Predictors of mortality in infants with sclerema ...

Annals of Tropical Paediatrics (2009) 29, 45–50

Predictors of mortality in infants with sclerema presenting
to the Centre for Diarrhoeal Disease, Dhaka

M. J. CHISTI, S. SAHA{, C. N. ROY, T. AHMED, A. S. G. FARUQUE, M. A. SALAM
& S. ISLAM*

International Centre for Diarrhoeal Disease Research, Bangladesh (ICDDR,B) and *Department of
Pharmacy, East West University, Dhaka, Bangladesh, and {Medical Research Council (UK), The Gambia

(Accepted December 2008)

Abstract
Background: Sclerema is an uncommon, life-threatening condition, usually of newborns, with a case-fatality rate
ranging from 50 to 100%. Very little is known about factors influencing outcome.
Aim: To identify clinical and biochemical predictors associated with fatal outcome of sclerema in infants with
diarrhoea.
Methods: Thirty infants with sclerema admitted to the Special Care Unit of the Dhaka Hospital of ICDDR,B with
diarrhoea from May 2005 to end April 2006 were studied prospectively. Nine infants who died (30%) were
considered to be cases while the 21 who survived constituted the comparison group. Hypothermia, severe
malnutrition, septic shock, serum ammonia and CRP levels were considered to be predictors of death. Differences
in proportions were compared by the x2 test and mean differences were compared using Student’s t-test or the
Mann–Whitney test, as appropriate.
Results: The mean age of the 30 infants was 2.1 months (range 12 d to 8 m). Fatal cases were more likely than
survivors to be associated with severe underweight, a positive blood culture and higher serum ammonia and serum
CRP levels. After adjusting for possible confounders in logistic regression analysis, the likelihood of death was
higher in infants admitted with septic shock or who developed it soon after admission (OR 17.96, 95% CI 1.5–
220.4, p50.024).
Conclusions: Sclerema is associated with a high fatality rate and scleremic infants with diarrhoea who present with
septic shock are at a greater risk of death.

Introduction diffraction.2–6 Signs of sclerema are more

Sclerema is defined as a tallow-like hard- frequently observed in neonates (sclerema
ening of subcutaneous tissue which usually
spreads very rapidly to underlying mus- neonatorum) but have also been reported in
cles.1–3 It is characterised by deposition of older infants.2–4 The oldest infant with
crystals, primarily of triglycerides, in the
subcutaneous fat as determined by X-ray sclerema in association with pseudomonas
sepsis was 106 days.2 Case fatality from
Reprint requests to: Dr Mohammod Jobayer Chisti,
Clinical Sciences Division, International Centre for sclerema has been as high as 100% and
Diarrhoeal Disease Research, Bangladesh (ICDDR,B),
68 Shaheed Tajuddin Ahmed Sarani, Mohakhali, death usually occurs within hours or days of
Dhaka 1212, Bangladesh. Fax: z880 2 882 3116, onset.1,2
z880 2 988 5657; email: [email protected]
Sclerema is almost always associated with
# The Liverpool School of Tropical Medicine 2009 severe sepsis.7,8 There is some evidence that
DOI: 10.1179/146532809X402024
it responds to exchange blood transfusions,

although the pathophysiology is yet to be
well investigated.8–11 In sclerema patients,

