Septic shock with petechial and/or purpuric rash is a life-threatening clinical syndrome predominantly caused by Neisseria meningitidis and characterised by a sudden onset and rapid progression in previously healthy young children and adolescents.1

Unfortunately, despite advances in understanding the pathogenesis of meningococcal septic shock (MSS) and the increase in therapeutic interventions, there is still high morbidity.2 Haemorrhagic skin necrosis, caused by disseminated intravascular coagulation, can lead to permanent cutaneous lesions. In severe cases, widespread vascular thrombosis causes irreversible ischaemia of digits and even limbs.

There are few data in the literature on the incidence and severity of long-term cutaneous and orthopaedic sequelae of MSS.3^–7 In addition, the risk factors for developing these sequelae are not well defined.

Better understanding of the long-term cutaneous and orthopaedic sequelae of MSS and their risk factors could lead to different management in the paediatric intensive care unit (PICU) and to anticipatory follow-up care for these patients after discharge from the PICU.

The aim of this study was to investigate the incidence and severity of long-term skin scarring and orthopaedic sequelae in patients who survived MSS in childhood. Additionally, we determined the predictors of these sequelae.

METHODS

Patient selection

This study investigated the medical and psychological follow-up of a cross-sectional cohort of all consecutive surviving patients with septic shock and purpura requiring intensive care at least 4 years previously (between August 1988 and October 2001). Patients were recruited from the PICU of the Erasmus MC-Sophia Children’s Hospital, a tertiary care university hospital. Patients aged 1 month to 18 years with a clinical picture of MSS, defined as septic shock with petechiae/purpura, requiring intensive care were eligible.8 Milder cases admitted to a general ward were excluded. The Medical Ethics Committee of the Erasmus Medical Center approved the study protocol. Informed consent was obtained from patients and parents who were sent a standard letter requesting their participation in the study. Patients and parents who were not Dutch speaking were excluded. Patients and parents who agreed to participate were sent an invitation to the follow-up clinic. The follow-up took place in 2005–2006.

Data analysis at the time of PICU admission

During the study period patients consecutively admitted with septic shock and purpura were included in several sepsis studies.9^–14 Severity of illness was determined using the Pediatric Risk of Mortality score (PRISM), Vasopressor score (VAS score) and Disseminated Intravascular Coagulation score (DIC score).15^–17

Assessment methods

Patients and parents were invited to the follow-up clinic 4–16 years after PICU discharge and were interviewed by one author (CB) using a standard questionnaire on the presence of skin scarring and orthopaedic sequelae, and medical care regarding these sequelae in the period after PICU discharge. A general physical examination of patients by one author (CB) was performed with special attention being given to skin scarring and orthopaedic sequelae (amputation, angular deformity and limb-length discrepancy). The Patient and Observer Scar Assessment Scale (POSAS) scoring system was used by a senior dermatologist (AO) to evaluate skin scarring (appendix A). POSAS, one of the very few validated scoring systems to assess the severity of skin scarring, is designed to assist assessment of scar severity, based on the opinion of both the doctor and the patient.18 All items are be scored on a scale from 1 (representing normal skin) to 10 (the worst possible scar). We also used a visual analogue scale with a score from 0 (worst possible scar, poorly healed scar) to 10 (normal skin, well healed scar). This scale was used by both parents and patients.19 20

All skeletal radiographs in patients with angular deformity and limb-length discrepancy were re-evaluated by our orthopaedic surgeon.

Statistical methods

Statistical analysis was performed with a statistical analysis software program (SPSS 12.0 for WINDOWS 95, SPSS, Chicago, IL).

