Indian Journal of Pediatrics (November 2023) 90(11):1152–1153

https://doi.org/10.1007/s12098-023-04606-9

PICTURE OF THE MONTH

Myriad of Mucocutaneous Manifestations in Multisystem

Inflammatory Syndrome Associated with COVID-19
Ashwini Prithvi1 · Chaitra Govardhan1 · Chitra Dinakar1

Received: 8 March 2023 / Accepted: 5 April 2023 / Published online: 29 May 2023
© The Author(s), under exclusive licence to Dr. K C Chaudhuri Foundation 2023

Multisystem inflammatory syndrome in children (MIS-C)
is a novel disease which has been increasingly recognised
in recent times. Children present with varied morphological
rashes such as non-specific eruptions, polymorphic, maculo-
papular, morbilliform, diffuse erythroderma, urticaria, reticu-
lar, petechial, purpuric, vasculitis lesions, hyperemia of lips,
strawberry tongue, periorbital and malar erythema [1, 2].
At the authors’ tertiary care centre, there were 84 children
who were diagnosed with MIS-C; among whom 44 (52.4%)
had mucocutaneous manifestations. The varied mucocuta-
neous manifestations have been presented here.
An adolescent girl with Kawasaki phenotype of MIS-C
had periungual desquamation in the subacute phase and
presented on follow up with livedoid vasculitic rashes dis-
tributed over bilateral lower limbs and foot (Fig. 1a-c). A
5-y-old girl presented with desquamation over periungual
and extensor aspect of hand on follow up (Fig. 1d). A 1 y
7 mo old girl presented with diffuse urticarial rashes at the
time of initial presentation (Fig. 1e, f). A 1 y 3 mo old girl
presented with non-specific eruptions over extensor aspects
of both hands (Fig. 1g). A 5-y-old boy presented with fea-
tures of incomplete Kawasaki disease like illness, had

Fig. 1 (a-c) An adolescent girl with periungual desquamation and live- bilateral lower limbs in a 1 y 7 mo old girl. (g) Non-specific eruptions
doid vasculitis. (d) Desquamation of skin from periungual and external over hand in a 1 y 3 mo old girl. (h) Strawberry tongue with lip ery-
aspect of hand in a 5-y-old girl. (e, f) Diffuse urticarial rashes over thema in a 5-y-old boy

Ashwini Prithvi
ashwini3891@gmail.com
1
Department of Pediatrics, St. John’s Medical College
Hospital, Bengaluru, Karnataka, India

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Indian Journal of Pediatrics (November 2023) 90(11):1152–1153 1153

Conflict of Interest None

strawberry tongue appearance with non-purulent conjuncti-
val congestion (Fig. 1h).
All children were treated with intravenous immuno-
globulins and steroids, and rashes resolved over time. An
in-depth knowledge regarding varied mucocutaneous mani-
festations of MIS-C is important for both pediatricians and
dermatologists to suspect and treat MIS-C, especially in the
acute phase for a better outcome.
References
1. Brumfiel CM, DiLorenzo AM, Petronic-Rosic VM. Dermatologic
manifestations of covid-19-associated multisystem inflammatory
syndrome in children. Clin Dermatol. 2021;39:329–33.
2. Panda M, Agarwal A, Hassanandani T. Dermatological manifes-
tations of covid-19 in children. Indian Pediatr. 2022;59:393–9.

Declarations Publisher’s Note Springer Nature remains neutral with regard to juris-
dictional claims in published maps and institutional affiliations.
Consent for Publication The identity of the children have not been
revealed and to the best of the authors' knowledge the anonymity of
the subject of interest has been ensured. Informed written consent was
obtained for publication by the parent of one of the children and verbal
consent for the others.