there are changes in the inflammatory

46 M. J. Chisti et al.

response. Increased IL1 and IL6 along with were the comparison group. A clinical
transient hyperammonaemia of the newborn diagnosis of sclerema was made on the basis
(THAN) have been found to be risk factors of pre-defined criteria and when at least two
for mortality.12,13 We also frequently clinicians, one of the investigators and
observe a fatal outcome in diarrhoeal infants another clinician not involved in the study,
with sclerema in the special care unit of the reached agreement. Sclerema was defined as
Dhaka Hospital of the ICDDR,B. To our a diffuse, doughy feeling of the skin and/or
knowledge, the clinical and biochemical risk tallow-like hardening of the subcutaneous
factors for death in scleremic infants with tissue in the absence of any localised skin
diarrhoea have not been described in the lesion, along with features of sepsis. Sepsis
medical literature. We conducted a prospec- was defined as the presence of any two of
tive, tertiary hospital-based surveillance the following: tachypnoea, tachycardia,
study to identify the clinical and biochem- thermo-instability (hypo- or hyperthermia)
ical predictors of death among diarrhoeal and abnormal WBC count (.11.06109/L
infants with sclerema. or ,4.06109/L or band and neutrophil
ratio >0.1) plus hypotension14 (in the
Materials and Methods absence of any sign of dehydration or after
correction of dehydration). Septic shock was
Patient enrolment defined as sepsis plus absent peripheral
pulse. Sclerema developed in 18 patients
Patients diagnosed with sclerema who were during their hospital stay and the remainder
admitted between May 2005 and April 2006 were diagnosed on admission. Admission
to the special care unit (SCU) of Dhaka diagnoses such as subcutaneous fat necrosis,
Hospital of the ICDDR,B, Dhaka were pseudoscleroderma and scleroderma of
included. The hospital treats around Buschke were exclusion criteria.1,13,15
100,000 patients annually. Usually, all have
diarrhoea with or without associated com- Patients were managed clinically accord-
plications or other health problems. Patients ing to the hospital’s standard guidelines.
with severe illnesses, including those with This included broad-spectrum antibiotic
marked lethargy or irritability, convulsions, therapy, rehydration by oral rehydration
severe pneumonia, cyanosis and hypoxia, solution or intravenous fluid, appropriate
suspected sepsis and non-hypovolaemic feeding with a caloric intake of 80–
shock are admitted to the SCU for further 144 kcal/day, and micronutrients such as
assessment, closer observation and appro- zinc, magnesium, potassium, calcium,
priate care and treatment. All of our study vitamin A, multivitamins and folic acid
patients in the SCU had diarrhoea. The as required. Broad-spectrum antibiotics
majority are from a poor socio-economic included combinations of ampicillin and
background in urban and peri-urban Dhaka. gentamicin, or cefriaxone and gentamicin /
Written informed consent was obtained amikacin, ceftazidime or ciprofloxacin and
from the legal guardians of study infants. cloxacillin. Acetate solution (cholera saline)
This study was approved by the Research or normal saline was used for intravenous
Review Committee and Ethical Review rehydration. Fresh blood transfusion was
Committee of ICDDR,B. given as required.11 Management of severe
malnutrition (severe underweight) followed
Study design protocol guidelines.16,17 Severe underweight
(,23 Z-score) was measured by calculating
Thirty diarrhoeal infants with sclerema were Z-scores against weight-for-age of the med-
enrolled. The nine who died were consid- ian of the National Centile for Health
ered to be the cases and the 21 survivors Statistics. Management of CRP and THAN
was done by administering broad-spectrum

Predictors of mortality in sclerema 47

antibiotic therapy which reduces CRP in proportions were compared by the x2 test
and mean differences were compared by
and ammonia levels. Hyperammonaemia Student’s t-test or the Mann–Whitney test,
as appropriate. A probability of ,0.05 was
in sclerema is usually owing to considered statistically significant. Strength
bacterial infection.18–20 Reduction of tem- of association was determined by calculating
odds ratio (OR) and 95% confidence inter-
perature (hypothermia) was not attempted vals (CI).

as it causes further deterioration of
sclerema.2,21,22

Statistical methods Results

We developed case report forms which were The median age (range) of sclerema patients
pretested and finalised for data acquisition. was 2.1 months (12 days to 8 months). The
Logistic regression analysis was performed case-fatality rate was 30% (9/30).
to identify characteristics significantly asso- Compared with survivors, the fatal cases of
ciated with sclerema after adjusting for the sclerema were severely underweight, had
other co-variates. Considering death as the higher serum ammonia and CRP levels and
outcome, all categorical and continuous had more positive blood cultures (Table 1).
variables significantly associated with death No scleremic infants with hyperammonae-
in univariate analyses were included as mia required haemodialysis or therapy with
independent variables in the multivariate sodium benzoate or by sodium phenylace-
model. tate. The results of blood culture are seen in
Table 2. Although the proportion of sclere-
All data were analysed using SPSS for mic infants who received blood transfusion
Windows (version 10.2, SPSS Inc., was higher among survivors than in those
Chicago, IL) and EpiInfo (version 6.0,
USD, Stone Mountain, GA). Differences

TABLE 1. Comparison of characteristics of sclerema in infants who died and those who survived.

