Factors associated with sclerema in infants with ...

Acta Pædiatrica ISSN 0803–5253

REGULAR ARTICLE

Factors associated with sclerema in infants with diarrhoeal disease:
a matched case-control study

Mohammod Jobayer Chisti ([email protected])1, Tahmeed Ahmed1, Abu Syed Golam Faruque1, Shuvra Saha2, Mohammed Abdus Salam1, Sufia Islam3

1.International Centre for Diarrhoeal Disease Research, Bangladesh (ICDDR,B), Dhaka, Bangladesh
2.Medical Research Council (UK), The Gambia
3.Department of Pharmacy, East West University, Dhaka, Bangladesh

Keywords Abstract
Case-fatality, Diarrhoea, Hypothermia, Infant, Aim: To identify clinical and biochemical factors associated with sclerema in infants with diarrhoeal
Sclerema illness, and their outcome.
Methods: In this case-control study, we enrolled 30 infants with clinical sepsis with sclerema (cases)
Correspondence and another 60, age- and sex-matched infants with clinical sepsis but without sclerema (controls)
Dr. Mohammod Jobayer Chisti, from among those admitted to the special care unit (SCU) and longer stay unit (LSU) of the Dhaka
Clinical Sciences Division, International Centre for Hospital of International Centre for Diarrhoeal Disease Research, Bangladesh (ICDDR,B) for their
Diarrhoeal Disease Research, diarrhoeal illness from May 2005 through April 2006. Sclerema as the dependant variable while
Bangladesh (ICDDR,B), hypoxia, hypothermia, C-reactive protein (CRP) level, serum total protein and prealbumin level were
68 Shaheed Tajuddin Ahmed Sarani, Mohakhali, the major independent variables compared in the analysis. Differences in proportions were compared
Dhaka 1212, Bangladesh. by the chi-square test and differences of mean were compared by Student’s t-test or Mann–Whitney
Tel: + (88-02) 8860523-32 ext: 2334 | test, as appropriate.
Fax: + (88-02) 8823116 | Results: The case-fatality was significantly higher among the cases than the controls (30% vs. 2%, CI
Email: [email protected] 2.9–565.5). After adjusting for confounders, infants with sclerema were more likely to be
hypothermic (OR 11.6, 95% CI 1.1–126.5), and have lower serum total protein (OR 1.12, 95% CI
Received 1.04–1.21) and prealbumin (OR 1.5, 95% CI 1.1–2.3).
23 September 2008; revised 27 November 2008;
accepted 3 December 2008. Conclusion: Diarrhoeal infants having clinical sepsis presenting with hypothermia, lower serum protein and
prealbumin are prone to be associated with sclerema.
DOI:10.1111/j.1651-2227.2008.01196.x

INTRODUCTION onset of the condition (2,14). We also observed high case
fatality among children presenting to the Dhaka Hospital
Sclerema is defined as a diffuse, doughy feeling of the skin of International Centre for Diarrhoeal Disease Research,
and/or rapidly spreading, tallow-like hardening of the sub- Bangladesh (ICDDR,B) with diarrhoea and sclerema and
cutaneous tissue. It is more frequently observed in neonates noted other abnormalities such as hypernatremia, hypona-
(a condition known as sclerema neonatorum [SN]); how- tremia, acidosis, hypothermia and sepsis in such popula-
ever, has also been reported in older infants (1–5), and the tions. To our knowledge, the clinical and biochemical factors
reported age of the oldest infant with sclerema in associa- associated with sclerema in infants with diarrhoeal disease
tion with Pseudomonas sepsis was 106 days (2). Sclerema is have not been described in the medical literature. We thus
characterized by deposition of crystals, primarily of triglyc- conducted a prospective, case-control study to identify the
erides, in the subcutaneous fat that can be determined by clinical and biochemical factors associated with this condi-
X-ray diffraction; however, some studies reported subcuta- tion, in an effort to identify better preventive and therapeutic
neous fibrosis, not crystallization of fat contents, was the options in the management of sclerema.
conspicuous feature (3–5).
MATERIALS AND METHODS
Most of the clinical features of sepsis are usually present Patient enrollment
in SN suggesting its clinical severity (6,7). The pathogene- This study was conducted at the Dhaka Hospital of
sis of this condition has not been fully elucidated, which is ICDDR,B, Dhaka, Bangladesh, which provides care and
important for optimizing management to reduce deaths, al- treatment to around 110 000 diarrhoeal patients with or
though there are encouraging reports on dramatic response without associated complications and with or without other
to exchange fresh human blood transfusion and fresh blood health problems each year. The vast majority of the patients
transfusion (8–12). However, not all infants with sepsis come from the poor socio-economic backgrounds from ur-
present with sclerema, and it is therefore likely that some ban and peri-urban Dhaka, the capital city of Bangladesh.
as yet undermined factors might play an important role for This study was approved by Research Review Committee
the development of this deadly condition (13). The reported (RRC) and Ethical Review Committee (ERC) of ICDDR,B.
case-fatality from SN in different series ranged from 50%
to 100%, and deaths usually occur within hours to days of