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Indian Journal of Pediatrics (November 2023) 90(11):1162
https://doi.org/10.1007/s12098-023-04666-x

CORRESPONDENCE

High Dose Dexamethasone in Complicated Typhoid Fever: What

is the Evidence?
Zulquar Nain1

Received: 18 April 2023 / Accepted: 4 May 2023 / Published online: 15 May 2023
© The Author(s), under exclusive licence to Dr. K C Chaudhuri Foundation 2023

To the Editor: The standard recommendation of giving a
high dose of dexamethasone in severe typhoid fever, espe-
cially when complicated by neurological findings, lacks
any systematic review or meta-analysis. The minimal ran-
domised evidence from two trials [1, 2] which was later dis-
puted by another trial [3] in a tropical disease with a high
incidence and a high rate of complications, is debatable.
These trials excluded the very high-risk patients who died
within 6 h, even though the trial specifically aimed to study
high-risk patients. In fact, 68 patients had been randomized
in the trial, but only 38 were analysed. For 2 of the 68 cases,
it is not even stated which arm they were randomized to. For
the other 66 patients, the death difference was not statisti-
cally significant (10 ⁄ 33 vs. 18 ⁄ 33, P = 0.057). These data
are over 25 y old, and this regimen has not been redemon-
strated to be effective in any recent or updated trials.
It is also relevant to discuss the maximum dose of steroid. It
is a point of discussion among the clinicians when dexametha-
sone in the dosage of 120 mg is prescribed to a 40 kg weight
teenager and 15 vials of dexamethasone are used. If the usual
mechanism postulated in treating the complication of typhoid
fever involves inhibition of the acute inflammatory cascade,
can this steroid regimen be used in other gram-negative sepsis?
It is a challenge for future trials as the culture results are
unknown at the time of presentation. Robust clinical trials
with a large number of participants are needed to further
strengthen the recommendations. In an ideal condition,
patient tailored treatment is needed, and evaluation of the
baseline cortisol level is pre-emptive to guide dexametha-
sone-based therapy in these patients.
Declarations
Conflict of Interest None.
References
1. Hoffman SL, Punjabi NH, Kumala S, et al. Reduction of mortal-
ity in chloramphenicol-treated severe typhoid fever by high-dose
dexamethasone. N Engl J Med. 1984;310:82–8.
2. Punjabi NH, Hoffman SL, Edman DC, et al. Treatment of severe
typhoid fever in children with high dose dexamethasone. Pediatr
Infect Dis J. 1988;7:598–600.
3. Leung DT, Bogetz J, Itoh M, et al. Factors associated with enceph-
alopathy in patients with Salmonella enterica serotype typhi bac-
teremia presenting to a diarrheal hospital in Dhaka, Bangladesh.
Am J Trop Med Hyg. 2012;86:698–702.
Publisher's Note Springer Nature remains neutral with regard to
jurisdictional claims in published maps and institutional affiliations.

* Zulquar Nain
zulquarnain1995@gmail.com
1
Department of Pediatrics, Jawaharlal Nehru Medical
College, Aligarh Muslim University, Aligarh,
Uttar Pradesh 202002, India

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Vol:.(1234567890)
Indian Journal of Pediatrics (November 2023) 90(11):1116–1122
https://doi.org/10.1007/s12098-023-04675-w

ORIGINAL ARTICLE

Treatment Outcomes of Childhood Medulloblastoma with the SIOP/

UKCCSG PNET‑3 Protocol
İbrahim Kartal1 · Ayhan Dağdemir1 · Oğuz Salih Dinçer1 · Hülya Kangal Şimşek1 · Alper Uygun1 ·
Şükriye Bilge Gürsel2

Received: 22 September 2022 / Accepted: 17 March 2023 / Published online: 19 June 2023
© The Author(s) 2023