Variables Died, n59 Survived, n521 OR (95% CI) p-value

Male 7 (78) 11 (52) 3.18 (0.42–28.92) 0.25

Neonatal age (age ,1 m) 2 (22) 4 (19) 1.21 (0.12–11.12) 1.0

Prematurity (,37 w gestation, 4 (44) 8 (38) 1.30 (0.20–8.31) 1.0

calculated from last menstrual period)

Dehydrating (some/severe) diarrhoea 5 (56) 17 (81) 0.29 (0.04–2.14) 0.19
Hypothermia ((35uC) 5 (56) 6 (29) 3.13 (0.48–21.87) 0.22

Hypoxia 4/4 (100) 6/14 (43) 0.09

Abdominal distension 6 (67) 9 (43) 2.67 (0.41–18.83) 0.42

Pneumonia 6 (67) 10 (48) 2.20 (0.34–15.37 0.44

Septic shock 5 (56) 1 (5) 25.00 (1.81–763.36) 0.004

WAZ (,23 Z-score) 7 (78) 6 (29) 8.75 (1.11–86.61) 0.02

Blood transfusion 5 (56) 18 (86) 4.8 (0.60–43.10) 0.15

Serum sodium, mean (SD) 136.6 (11.2) 133.9 (9.0) – 0.52

Serum potassium, mean (SD) 4.9 (1.8) 3.5 (1.5) – 0.06

Serum ammonia, mmol/L (median, 113.60 (82.93, 219.70)44.90 (38.10, 67.10) – 0.003

IQR)* 6.67 (4.67, 13.15) 2.33 (1.51, 4.56) – 0.008
CRP, mg/dl (median, IQR){

Growth on blood culture 6 (67) 4 (19) 8.50 (1.12–77.07) 0.03

Figures represent n (%), unless otherwise specified. OR, odds ratio; CI, confidence interval; WAZ, weight-for-
age Z-score; SD, standard deviation; IQR, interquartile range. * Normal value 47–65 mmol/L; { normal value

,1 mg/dl.

48 M. J. Chisti et al.

who died, it did not reach statistical whereas the majority of our cases (80%)
significance (Table 1). Male gender, neona- were older.
tal age, history of prematurity, dehydrating
diarrhoea, hypothermia, hypoxia, abdom- Septic shock was an independent predic-
inal distension, pneumonia, serum sodium tor of death: it is likely that the compro-
and serum potassium were not associated mised and ineffective peripheral circulation
with death in scleremic infants (Table 1). In in septic shock was a contributing factor.2,24
logistic regression analysis, the likelihood of Septic shock as a risk of death in sclerema
death was greater in the scleremic infants has been observed in earlier studies also.4,8
with septic shock (OR 17.96, 95% CI 1.5– The association of gram-negative bacterae-
220.4, p50.024). mia with fatal outcome in this study might
relate to endothelial leakage secondary to
Discussion gram-negative bacteraemia, which often
compromises peripheral circulation and
Sclerema is markedly life-threatening and leads to septic shock.25 Fatality was higher
the majority of cases die within hours or in patients with raised CRP, which is a
days of onset, regardless of intensive treat- marker for bacterial sepsis.19 The higher
ment.2 Although the fatality rate in our levels of serum ammonia among patients
study was high, it was substantially lower who died has been reported earlier.19
than in previous reports.8–10,23,24 We do not Scleremic infants were severely under-
have a ready explanation for the lower rate weight, potentially putting them at greater
in our study; however, prompt and efficient risk owing to their compromised immune
correction of dehydration in the event of status.4,26,27
watery diarrhoea might have played a role.
Patients in previous studies did not have A higher proportion of scleremic infants
diarrhoea and reported death rates were who survived received blood transfusion,
considerably higher among patients who did though this association failed to reach
not receive transfusion (blood transfusion or statistical significance. Blood transfusion in
exchange transfusion).8–10,23,24 The rela- sclerema has been shown to be beneficial.11
tively older age of our infants compared Unfortunately, this important treatment
with previous reports (mainly neonates) regimen failed to show a beneficial effect in
might be another element in their better this study, probably owing to the small
survival.4–7 The majority of cases of scler- sample size. In a number of previous
ema previously investigated were neonates studies, prematurity, hypothermia, hypoxia,
abdominal distension and pneumonia have
TABLE 2. Results of blood culture of the deaths and been found to be associated with a high
the survivors of diarrhoeal infants with sclerema. fatality rate in sclerema.2,3,21–24 The failure
to observe differences between the groups
Bacterial isolates Deaths Survivors for these clinical features might again be
n59 (%) n521 (%) because of small sample size.