The Mann–Whitney U test was used to compare quantitative variables between those children included in the study and those not followed up, and the χ² test was used for counts. We tested the association between the patient section and the observer section of the POSAS scoring system using Spearman correlation. The Mann–Whitney U test was used to compare quantitative variables between the groups with and without skin scarring or orthopaedic sequelae, and the χ² test was used for counts. The most predictive severity of illness score (PRISM, VAS score or DIC score) of major sequelae was determined with receiver-operating characteristics (ROC) curve analysis. Logistic regression analysis was applied to determine the predictive chance of major sequelae for each severity of illness score. For the purpose of this predictive model, major sequelae were defined as the presence of major scars and/or amputation of extremities and/or limb-length discrepancy. Scars were defined by two observers as minor or major depending on their number, diameter and position. There was full agreement between these two observers, independent of each other’s score, in 92% of cases (110/120). Calculation of kappa as a measure of interobserver variability resulted in 0.77, which can be considered good agreement. Final consensus was reached by the two observers in case of discrepancy (n = 10).

The χ² test was used to investigate any secular trend in the frequency of skin scarring and/or orthopaedic sequelae over the period of the study.

A p value of 0.05 (two-sided) was considered the limit of significance.

RESULTS

Patient sample

The target population consisted of 179 patients. Nine of these 179 patients were lost to follow-up. Of these nine, one patient with severe adverse outcome (mental retardation) died several years after MSS, seven patients lived abroad at the time of the follow-up and one was untraceable. Of the remaining 170 eligible patients, 145 agreed to participate. Of these 145 participants, 120 visited the follow-up clinic. The median follow-up interval was 9.8 years (range 3.7–17.4 years) and the median age of patients at the time of their visit to the follow-up clinic was 14.5 years (range 5.3–31.1 years). Twenty five patients and/or parents did not want to visit the follow-up clinic on practical (eg, because of lack of time) or emotional (a visit to the hospital would be upsetting) grounds and preferred to fill in the questionnaires at home. Another twenty five patients and/or parents did not respond to the invitation or refused to participate on practical or emotional grounds. The overall response rate, corrected for patients lost to follow-up, was 71% (120/170). To check for possible selection bias, we compared characteristics between participants and non-participants (table 1).

Incidence and severity of skin scarring

Of the 120 patients who visited the follow-up clinic, 58 (48%) had skin scarring due to necrotic purpura at the time of MSS. Most scars were positioned on the extremities (legs 86%, arms 55%). Eleven patients (19%) also had scars on the face and 13 patients (22%) had scars on the trunk. Scars varied from mild to severe as regards number, diameter and position. In some patients scars were barely visible, while other patients were extremely disfigured. The patient section of the POSAS scoring system was completed for 44 (76%) of the 58 patients with a median score of 9 (range 6–29). Fourteen patients and/or parents did not score the scars for different reasons (eg, because the scars were barely visible or according to patients and/or parents it was difficult to score items). The observer section was completed for 24 patients (41%) with a median score of 22 (range 5–34). In 34 patients the observer section was not filled in because of logistic reasons (ie, unavailability of the senior dermatologist). This resulted in 21 complete POSAS scores (36%) with a median complete POSAS score of 28 (range 11–53). There was a significant correlation between the scores of the patient and observer sections in these 21 patients (9 and 19, respectively; correlation coefficient 0.69). Using the visual analogue scale, the median score given by the parents of 50 patients (86%) was 7 (range 2–10) and the median score given by 46 patients (79%) was also 7 (range 0–10).

Of the 58 patients with skin scarring, 19 (33%) underwent debridement and skin grafting in the weeks following PICU admission because of skin necrotic lesions resulting from purpura. One girl had plastic surgery of the face for aesthetic reasons (disfiguring scars) several years later. Three patients (5%) still had physical complaints (two had painful scars, and one had non-healing lesions on both heels) at the time of the visit to the follow-up clinic.

Signs of post-thrombotic syndrome (chronic swelling of the right lower limb, recurrent venous ulcers on the right heel) were observed in a 21-year-old woman. This occurred after symptomatic deep vein thrombosis following the use of a central venous line in the right femoral vein at the time of MSS.