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Factors associated with sclerema Chisti et al.

A written informed consent was obtained from respec- culating odds ratio (OR) and their 95% confidence inter-
tive parents/guardians of the each participating infant. We vals (CI). In the univariate model, characteristics analysed
enrolled most of the eligible infants from among those admit- include age, sex, admission dehydration, nutritional status,
ted to the special care unit (SCU), but also a few from longer abdominal distension, hypoxia, hypoglycemia, shock after
stay unit (LSU) of the hospital from May 2005 through April admission, hypothermia on/after admission (assessed by
2006. A clinical diagnosis of sclerema was made when at rectal temperature), duration of stay at SCU and LSU, total
least two clinicians of the hospital, including at least one of blood leukocyte count, CRP level, serum ammonia, serum
the investigators reached an agreement. total protein and prealbumin level and outcome. Finally, we
performed logistic regression analysis to identify character-
Study design istics those were significantly associated with sclerema after
In this age- and sex-matched case-control study, we enrolled adjusting for the co-variates. All categorical and continu-
30 cases and 60 controls from a total of 450 infants with clin- ous variables significantly associated with sclerema in uni-
ical sepsis who were admitted to the study units during the variate analyses were included in the model as independent
study period. Infants presenting with sclerema, defined as variables where sclerema was the dependent variable.
diffuse, doughy feeling of the skin and/or tallow like hard-
ening of the subcutaneous tissue in the absence of any lo- RESULTS
calized skin lesion, along with features of sepsis constituted Out of the total 30 infants with sclerema, 18 (60%) were
cases. We defined sepsis as presence of any two of the fol- male and the median age of the cases and controls were
lowing: tachypnoea, tachycardia, thermo-instability (hypo 2.1 and 2.2 months, respectively. The oldest infant with
or hyperthermia) and abnormal WBC count (>11 000/cc sclerema, aged 8 months, presented with diarrhoea, sepsis
or <4000/cc or, band and neutrophil ration ≥0.1) plus hy- and pneumonia (defined on the basis of radiological evi-
potension (15) in the absence of clinical dehydration (those dence). Twelve (40%) of the cases and 20 (33%) of the
who presented with severe dehydration enrolled after full controls infants were born premature (Table 1). Pneumo-
hydration). All of our study infants had sepsis, and those nia was associated in similar proportions (53%) among the
with features of sepsis but without sclerema constituted con- cases and the controls. Nearly all infants with clinical de-
trols. After enrollment of a case, the next two consecutively hydration presented with isotonic but mild hyperchloremic
admitted age- and sex-matched infants fulfilling the crite- dehydration, with mean sodium and chloride among the
ria were enrolled as controls. Sclerema was the presenting cases and the controls of 133.9 and 107.3, and 136.4 and
feature of 12 infants on admission and 18 developed the 113.3, respectively. The median creatinine level among the
condition while in the hospital. Relevant clinical informa- cases and the controls were 107.5 and 94.5, respectively
tion were collected soon after an infant with sclerema was (Table 2). The prevalence of severe stunting, severe un-
identified and enrolled into the study, subject to consent of derweight (defined as length-for-age and weight-for-age of
respective parents/guardians and samples collected for lab- <−3 z scores of National Centre for Health Statistics
oratory tests. [NCHS] median respectively) (Table 1), and serum con-
centrations of ammonia (Table 2) were similar among the
Clinical management of infants (cases and controls) was cases and the controls. However, at admission, higher pro-
done according to standard management guidelines of the portion of children with sclerema presented with severe de-
hospital. These include management of dehydration using hydration, hypoxia, abdominal distention (Table 1), higher
oral (for those with some dehydration) or intravenous flu- peripheral blood WBC (>11 000/cc) but lower (<150 000)
ids (for those with severe dehydration and also those who platelet counts, higher serum CRP (mg/dL) concentration,
were unable to drink due to any reason); appropriate an- hypoglycemia and hypocalcaemia (Table 2), and higher pro-
timicrobial therapy; appropriate feeding, micronutrients, vi- portion of them developed septic shock after admission
tamins and minerals as and when required. The infants with (Table 1). Severe wasting (weight-for-length <−3z score of
sclerema additionally received transfusion of fresh, whole NCHS median) (Table 1), admission hyperglycemia (blood
human blood (10 mL/kg) (11). Management of severe glucose >11 mmol/L) and isolation of bacterial pathogens
protein-energy malnutrition followed the hospital’s proto- from blood culture (Tables 2 and 3) occurred in higher pro-
colized guidelines (16,17). portion of cases, but the differences were not statistically
significant. Twenty-three (77%) of the cases received trans-
Statistical methods fusion of fresh whole human blood according to hospital
We developed case report forms (CRF), pretested, and management protocol, and only one (2%) of the control
finalized them for data acquisition. All data were entered children received whole blood transfusion for disseminated
onto personal computer and edited before analysis using intravascular coagulation (DIC) with severe anaemia. The
SPSS for Windows (version 10.2; SPSS Inc, Chicago, IL, duration of stay of children with sclerema in the SCU was
USA) and Epi Info (version 6.0, USD, Stone Mountain, GA, longer than the control infants, and their case-fatality was
USA). Differences in proportions were compared by the significantly higher (Table 1). In logistic regression, infants
chi-square test, and differences of means were compared with sclerema were more likely to be hypothermic (≤35◦C)
by Student’s t-test or Mann–Whitney test, as appropriate. (OR 11.6, 95% CI 1.1–126.5, p = 0.04), and have lower levels
A probability of less than 0.05 was considered statistically
significant. Strength of association was determined by cal-