Abstract
Objectives To retrospectively compare the overall and event-free survival rates of patients with standard and high risk
medulloblastoma who received postoperative radiotherapy (RT) followed by maintenance chemotherapy.
Methods The study included 48 patients with medulloblastoma who were treated and followed-up between 2005 and 2021.
Patients were classified according to the Chang classification because no molecular analysis was done. Immediately after
surgery all patients received postoperative RT followed by eight cycles of chemotherapy (SIOP/UKCCSG PNET-3 protocol);
if thrombocytopenia developed, carboplatin was replaced by cisplatin to avoid treatment delay. The clinical characteristics,
risk categories and treatment outcomes of all patients were analyzed.
Results The mean age of the 48 patients (26 males, 22 females) at diagnosis was 7.27±4.21 y. The median start time of
RT after surgery was 37 (range 19–80) d. The median follow-up was 56 (3–216) mo. The 5-year event-free survival was
61.2±10% in the high-risk group and 82.5±11.5% in the standard-risk group. The 5-year overall survival was 73.2±7.1%;
it was 61.2±10% and 92.9±6.9% for high- and standard-risk patients, respectively (p = 0.026).
Conclusions The outcomes of patients who were started on the modified SIOP/UKCCSG PNET-3 chemotherapy protocol,
in which RT was begun as soon as possible after surgery, were comparable to those of current treatment protocols. Although
a definitive conclusion is difficult, given the limited number of patients in the present study, authors suggest that their treat-
ment protocol is a viable option for centers with limited facilities (such as an inability to perform molecular analysis).

Keywords Medulloblastoma · Treatment · Prognosis · Childhood · Radiotherapy timing

Introduction histopathology and MYC amplification have been identified

Medulloblastoma (MB) is the most common malignant brain
tumor in children [1], and comprises about 20% of all child-
hood central nervous system tumors. The annual incidence is
5.07 children per million, with bimodal peaks at 3–4 and 7–8
y of age [2]. Patients younger than 3 y of age, with metas-
tasis at diagnosis, or residual tumors >1.5 ­cm2 in the area
are considered high risk [3]. Recently, large cell/anaplastic
as high-risk factors, while WNT over-expression has the best
prognosis [4]. Here, authors present the clinical character-
istics, risk categories, treatments, and outcomes of 48 MB
patients who received the SIOP/UKCCSG PNET-3 chemo-
therapy protocol between 2005 and 2021 in their institution.
Material and Methods

Forty-eight patients diagnosed with MB between 2005 and

2021 who were treated and followed at authors’ institution
* İbrahim Kartal
ibrahim_kartal28@hotmail.com were reviewed; the last date of data collection was 12 July,
2022. The clinical features, histopathology, treatment modal-
1
Division of Pediatric Hematology and Oncology, ities, prognostic criteria, and survival rates were analyzed.
Department of Pediatrics, Faculty of Medicine, Ondokuz Primary tumors were evaluated by brain magnetic resonance
Mayıs University, Samsun, Turkey
imaging (MRI). Spinal involvement was explored using
2
Department of Radiation Oncology, Faculty of Medicine,
Ondokuz Mayıs University, Samsun, Turkey

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Indian Journal of Pediatrics (November 2023) 90(11):1116–1122 1117