Streptococcus spp Nil 1 (5) For reasons related to consent, we did not
Escherichia coli 1 (11) Nil include histopathological findings of skin
Klebsiella 1 (11) Nil biopsy in our diagnosis of sclerema. We
Pseudomonas aeruginosa 1 (11) 1 (5) selected the sclerema cases on the basis of
Acinetobacter spp 1 (11) 2 (10) clinical parameters only because of the
Enterobacter spp 1 (11) Nil importance of initiating early and efficient
Shigella flexneri 1 (11) Nil management.28

The main finding of this study was the
identification of septic shock as a strong
predictor of death in scleremic infants and it
is likely to be associated with gram-negative

Predictors of mortality in sclerema 49

bacteria. Important aspects of management endocardial fibroelastosis. Acta Pathol Jpn 1977;
of sclerema include circulatory support, 27:917–25.
blood transfusion, appropriate antibiotics 7 Bhakoo ON. Prognosis and treatment of neonatal
and management of malnutrition. septicaemia—a clinico-bacteriological study of 100
cases. Indian Pediatr 1974; 11:519–28.
Acknowledgments 8 Narayanan I, Mitter A, Gujral VV. A comparative
study on the value of exchange and blood transfu-
The research was funded by ICDDR,B and sion in the management of severe neonatal
its donors who provide unrestricted support septicemia with sclerema. Indian J Pediatr 1982;
to the centre for its operations and research. 49:519–23.
Current donors include: Australian Agency 9 Vain NE, Mazlumian JR, Swarner OW, Cha CC.
for International Development (AusAID), Role of exchange transfusion in the treatment of
Government of the People’s Republic of severe septicemia. Pediatrics 1980; 66:693–7.
Bangladesh, Canadian International Develop- 10 Sadana S, Mathur NB, Thakur A. Exchange
ment Agency (CIDA), Embassy of the transfusion in septic neonates with sclerema: effect
Kingdom of the Netherlands Development on immunoglobulin and complement levels. Indian
(EKN), Swedish International Develop- Pediatr 1997; 34:20–5.
ment Cooperation Agency (Sida), Swiss 11 Sarwono E, Marseno FX, Kwari Satjadibrata R,
Agency for Development and Cooperation Polanunu AR. Effect of fresh blood transfusion in
(SDC) and Department for International the treatment of sclerema neonatorum. Paediatr
Development, UK (DFID). The sponsors Indones 1973; 13:120–33.
of the study collaborated on study design 12 Linderberg JA, Milstein JM, Cox KL. Sclerema
and data collection and analysis. We grate- neonatorum: a sign of transient hyperammonia of
fully acknowledge their support and com- the newborn. J Pediatr Gastroenterol Nutr 1987;
mitment to the centre’s research. Sincere 6:474–6.
thanks to Dr Julian Kelly, Dr P. K. 13 Sharma S, Mink S. Septic shock. http://www.
Bardhan, Ashish Kumar Chowdhury and emedicine.com/MED/topic2101.htm, accessed 19
Dr Debasish Saha for invaluable comments October 2004.
and suggestions. There are no competing 14 Goldstein B, Giroir B, Randolph A. International
interests. pediatric sepsis consensus conference: definitions