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Chisti et al. Factors associated with sclerema

Table 1 Clinical characteristics of children with sclerema (cases) and without sclerema (controls) admitted for the treatment of diarrhoea

Characteristic Cases Controls OR 95% CI p-value
(n = 30) (n = 60)

Male 18 (60) 36 (60) 17.96 2.01–410.45 0.002
Age in months (Median, IQR) 2.1 (1.1, 4.0) 2.2 (1.25, 4.37) 1.00 0.33–2.98 0.80
Premature (gestational age: 28–36 weeks) 12 (40) 20 (33) 1.07 0.40–2.84 0.94
Sepsis 29 (97) 60 (100) 2.80 0.58–13.85 0.15
Associated pneumonia 16 (53) 32 (53) 16.79 3.06–121.27 <0.001
Not received blood transfusion 7 (23) 59 (98)
HAZ (<−3 z score) 8 (27) 16 (27) 5.21 1.22–23.52 0.02
WAZ (<−3 z score) 13 (43) 25 (42) 3.62 1.28–10.39 0.01
WHZ (<−3 z score) 5 (17) 4 (7) 5.36 1.45–22.68 0.008
Admission hypothermia (temp ≤ 35˚C) 11 (37) 2 (3) 14.75 1.60–343.01 0.005
Admission dehydration <0.001
8 (27) 25 (42) 25.29 2.94–565.49 <0.001
No sign 10 (33) 6 (10)
Severe 15 (50) 13 (22)
Abdominal distension 10 (56) 8 (18)
Hypoxia (SPO2 < 95%) 6 (20) 1 (2)
Septic shock after admission 4 (2.0, 5.5) 1 (0, 2.0)
Duration at SCW, days (Median, IQR) 9 (30) 1 (2)
Death

Figures represent n (%), unless specified.
OR = odds ratio; CI = confidence interval; IQR = interquartile range; HAZ = height for age z score; WAZ = weight for age z score; WHZ = weight for height z score.