Incidence and severity of orthopaedic sequelae

Ten patients (8%) had to undergo amputation of extremities because of irreversible necrosis of tissue (skin, muscle and/or bone) (table 2). Four patients (nos. 1, 3, 5 and 8) underwent one or more revision amputation(s) in the years following MSS because of stump or bone overgrowth. One patient (no. 3) was still in orthopaedic follow-up (12 years after MSS) because bone overgrowth was causing chronic ulcerations. Patients who required prostheses were still seen regularly by a rehabilitation team for prosthetic review.

Seven patients (6%) had limb-length discrepancy (table 3). The majority of patients still had pain in the affected limb at the time of their visit to the follow-up clinic. Pain, which occurred mainly during walking or running, resulted in functional impairment in severe cases (eg, patient no. 4). Patient no. 2 could only walk a few meters with a prosthesis.

All but one patient were already under the treatment of the orthopaedic surgeon in our hospital. The most common presenting symptoms in patients with lower limb-length discrepancy were limping, pain in the limbs, difficulty walking and angular deformity. In one patient (no. 7) the lower limb-length discrepancy and varus deformity of the right ankle were diagnosed at the time of her visit to the follow-up clinic. Subsequently she was referred to the orthopaedic surgeon.

All patients, except for patient no. 2, underwent one or more (maximum of four) surgical intervention(s) (osteotomy, epiphysiodesis) for their lower limb-length discrepancy and/or angular deformity in the months and years following the diagnosis of these sequelae. All patients remained in orthopaedic follow-up.

Predictors of skin scarring and orthopaedic sequelae

Patients with scars or orthopaedic sequelae (amputation, limb-length discrepancy) had significantly higher severity of illness scores (table 4).

Using logistic regression analysis, both PRISM and the DIC score, but not the VAS score, were significantly associated with the presence of major sequelae. In figure 1, the ROC curves for each severity of illness score are displayed separately, together with the ROC curve for PRISM and the DIC score combined. The area under the curve was 0.73 for the VAS score, 0.74 for the DIC score, 0.77 for PRISM and 0.82 for the calculated risk score combining PRISM and the DIC score. The predictive chance of major sequelae according to the combined risk score was calculated as follows: −7.53+0.1×PRISM +0.77×DIC score (fig 2).

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Figure 1

ROC curves for the presence of major sequelae according to severity of illness scores. DIC score, Disseminated Intravascular Coagulation score; PRISM, Pediatric Risk of Mortality score; VAS score, Vasopressor score.

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Figure 2

The predictive probability (p) of major sequelae according to risk score. Equation of the curve: log (odds) = risk score, with odds representing the odds (p/1−p) of the predicted probability p. The risk score, combining PRISM and the DIC score, was calculated as −7.53+0.1×PRISM+0.77×DIC score. DIC score, Disseminated Intravascular Coagulation score; PRISM, Pediatric Risk of Mortality score.

There was no significant trend in the frequency of severe skin scarring and orthopaedic sequelae over the period of the study: from 1988 to 1990 three of 16 patients (19%) had severe skin scarring and/or orthopaedic sequelae, from 1991 to 1995 10/42 (24%), and from 1996 to 2001 16/62 (26%).

None of the patients in our study population had compartment pressures measured or fasciotomies performed during PICU admission.

A subgroup of our patient sample (n = 20) was included in a study where protein C concentrate was supplied.10 Patients who received protein C concentrate did not differ significantly with regard to the presence of scars or orthopaedic sequelae in comparison with patients who received placebo.

DISCUSSION

In our long-term outcome study in survivors of MSS, we found that nearly half of the patients (48%) had skin scarring, ranging from barely visible to extremely disfiguring scars. Also, a high number of patients (14%) had orthopaedic sequelae (amputation, limb-length discrepancy) with important long-term morbidity (surgical intervention(s), pain or functional impairment). Patients with scars or orthopaedic sequelae had significantly higher severity of illness scores.