spinal MRI preoperatively or 3 wk postoperatively. Cer-

ebrospinal fluid (CSF) was analyzed at least 3 wk postop-
eratively. The Chang staging system was used: M0 indicates
no evidence of gross residual tumor or metastasis, M1 is the
presence of microscopic tumor cells in the cerebrospinal
fluid, M2 is gross nodular seeding within the central nerv-
ous system other than the spinal space, M3 is gross nodular
seeding in the spinal subarachnoid space, and M4 is metas-
tasis outside the cerebrospinal axis [5]. The extent of resec-
tion and any residual tumor were evaluated by postoperative
MRI. Gross/total resection was defined as the absence of a
visible tumor on postoperative imaging; subtotal resection
was defined as when over 50% of the tumor was removed.
The histological subtypes were those of the World Health
Organization, but authors were not able to perform molecu-
lar classification [6]. Patients with postoperative residual
tumors (>1.5 ­cm2 in area), who were younger than 3 y of
age, and metastasis staging ≥M1 ­(Mrisk) were considered to
be at high risk.
After surgery, all patients older than 3 y of age were
prescribed fractionated, intensity modulated external radio-
therapy (RT) to both the cranium and spinal cord commenc-
ing 3–7 wk after surgery. The craniospinal irradiation (CSI)
doses were 23.4 Gy for standard and 36 Gy for high-risk
patients and boost doses were delivered to a total of 54 Gy Fig. 1  Patient management diagram
to the primary tumor bed. Radiotherapy was not given to
children under 3 y of age; in these children, chemotherapy
continued until 3 y of age. If a child received the total chem- The study was approved by the Medical Ethics Commit-
otherapy protocol dose, temozolomide 200/mg/m2/d was tee (16/12/2021, no. 2021000540). Informed consent to treat
given for 5 d every 4 wk until radiotherapy. Vincristine was the disease was obtained from the patients’ parents.
administered weekly during RT. Adjuvant chemotherapy IBM SPSS ver. 23 was used for all analyses. Overall sur-
was commenced in all patients (both standard and high-risk) vival (OS) was defined as the time from diagnosis to death
approximately 2–3 wk after the end of RT; eight courses of or the day of the last checkup with the healthcare team.
the SIOP/UKCCSG PNET-3 protocol were delivered at an Event-free survival (EFS) was defined as the time from
interval of at least 3 wk. In authors’ institution, based on the diagnosis to the first recurrence or death. Kaplan–Meier
decision of the multidisciplinary tumor council, the timing survival curves were drawn and log-rank tests performed to
of radiotherapy was earlier than in the original protocol; compare OS and EFS based on the known prognostic factors
in patients with severe thrombocytopenia, 70 mg/m2 cispl- and the timing of RT after surgery. Independent mortality
atin was substituted for carboplatin in each course to avoid risk factors were analyzed by Cox’s regression. Multivari-
treatment prolongation (Fig. 1). In patients who relapsed or able analysis was performed for factors with a p value <0.1
progressed, “8 drugs in a day” were usually used as salvage in the univariable analyses. The level of significance was
chemotherapy and other alternatives. taken to be p <0.05.
The chemotherapy protocol was conducted over four
alternate cycles at a 3-wk interval (eight cycles). The regi-
men consisted of vincristine 1.5 mg/m2, given three times Results
weekly; etoposide 100 mg/m2/d, given for three consecutive
days; and carboplatin 500 mg/m2/d, given on the first two Twenty-six (54.2%) patients were male and 22 (45.8%) were
days or vincristine 1.5 mg/m2, given three times weekly; female. The mean age at diagnosis was 7.27±4.21 (median
etoposide 100 mg/m2/d, given for three consecutive days; 6.5, range 1–17) y; 70.8% of the patients (n = 34) underwent
and cyclophosphamide 1.5 g/m2, with mesna given on the their initial surgery at authors’ institution. A second surgery
first day. Patients who received at least one course of chem- was performed for four patients. At diagnosis, 75% of the
otherapy were included in the study, even if they did not patients (n = 36) lacked spinal involvement. Postoperative
complete the treatment. residues (≥1.5 c­ m2) were detected in 29.2% of the patients

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1118 Indian Journal of Pediatrics (November 2023) 90(11):1116–1122