for sepsis and organ dysfunction in pediatrics.
References Pediatr Crit Care Med 2005; 6:2–8.
15 Jardine D, Atherton DJ, Trompeter RS. Sclerema
1 Zeb A, Darmstadt GL. Sclerema neonatorum: a neonatorum and subcutaneous fat necrosis of the
review of nomenclature, clinical presentation, his- newborn in the same infant. Eur J Pediatr 1990;
tological features, differential diagnoses and man- 150:125–6.
agement. J Perinatol 2008; 28:453–60. 16 Ahmed T, Ali M, Ullah MM, et al. Mortality in
severely malnourished children with diarrhoea and
2 Urbatsch AJ, Elmets CA, Siegel DM, et al. Sclerema use of a standardised management protocol. Lancet
neonatorum. http://www.emedicine.com/derm/ 1999; 353:1919–22.
topic386.htm, accessed 9 January 2004. 17 World Health Organization. Management of
Severe Malnutrition: a Manual for Physicians and
3 Horsfield GI, Yardley HJ. Sclerema neonatorum. Other Senior Health Workers. Geneva: WHO,
J Invest Dermatol 1965; 44:326–32. 1999.
18 Ehl S, Gering B, Bartmann P, Hogel J, Pohlandt F.
4 Dasgupta A, Ghosh RN, Pal RK, Mukherjee N. C-reactive protein is a useful marker for
Sclerema neonatorum—histopathological study. guiding duration of antibiotic therapy in suspected
Indian J Pathol Microbiol 1993; 36:45–7. neonatal bacterial infection. Pediatrics 1997;
99:216–21.
5 Pasyk K. Sclerema neonatorum. Light and electron 19 Ballard RA, Vinocur B, Reynolds JW, et al.
microscopic studies. Virchows Arch A Pathol Anat Transient hyperammonemia of the preterm infant.
Histol 1980; 388:87–103. N Engl J Med 1978; 299:920–5.
20 Clay AS, Hainline BE. Hyperammonemia in the
6 Sato T, Takahashi K, Kojima M. Sclerema ICU. Chest 2007; 132:1368–78.
neonatorum associated with systemic fibrosis and 21 Navarini-Meury S, Schneider J, Buhrer C. Sclerema
neonatorum after therapeutic whole-body
hypothermia. Arch Dis Child Fetal Neonatal Ed
2007; 92:F307.

50 M. J. Chisti et al.

22 Battin M, Harding J, Gunn A. Sclerema neona- research agenda. Pediatr Crit Care Med 2005;
torum following hypothermia. J Paediatr Child 6:S157–64.
Health 2002; 38:533–4. 26 de Onis M, Monteiro C, Akre J, Glugston G.
The worldwide magnitude of protein-energy mal-
23 Prod’hom LS, Choffat JM, Frenck N, Mazouni M, nutrition: an overview from the WHO global
Relier JP, Torrodo A. Care of the seriously ill database on child growth. Bull WHO 1993;
neonate with hyaline membrane disease and with 71:703–12.
sepsis (sclerema neonatorum). Pediatrics 1974; 27 Islam MA, Rahman MM, Mahalanabis D.
53:170–81. Maternal and socio-economic factors and the risk
of severe malnutrition in a child: a case-control
24 Bwibo NO, BarbaraTA. Sclerema neonatorum (a study. Eur J Clin Nutr 1994; 48:416–24.
study of 16 cases in the Special Care Unit, Mulago 28 Milunsky A, Levin SE. Sclerema neonatorum: a
Hospital, Kampala). East Afr Med J 1970; 47:50– clinical study of 79 cases. S Afr Med J 1966;
5. 40:638–41.

25 Carcillo JA. Reducing the global burden of
sepsis in infants and children: a clinical practice