Incidence and severity of skin scarring

A high number of patients (48%) had skin scarring, mostly on the legs. Our findings are in contrast to a study by Erickson and De Wals, which is probably due to their heterogeneous study population.5

Scars were barely visible in some patients, while other patients were extremely disfigured. A possible explanation could be differences in the extensiveness and appearance of purpura in patients at the time of PICU admission, mainly due to variation in illness severity.

This is the first study using the POSAS scoring system in patients who survived MSS. The scarring scores of patients and/or parents were comparable with those of the observer. This is in line with a study in burn injury patients.18 However, we need to be careful in comparing the patient and observer sections since they do not cover the same items and have a different total score.

Also parents and patients seemed to evaluate the scars the same way, as reflected by the same visual analogue scale score in parents and patients. In interviews carried out during their visit to the follow-up clinic, parents and/or patients often seemed not to be disturbed by the presence or appearance of scars; most patients reported they adapted to their scars over time.

Unfortunately no validated, standardised scoring system is available to assess the extensiveness (number, diameter and position) of scars.

Incidence and severity of orthopaedic sequelae

A relatively high number of patients (14%) had orthopaedic sequelae due to MSS. Irreversible necrosis of tissue (skin, muscle and/or bone) can necessitate amputation of extremities in severe cases of MSS. Limb-length discrepancy after MSS is probably caused by necrosis of the growth plate due to disseminated intravascular coagulation leading to premature closure or destruction of the growth plate.

The study of Bache and Torode4 found that 13% of their subjects had epiphyseal growth arrest, mainly in the lower limbs, which is comparable with our results.

Most of the patients with more extensive amputation (foot, leg or arm) or lower limb-length discrepancy had long-term morbidity because of significant functional impairment and the need for surgical reintervention(s) in the years following MSS. Furthermore, the majority of patients with lower-limb length discrepancy still suffered from pain in the affected limb.

Predictors of skin scarring and orthopaedic sequelae

This is the first study to determine predictors of skin scarring and orthopaedic sequelae by using severity of illness scores. Patients with scars or orthopaedic sequelae had significantly higher PRISM, VAS and DIC scores. Using ROC curve analysis, we demonstrated that the underlying disease, expressed by PRISM and the DIC score but not therapy with vasopressors, is predictive for the presence of major sequelae. Also younger children at the time of PICU admission seemed to be more at risk of limb-length discrepancy several years after MSS. This is probably due to age-dependent differences in the vulnerability of bone vasculature as well as the stage of bone maturity and development.21

Although survival of children with MSS has improved over the last two decades, the frequency of severe skin scarring and orthopaedic sequelae remained the same throughout our study period.22 Improved survival could be due to better and earlier interventions as international treatment guidelines have been implemented, health care workers have received additional training and public awareness has increased, resulting in decreased delay before hospitalisation.

Limitations of the present study

Several limitations of our study should be acknowledged. This is an observational study (with no controls) in one centre and the response rate was relatively low (71%). However, we do not think that this has influenced the results since participating patients and non-participants did not differ with respect to age at the time of PICU admission or severity of illness. Further, baseline assessments of the extent and appearance of purpura at the time of PICU admission were not available. In addition, we did not take into account the local treatment of purpura during the acute phase or plastic surgery. Unfortunately, we were not able to obtain reliable data since skin grafting and amputation were most often performed after PICU discharge and not during the acute phase of the illness. Furthermore, some of our patients were transferred to regional hospitals after PICU discharge.

POSAS scoring was not completed in all patients, especially the observer section. In future studies two or three (rather than just one) dermatologist or clinical investigator should be available not only for applying the POSAS scoring system but also for checking interobserver variability.

Implications

Since a significant number of patients who survive MSS in childhood have skin scarring and orthopaedic sequelae with important long-term morbidity, special attention should be given to studying the impact of these sequelae on long-term health related quality of life and psychological outcome. Awareness of these long-term consequences and their possible risk factors could lead to the establishment of standard multidisciplinary follow-up clinics for these patients.