Table 1
Patient (No.)
|
Sex (w/m)
|
Genetic mutation
|
Age at diagnosis (years)
|
Period of CVC use
(age in years)
|
Cumulative months of CVC use
|
Age at follow-up (years)
|
Venous access at follow-up
|
1
|
w
|
LDLR homozygous
|
3
|
5 to 7
|
24
|
8
|
peripheral
|
2
|
w
|
LDLR homozygous
|
2
|
4 to 6
|
23
|
7
|
peripheral
|
3
|
w
|
LDLR homozygous
|
2
|
5 to 7
|
30
|
8
|
peripheral
|
4
|
m
|
LDLR homozygous
|
1
|
3 to 5
|
8
|
7
|
AVF
|
Initially, the permanent CVCs were surgically implanted in four children with hoFH (three girls, one boy) aged 3 to 5. All patients started with biweekly LA, later intensified to weekly intervals for three of them. Patient 4 had several CVC complications and therefore received an AVF eight months later, at the age of 5 years. The venous situation and tolerance to peripheral venous punctures progressively improved in the three female patients; therefore, CVCs could be removed at the age of 6 years in one girl and 7 years in the other two. (Table 1).
All four children needed iron supplementation throughout LA, indicating chronic iron deficiency anemia.
Mean baseline LDL-C levels with a maximum dose of lipid-lowering medication before the start of LA ranged from 535 to 742 mg/dL. With LA, mean LDL-C levels decreased to 244 up to 411 mg/dL pre-LA, and 76 up to 154 mg/dL post-LA (Table 2). Thus, LA reduced LDL-C levels by more than 60% in all four children. As a positive side effect, LA also decreased Lipoprotein (a), if elevated (not shown).
In three children undergoing weekly LA procedures, the pre-LA LDL-C remained high one week after LA, with values between 252 to 411 mg/d, whereas one girl continued biweekly sessions, with pre-LA LDL-C values of around 244 mg/dL two weeks after LA (Table 2).
Table 2
LA treatment: Lipid levels at baseline and after 3 years of LA.
Pat.
|
LDL-C [mg/dL] on max. oral medication
|
Steady state Pre-LA
LDL-C [mg/dL]
|
Steady state Post-LA
LDL-C [mg/dL]
|
1
|
688.8A
|
411.2
(288.8-564.6)
|
153.5
(113.8-227.8)
|
2
|
535.4
(534.8–536.0)
|
337.2
(265.0-443.0)
|
104.7
(84.8-151.6)
|
3
|
597.1
(521.2–732.0)
|
244.2B
(223.0-287.4)
|
81.0 B
(67.4–99.0)
|
4
|
742.0A
|
251.7
(205.0-297.4)
|
76.4
(57.2–94.8)
|
Values are displayed as means, minimum and maximum over a period of 3 months
Aonly one measurement available
Bbiweekly
|
Values at baseline are on maximum oral medication with statins and ezetimibe in all patients and colesevelam in patient 2. Lipid values were measured before and after weekly/biweekly LA.
Between October 2016 and November 2019, the four patients had a total of 106, 104, 75, and 94 LA sessions, respectively. In patient 1, starting LA aged 5, the critical peripheral venous situation required a CVC implantation due to high blood flow. Infections and accidental self-removal of the CVCs occurred five times, and in between, several unsuccessful venous punctures were attempted, which were painful and stressful for the child, despite extensive psychological support. Nine LA sessions were missed, and four were interrupted. The implantation of a new CVC stabilized LDL-C values.
After three years of LA treatment, skin xanthomas decreased or disappeared in all patients. (In detail, patient 1 showed a remission of the xanthoma on the elbows, knees, and upper legs. In patient 2, the xanthoma on both Achilles tendons, knees, and dorsum of both feet nearly disappeared except for small residues on the left knee and right Achilles tendon. In patient 3, the xanthoma on hands, knees, and dorsum of both feet decreased, and the arcus lipoides diminished. Patient 4 showed complete remission of the xanthoma on both Achilles tendons, right knee, and left foot dorsum.)
Pre-treatment echocardiography revealed mild aortic insufficiency in two children, while another child had mild aortic insufficiency at 3-year follow-up. Three children showed increased age- and gender-specific baseline carotid IMT levels, which remained unchanged, decreased, or normalized after three years of LA treatment. Patient 1 developed a new vascular plaque formation in the left external carotid artery, without hemodynamic significance. Before starting LA, a coronary CT angiography performed on all patients revealed normal coronary arteries without plaque formation or stenosis.