Table 1  Clinical characteristics and event-free survival (EFS) disease (two high risk, two standard risk; one survived and
Characteristics n 5-year EFS P value the other three died). The median follow-up was 56 (3–216)
mo. All patients under 3 y of age at diagnosis were ulti-
Age (years) 0.038 mately given radiotherapy, except one who died before 3 y
<3 5 30±23.9 of age while on chemotherapy.
≥3 43 74.2±7.7 The 5-year event-free survival of those younger (n = 5) and
Residue ­(cm2) 0.090 older (n = 43) than age 3 was 30.0±23.9% and 74.2±7.7%,
>1.5 ­cm2 14 57.1±16 respectively (P = 0.038). The median start time of radiother-
≤1.5 ­cm2 34 75.1±8.4 apy after surgery was 37 (range 19–80) d for patients >3 y
Postoperative radio- 0.385 old. Radiotherapy was interrupted for more than 1 wk in one
therapy time (weeks)
patient only (now alive). The 5-year event-free survival of
>7 16 59.7±14.6
patients for delayed (beyond 7 wk) and non-delayed radio-
≤7 31 76.7±8.7
therapy was 59.7±14.6% and 76.7±7.4% (P = 0.385), respec-
Metastasis 0.551
tively, without considering the risk group. Table 1 summa-
M0 19 76±12.3
rizes the clinical characteristics and EFS of the patients.
M1 4 75±21.7
Overall, 13 of 48 the patients died and 35 are still alive
M2 13 69.2±12.8
(72.9%); 12 of 30 high-risk patients and 1 of 18 standard-risk
M3 12 59.5±16.2
patients died. Kaplan–Meier analysis revealed that the over-
Overall 0.072
all survival rate was 53.6±16.4%, including 39.0±17.3%
High risk 30 61.2±10
for the high-risk and 92.9±6.9% for the standard-risk
Standard risk 18 82.5±11.5
patients (P = 0.014) (Fig. 2a). Overall 5 y, 73.2±7.1% of
EFS Event-free survival the patients survived: 61.2±10% for the high-risk group
and 92.9±6.9% for the standard-risk group (P = 0.026)
(Fig. 2b). The overall EFS at 5 y was 69.7± 7.6%:
(n = 14). The histology was classical in 72.9% (n = 35) of the 61.2±10% in the high-risk group and 82.5±11.5% in the
patients, desmoplastic nodular in 10.4% (n = 5), and large standard-risk group (P = 0.072).
cell/anaplastic in 16.7% (n = 8). Recurrent disease developed Although authors found no significant risk factor effect-
in 18.7% (n = 9), of whom seven died and two are alive. ing survival on univariate Cox regression analysis, the
Of the recurrences, five were metastatic and four had local values for residual disease and age risk were borderline

Fig. 2  Overall (a) and 5-year (b) survival of the patients by risk group

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Indian Journal of Pediatrics (November 2023) 90(11):1116–1122 1119

(P <0.1). On multivariable analysis, neither residual disease
nor age risk were not significant but the value was P <0.1
for residual disease (Table 2).
Three of the 35 surviving patients were followed-up in
another hospital; another five were over the age of 21 and
had to be followed up at adult centers. The remaining 27
patients were followed regularly. One year after treatment
cessation, authors began to check for ototoxicity and detected
it in five patients (two at standard risk, three at high risk); it
was severe in three and mild in two. One patient had bilateral
mild mixed hearing loss and this patient also had Apert syn-
drome. Both tympanic membranes were perforated in one
patient due to chronic otitis, and he had conductive hearing
loss severe enough to require a hearing aid; he underwent
tympanoplasty. All the patients had neurology referrals,
while there was no routine neurocognitive follow-up. The
median number of episodes of febrile neutropenia was 3
(0–8) (grade 3/4) and 11 patients did not have any episodes
of febrile neutropenia; no one died of febrile neutropenia.
Nine patients did not require thrombocyte transfusion and
the median transfusion frequency was 3 (0–7) (grade 3/4).
No severe bleeding arose due to thrombocytopenia. Table 3
summarizes the adverse effects detected during follow-up.
Discussion
The five medulloblastoma subgroups are defined histopatho-
logically: classical, desmoplastic/nodular, extensive nodu-
lar MB, large cell, and anaplastic (the last two were subse-
quently combined into a single histopathological category)
[7]. Medulloblastomas have also been categorized into four
molecular subtypes: WNT, SHH, Group 3, and Group 4,
according to the clinical and genetic features [8, 9]. As authors
could not perform molecular analyses in their patients, they
used the Chang Staging System for risk stratification.

Table 2  Independent risk Univariable (Cox) Exp(B) (%95 CI) P value

factors affecting overall survival
(Cox regression analysis) Gender
Male 0.823 (0.273–2.477) 0.728
Female
Spinal involvement
Yes 2.069 (0.676–6.329) 0.203
No
Residue
>1.5 ­cm2 2.989 (0.986–9.064) 0.053
≤1.5 ­cm2
Metastasis
≥M1 0.795 (0.264–2.396) 0.684
M0
Age (year)
<3 3.532 (0.953–13.091) 0.059
≥3
Timing of radiotherapy (week)
>7 0.687 (0.217–2.170) 0.522
≤7
Large cell/anaplastic histology
Yes 0.038 (0–32.165) 0.342
No
Multivariable (Cox) Exp(B) (%95 CI) P value

