax showed a new pulmonary embo-

lism in the left lower lobe.

Therapeutic options such as thrombolysis, embolec-

tomy, and plasmapheresis were discussed.

Finally we decided to change the anticoagulation to

subcutaneous enoxaparine (2 × 60 mg/d). Warfarin and

corticosteroid therapy was tapered.

Six weeks later during an outpatient visit the boy com-

plained about generalized malaise. He felt that he was

unable to attend school. Cardiopulmonary exercise (CPX)

testing showed an impressive reduce of peak oxygen

uptake with predominant pulmonary limitation (Table 1).

Pulmonary hypertension was excluded by echocardiogra-

phy. Also congestive heart failure appeared very unlikely

as NT-Pro-BNP levels were normal (Ta bl e 2). However,

heart rate variability was reduced as determined by

Holter ECG.

We decided to treat the suspected pulmonary inflam-

mation with inhaled corticosteroids (fluticasone). A rea-

peted CPX test and Holter ECG showed an impressive

improvement of exercise capacity and heart rate variabil-

ity (Table 1). Nearly 5 months later the patient com-

plained of erythema and urtication after injection of sub-

cutaneous enoxaparine. We changed his anticoagulation

therapy from subcutaneous enoxaparine to moderate-in-

tensity warfarin and low dose acetylsalicylic acid (ASS)

[16]. As before, target INR was 2.0 - 3.0. Laboratory

analyses showed a progressive improvement of CRP and

D-Dimer values (Table 2).

3. DISCUSSION

Pulmonary embolism in our patient was the first mani-

festation of primary APS [2]. The diagnostic criteria of

SLE [9] were not met because no organ manifestations

other than deep vein thrombosis with pulmonary embo-

lism were present and specific laboratory features were

negative. However, septic fever unresponsive to antibi-

otics and the impressive clinical improvement after the

first dose of corticosteroids clearly indicate the inflam-

matory origin of our patient’s disease. Systemic corti-

costeroid therapy could be terminated after 5 weeks.

Despite an evidence based anticoagulation with war-

farin [14,15] the patient developed a second pulmonary

embolism two weeks after discharge from hospital. In

this situation he was at risk for the development of

CTEPH that usually has a fatal outcome in APS patients

[4]. Together with the patient and his parents, we decided

against plasmapheresis [17] or local therapies like throm-

bolysis [18-20] or vena cava filter [21,22].

After a therapeutic switch to subcutaneous enoxa-

parine and thereafter to warfarin and low dose ASS [23]

a progressive decrease of D-Dimer values were observed

(Table 2).

We had no evidence for heart failure indicated by

normal pro-BNP values or for pulmonary hypertension

indicated by normal tricuspid regurgitation velocity (Ta-

ble 2). However, for complete clinical recovery and res-

titution of his exercise capacity the patient depended on

inhaled corticosteroid therapy (Table 1), upon our hy-

pothesis of persistent pulmonary inflammation.

4. CONCLUSION

In summary, this case shows that pulmonary inflam-

C. Müller et al. / Case Reports in Clinical Medicine 2 (2013) 310-314

312

Table 1. Monitoring by spirometry and Holter ECG before and after inhaled corticosteroid.

Before fluticasone After fluticasone Reference values

Spirometry

Vital capacity [L] 2.57 3.09 4.3

FEV1 [L] 1.35 2.76 3.6

FEV1/VC [% pred.] 52.4 107.2 >75

Spiroergometry

VO2 peak [L/min/m2] 21.1 31.0 >25

VE peak [L/min] 51 86 104

Breathing reserve [%] 0 11 28

RQ 0.97 1.06 >1

Heart rate max [1/min] 173 175 187

Holter ECG

Mean heart rate [1/min] 99 88 85

Triangle index 16 33 22 - 52

pNN50 [%] 1,68 7,58 5 - 47

SDNN [ms] 70 119 102 - 180

RMSSD [ms] 23 36 15 - 39

FEV1: forced exspiratory volume in one second; W: Watts; VE: minute ventilation; RQ: respiratory quotient; VO2: oxygen uptake. Holter ECG: electrocardi-

ography 24 h; pNN50: number of pairs of adjacent NN intervals differing by more than 50 ms divided by the total number of all NN intervals; SDNN: standard

deviation of all NN intervals; RMSSD: the square root of the mean of the square of differences between adjacent NN intervals.

Table 2. Laboratory values and echocardiographic parameters during the whole treatment.

1. embolism acute 1. embolism subacute2. embolism Discharge 2 months later 4 months later Reference

values

Therapy Antibiotics Corticoid aspirine

heparine

Corticoid

warfarin Enoxaparine Enoxaparine

fluticasone

Warfarin ASS

fluticasone

Laboratory

CRP [mg/dl] 6.3 0.4 1.36 1.78 0.18 0.34 0 - 1

INR 1.23 0.99 2.18 1.02 1.1 2.27 0.8 - 1.25

PTT [s] 103.6 76.4 55.3 114.4 104.5 67.3 28 - 40

D-Dimers [μg/l] 7620 2980 900 1730 230 50 0 - 500

NT-proBNP [pg/ml] 64.1 <5 19.6 0 - 85

Cardiolipin IgG 66 14 52 <10

Cardiolipin IgM <5.0 <5.0 <5.0 <7

β-2-Glykoprotein IgG 69 13 40 <10

β-2-Glykoprotein IgM 7 21 3 <12

LVEDD [mm] 42 43 40 44 43 43 35 - 51

FS [%] 42 36 36 45 46 35 >30

TI [m/s] 2.4 2.2 2.2 2.4 2.5 <2.5

(PASP [mmHg]) (28) (25) (25) (28) (30) (20 - 30)

CRP: C-reactive protein; INR: international normalized ratio; PTT: partial thromboplastin time; BNP: N-terminal pro brain natriuretic peptide; LVEDD: left

ventriclular enddiastolic diameter; FS: fractional shortening; TI: tricuspidal regurgitation velocity; PASP systolic pulmonary arterial pressure derived from TI;

Ig: Immunglobuline.

C. Müller et al. / Case Reports in Clinical Medicine 2 (2013) 310-314 313

mation can play an important role in manifestation of

primary APS that requires consequent immunosuppres-

sant treatment. Inflammation and anticoagulation have to

be monitored by D-Dimer values, CRP values and spe-

cific tests that depend upon the regiments.

A critical cardiopulmonary monitoring including echo-

cardiography, ECG, spirometry, CPX and Holter ECG is

necessary to recognize pulmonary hypertension and de-

creased endurance of the patient. Cardiac limitations due

to pulmonary hypertension may be treated by endarter-

ectomy or endothelin receptor antagonist, if patients are

deemed inoperable.

In patients with only pulmonary limitations like in our

case inhaled corticosteroid seems to be a good course of

treatment.

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ABBREVIATIONS

APS: antiphosphorlipid syndrome

ASS: acetylsalicylic acid

BMI: body mass index

CPX: cardiopulmonary exercise

CT: computed tomography

CTEPH: chronic thromboembol pulmonary hypertension

ECG: electrocardiography

INR: international normalized ratio

SLE: systemic lupus erythematosus