Table 2 Laboratory characteristics of children with (cases) and without sclerema (controls) admitted for the treatment of diarrhoea

Characteristic Cases Controls p-value
(n = 30) (n = 60)
0.008
Total WBC count (number/cu. mm) 18840.0 ± 8442.6 14751.7 ± 5765.6 0.001
Platelet count (number/cu. mm) (Median, IQR) 40 000 (135 000, 170 000) 250 000 (200 000, 325 000) 0.001
CRP (mg/dL) (Median, IQR) 3.8 (1.9, 7.2) 1.2 (0.4, 3.2) 0.001
Serum total protein (g/dL) 45.4 ± 9.8 62.1 ± 10.5 0.001
Serum prealbumin (g/dL) 6.6 ± 2.4 8.7 ± 2.6 0.60
Serum ammonia (mmol/L) (Median, IQR) 55.4 (41.7, 103.9) 68.0 (40.7, 90.0) 0.36
∗∗Serum Sodium (mmol/L) 133.9 ± 9.0 136.4 ± 10.8 0.23
∗∗Serum chloride (mmol/L) 107.3 ± 24.1 113.0 ± 10.8 0.94
∗∗Serum creatinine (μmol/L) (Median, IQR) 107.5 (58.5, 177.0) 94.5 (60.0, 113.0) <0.001
Serum calcium (<2.12 mmol/L) 12 (40) 5 (8) 7.33 (2.02–28.11)∗
<0.001
Hypoglycemia (Blood glucose < 3mmol/L) 11 (37) 4 (7) 8.11 (2.04–34.82)∗
0.06
Hyperglycemia (≥11 mmol/L) 6 (20) 3 (5) 4.75 (0.94–26.52)∗
0.08
Growth on blood culture 10 (33) 8 (13) 2.83 (0.89–9.08)∗

Figures represent mean ± SD (standard deviation), unless specified.
∗OR (95% CI).
∗∗Cases and controls having dehydration.
IQR = interquartile range; SCU = special care unit.

of serum protein (OR 1.12, 95% CI 1.04–1.21, p = 0.003) inevitable in majority of cases of sclerema despite energetic
and prealbumin level (OR 1.5, 95% CI 1.1–2.3, p = treatment (2). Although our observed case-fatality was also
0.03). significantly high (30%), the rate was substantially lower
than the previously reported (7,8,10,18,19). We do not have
DISCUSSION a ready explanation for this difference in the case-fatality
Since first description of this rare but abject skin condition rate; however, prompt and efficient correction of dehydra-
by Underwood in 1784, it is widely believed that death is tion and acidosis and hypocalcaemia could have played a

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Factors associated with sclerema Chisti et al.