Residue
>1.5 ­cm2 2.729 (0.884–8.431) 0.081
≤1.5 ­cm2
Age (year)
<3 3.028 (0.802–11.432) 0.102
≥3

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1120 Indian Journal of Pediatrics (November 2023) 90(11):1116–1122

Table 3  Side effects seen during patient follow-up survival of the present high-risk patients was similar to
Side effects n % that reported, while the survival of standard-risk patients
was > 80%, consistent with the results of the SIOP PNET-4
Alive on follow-up 27 study [11]. There were no significant risk factor on multi-
Ototoxicity 5 18.5 variable analysis, however, if there were large number of
SNHL 3 patients, residual disease might be a candidate to be a risk
CHL 1 factor because of borderline value (P = 0.081).
MHL + Apert syndrome 1 In metastatic MB (M2/3) patients who received SIOP/
Infertility (Azospermia) 3 11.1 UKCCSG PNET-3 chemotherapy, the OS was 50% at 3 y
Hypogonadotropic hypogonadism 3 11.1 and 43.9% at 5 y. The EFS was 39.7% at 3 y and 34.7% at 5
Central hypothyroidism + Growth hormone 4 14.8 y. In this study, the median interval from surgery to RT was
deficiency
117 (mean 121, range 29–212) d [12]. In the present cases,
Panhypopituatiarism 1 3.7
the mean start of postoperative RT was 37 d after surgery.
Central hypothyroidism 2 7.4
The 5-year EFS of high-risk patients was 61.2%, while the
Epilepsy 2 7.4
5-year EFS of M3 patients with only spinal involvement was
+ home MV, tracheostomy, PEG 1
59.5%. These results are better than those of the original
+ Urinary incontinence 1
chemotherapy protocol, and similar to those of more recent
CHL Conductive hearing loss, home MV Home mechanical ventila- studies in which RT was begun immediately [11, 13].
tor, MHL Mixed hearing loss, PEG Percutaneous endoscopic gastros- In developing countries, limited resources, the level of
tomy, SNHL Sensorineural hearing loss patient awareness, and difficulties in accessing treatment are
the main causes of the failure of optimal treatment [14]. To
It has been shown that the addition of chemotherapy prevent this, the patients in the present study were closely
to radiotherapy and completion of RT within 50 d after followed; the pediatric oncologists in authors’ institution fol-
inception are independent predictors of improved EFS in low patients on their own personal phones and are in close
non-metastatic patients with SIOP/UKCCSG PNET-3 communication with the patients’ parents to ensure that they
in a multivariable analysis [10]. In a study of HIT-SIOP come to treatment regularly and undergo optimal manage-
PNET-4 [11], the median time from diagnosis to RT was ment of their complications. When there are difficulties,
37 d and the prognosis was poorer in patients in whom RT families can get social assistance from the government. In
was delayed for over 7 wk. Excellent survival rates were Table 4, the current treatment outcomes in some centers in
reported in patients with no postoperative residual tumor developing countries that treat patients without molecular
and no delay in RT. In the present study, authors used SIOP/ analyses are summarized [15–27]. Some of these centers
UKCCSG PNET-3 and initiated radiotherapy a median of mention limited resources regarding treatment access [15,
37 d after surgery, together with weekly vincristine. The 17, 18, 23, 24]. Some focused on the negative consequences

Table 4  Published reports on pediatric medulloblastoma from developing countries