Table 3
Complications
|
Number total
|
Number of patients
with at least 1 event
|
Infections
|
9
|
4
|
-) Systemic infection: Sepsis/SIRS
|
3
|
2
|
-) Systemic infection: CRBSI
|
4
|
2
|
-) Local CVC-infection
|
2
|
1
|
Mechanical
|
9
|
3
|
-) Self-removal by accident
|
6
|
3
|
-) Dislocation
|
3
|
2
|
Malfunction: occlusion
|
0
|
0
|
Thrombosis
|
0
|
0
|
Complications associated with implantation
|
0
|
0
|
Other: Pneumo-Mediastinum/Pericard
|
1
|
1
|
Different subgroups defined as CVC related complications. Each patient suffered from at least one infection, in 3 cases sepsis occurred. The most frequent complication was accidental self-removal of the catheter. CRBSI: Catheter-Related Blood Stream Infection
Complications associated with CVCs are listed in Table 3. Infections and mechanical complications occurred most frequently. All four patients suffered from a bacterial infection progressing to bacterial sepsis in three instances (Table 3): Staphylococcus aureus in five cases and Plesiomonas shigelloides in one.
Patient 1 was hospitalized twice for 13 and 15 days, respectively, due to catheter-related sepsis caused by Staphylococcus aureus, and each time a new CVC had to be implanted. The family excluded the option to place an AVF. Thus, patient 1 had a total of four CVC replacements over a 3-year period (Table 4).
Patient 2, who presented with catheter related complications twice, had an CRBSI event that resolved without further issues. Plesiomonas shigelloides was identified in the blood culture.
Patient 3 experienced one severe complication shortly after the first CVC implantation and had to be hospitalized with Systemic Inflammatory Response Syndrome that later induced Staphylococcal Scalded Skin Syndrome.
Patient 4 had multiple catheter-related complications in the first year of LA: four CVC dislocations, leading to catheter loss twice, and three episodes of CRBSI requiring hospitalization. Therefore, he received an AVF eight months later (Table 4).
Mechanical complications such as accidental self-removal and dislocation of the CVCs occurred in three children. Patient 1 needed five CVCs in total (Table 4).
In two girls, patients 2 and 3, CVCs were stable and could be used for 595 days (19 months) and 698 days (23 months), respectively (Table 4). After accidental self-removal in patient 2 at the age of 6, the switch to peripheral punctures succeeded, thanks to the emotional support given by the child’s mother. Peripheral puncture attempts in patient 3 at the age of 7 were less successful due to anxiety, stress, and psychological pressure, requiring implantation of a new CVC 1.5 months later.
Aged 6, patient 1 referred thoracic pain and dyspnea suddenly after a ball shot to the upper thorax during school sports. Small pneumomediastinum and pneumopericardium were diagnosed, and the girl was hospitalized for observation. The CVC was still intact, and the air was rapidly absorbed without further complications.
No other catheter-related complications like occlusion, venous thrombosis, or perioperative problems were observed (Table 3). Ultrasound measurement always showed normal central veins anatomy and blood flow.
Table 4
Site of venous access, dwell time and reason for removal of CVC per patient in chronological order
Patient (No.)
|
Site of venous access
|
dwell time in days
|
reason for removal
|
1
|
|
|
|
|
V. jug. sin.
|
19
|
Sepsis
|
|
V. subcl. sin.
|
411
|
Sepsis, Self-removal by accident
|
|
V. jug. sin.
|
51
|
Self-removal by accident
|
|
V. subcl. dex.
|
66
|
Self-removal by accident
|
|
V. subcl. sin.
|
183
|
Dislocation, local infection
|
|
Peripheral access
|
at the age of 7 years
|
|
2
|
|
|
|
|
V. subcl. sin.
|
698
|
Self-removal by accident
|
|
Peripheral access
|
at the age of 6 years
|
|
3
|
|
|
|
|
V. jug. sin.
|
14
|
Sepsis
|
|
V. subcl. sin.
|
595
|
Elective removal
|
|
V. subcl. dex.
|
280
|
Elective removal
|
|
Peripheral access
|
at the age of 7 years
|
|
4
|
|
|
|
|
V. jug. sin.
|
71
|
Self-removal by accident
|
|
V. subcl. sin.
|
55
|
CRBSI, Self-removal by accident
|
|
V. jug. dext.
|
102
|
CRBSI
|
|
AVF
|
at the age of 5 years
|
|
Mean dwell time per catheter
|
212
|
|
Two girls, patients 2 and 3 tolerated the CVCs with only few complications and maximum dwell times of 698, and 595 days, respectively. Patients 1 and 4 suffered from repeated infections and dislocations, therefore, patient 4 received an AVF after eight months of LA. CRBSI: Catheter-Related Blood Stream Infection
In total, there were 12 (re)implantations of CVCs in four young children with hoFH treated with LA over three years. Patency of CVCs was most difficult to maintain within the first months. Six out of twelve CVCs were still in place after three months. Predominant reasons for early CVC loss were infection or accidental self-removal. Long-term patency rates were otherwise stable.