Table 3 Bacterial isolates from blood culture of infants with (cases) and tivity and specificity in favour of sepsis) also survived follow-
without sclerema (controls) ing broad-spectrum antimicrobial therapy, findings similar
to that reported earlier (19,22). Only one infant in the con-
Bacterial isolates Cases (30) Controls (60) trol group with Enterococcus sepsis required blood transfu-
sion for severe pallor.
Streptococcus species 1 (3) 1 (2)
Coagulase negative Staphylococcus Nil 2 (3) In our study, infants with sclerema more frequently pre-
Escherichia coli 1 (3) 1 (2) sented with severe dehydration, abdominal distension, hy-
Klebsiella 1 (3) Nil poxia, hypoglycemia and hypocalcaemia on admission, and
Pseudomonas aeruginosa 2 (7) Nil a higher proportion of them presented with septic shock
Acinetobacter species 3 (10) 2 (3) or developed it soon after admission than the control in-
Enterobacter species 1 (3) 1 (2) fants. Both severe dehydration and septic shock are asso-
Shigella flexnari 1 (3) Nil ciated with ineffective peripheral circulation, which might
Campylobacter jejuni Nil 1 (2) contribute to hardening of subcutaneous fat and thickening
of collagen fibre by causing alterations in the saturated to
Figures represent n (%). unsaturated fatty acid ratio (2,19). All of our infants, cases
and controls, had diarrhoeal illness and nearly all of them
role. The relatively higher age of our infants (median of presented with clinical sepsis; the abdominal distension in
2.1 months, and the oldest 8 months), slightly higher than our infants could either be due to sepsis and/or related to
reported from earlier studies could be a factor contributing their primary enteric infections (2,19). Hypoxia is a feature
to their better survival (3–6). of sepsis, which causes metabolic disturbances and derma-
tological problems (21). Hypocalcaemia, along with other
We observed sclerema to be significantly associated with favourable conditions like sepsis also potentiates sclerema
hypothermia, which has been observed previously (16,20). (22).
Infants’ fat has higher saturated to unsaturated fatty acid ra-
tio than in adults, which is likely due to underdevelopment Higher peripheral blood leukocyte count, elevated CRP
of the enzyme systems involved in desaturation of palmitic level and lower platelet count in scleremic infants are also
and stearic acid. Hypothermia along with hypoxia, and pos- features of sepsis. But CRP level was not as high as the level
sible altered coagulation profile and metabolic disturbances that could have been expected in severely ill infants. We
could further increase the ratio of saturated to unsaturated do not have a ready explanation for this observation, but
fatty acid, possibly by enzymatic alterations, resulting in pre- receiving antimicrobial therapy before hospitalization could
cipitation of fatty acid crystals within the lipocytes leading be one since such therapy might quickly change the CRP
to the dramatic clinical findings of sclerema (2,21). In our levels (23). Infants with sclerema stayed for longer duration
study sclerema was also associated with lower serum pro- in the SCU, which reflects severity of their illness as has
tein and prealbumin concentrations, which are features of been observed in other studies (18,19). We observed slight
severe illness and particularly the later represent acute phase male predominance in the development of sclerema that
response and reduced body protein synthesis. These are the has been well known and reported in a number of previous
new findings in our study, which might represent the conse- studies (2,18). However, in our study this could be explained
quences of sepsis, and they along with hypothermia, hypoxia by community bias in seeking health care favouring males,
and metabolic disturbances contributed to the development as our hospital surveillance data also revealed the ratio of
of sclerema (2,16,19). Higher proportions (40%) of our cases male and female patient during the same period as 3:2.
were born premature (gestational age 28–36 weeks in both
groups, calculated from the 1st day of the last menstrual pe- The frequency of admission hyperglycemia, bacteraemia
riod), which corroborates with earlier findings (3,18). Pre- and severe malnutrition (stunting, underweight and wast-
mature children are more vulnerable to hypothermia and ing) were not different between cases and controls.
consequently more prone to develop sclerema (2). Hyperglycemia might occur in stressful conditions, includ-
ing severe diarrhoea (24). All of our control infants also had
Transfusion of whole human blood has been reported to clinical sepsis, which might explain similar distribution of
improve survival of infants with sclerema (11), and is fol- bacteraemic infants in our study. Severely stunted, under-
lowed in case-management guidelines of our hospital. Seven weight and wasted infants have minimal subcutaneous fat
(23%) of our infants with sclerema did not receive the trans- and it is thus plausible that sclerema would be less likely
fusion; three of them (43%) died while transfusion was be- in such infants. We observed the serum ammonia levels to
ing arranged. Three of the remaining four infants: one with be similar in children with and without sclerema. Previous
severe acidosis (TCO2 < 6.0 mmol/L), one with severe de- studies observed that transient hyperammonaemia of new-
hydration and severe acidosis, and the other with moderate born (THAN) was closely associated with sclerema (12,25);
acidosis (TCO2 = 8.8 mmol/L) and hypocalcaemia (serum however, those studies involved only neonates, particularly
calcium = 1.8 mmol/L); their clinical condition improved during the first few days of life and hyperammonaemia is not
substantially after correction of dehydration, acidosis and uncommon in preterm infants (25); in our study the distri-
hypocalcaemia and they survived. The fourth infant with to- bution of preterm infants (40% vs. 33%) was similar among
tal peripheral blood leukocyte count of 22 500/mm3 and a the cases and controls, which might have confounded the
neutrophil–band ratio of 0.9 (a ratio of ≥0.1 has high sensi- observations.

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Chisti et al. Factors associated with sclerema

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