Author Country Year n Survival

Ali et al. [15] Egypt 2019 53 5-year OS 54.6%, DFS 74.8%

Sirachainan et al. [16] Thailand 2018 23 5-year OS 41.8%, DFS 60.0% (high risk)
Mehrvar et al. [17] Iran 2018 126 7-year OS 59%, PFS 53.8%
Bleil et al. [18] Brazil 2019 69 5-year OS 44.5%, EFS 36.4%
Muzumdar et al. [19] India 2011 365 5-year PFS: 73% (average risk), 34% (high risk)
Gupta et al. [20] India 2012 20 3-year relapse-free survival: 83% (average risk, age >5 y)
Kumar et al. [21] India 2015 31 3-year OS: 40%
Gaur et al. [22] India 2015 58 91% alive at 1.5 y
Wang et al. [23] China 2016 67 3-year OS: 55.1%, PFS: 45.6%
Rajagopal et al. [24] Malaysia 2017 43 5-year OS: ≥3-y-old 41.7%, <3-y-old 45.6% (high risk)
Das et al. [25] India 2019 26 4-year EFS: 100% (average risk), 63% (high risk)
Bokun et al. [26] Serbia 2018 87 5-year OS: 66.2%
Küpeli et al. [27] Türkiye 2020 84 5-year OS: 58.1%, EFS: 57.6%
Kartal et al. (Current study) Türkiye 2022 48 5-year OS: 73.2%, EFS: 69.7%

DFS Disease-free survival, EFS Event-free survival, OS Overall Survival, PFS Progression-free survival

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Indian Journal of Pediatrics (November 2023) 90(11):1116–1122
of patients refusing or abandoning treatment [23, 25]. Some
centers point out the general problems with malnutrition,
infection, and parasitic diseases in developing countries [17,
27], even when all treatment conditions are optimal.
Ototoxicity is an important risk considering the RT doses
used in MB protocols; RT and cisplatin may have syner-
gistic toxic effects. Approximately 40–60% of long-term
survivors of childhood MB experience moderate to severe
hearing loss [28]. In a meta-analysis of 5077 individuals, the
prevalence of ototoxic hearing loss associated with carbo-
platin-only regimens was 13.47% (approximately one-third
of that associated with cisplatin alone) [29]. Comparing
intensity modulated radiotherapy (IMRT) and standard CSI,
IMRT was found to give a reduced dose to the cochlea and
grade 3/4 hearing loss occurred in only 13% of the IMRT
group (median follow-up 18 mo) compared to 64% of the
other group (median follow-up 51 mo) [28]. IMRT treat-
ment has been used in authors’ institution for about 10 y.
In present patients, the ototoxicity rate was 18.5% in the
patients (5/27) followed up: one patient developed ototoxic-
ity and additional complications after surgery; another had
Apert syndrome, which has a deafness component; two had
received cisplatin instead of carboplatin due to refractory
thrombocytopenia; and one had no risk factors. The lower
ototoxicity in present patients might be due to the use of
carboplatin and IMRT, but the frequency could increase over
time with follow-up.
This study has some limitations. It was a single center
study with a small number of patients. The authors could
not perform molecular analysis and had to group the patients
according to the Chang system. There were no neurocogni-
tive evaluations and it was not a randomized prospective
study. The authors have begun to refer their patients for
molecular analysis to a feasible center and are considering
as part of the risk stratification for the same treatment proto-
col. As patient survival increases, the long-term effects will
become more important, like short stature, infertility, and
neurocognitive dysfunction.
In summary, the authors prioritized the RT timing of the
original SIOP/UKCCSG PNET-3 protocol and changed car-
boplatin to cisplatin in patients with thrombocytopenia to
eliminate any treatment delay in patients with medulloblas-
toma. The patients’ outcomes were similar to those of cur-
rent protocols using molecular studies. Although a definitive
conclusion is impossible given the small number of patients,
authors suggest that the present protocol is a viable option
for centers with limited facilities.
Authors' Contributions İK, AD, OSD, HKŞ, AU, ŞBG: Constructing
the hypothesis or idea of research and/or article, providing personnel,
environment, financial support tools that are vital for the study, biologi-
cal materials, taking responsibility of the referred patients; İK, AD:
1121
Planning methodology to reach the conclusions, organizing, supervis-
ing the course of progress and taking the responsibility of the research/
study, literature review, writing the article, reviewing the article before
submission scientifically besides spelling and grammar; İK, AD, OSD,
AU, HKŞ: Data collection and/or processing; İK, AD, OSD: Taking
responsibility in logical interpretation and conclusion of the results.
All authors read and approved the final manuscript. İK will act as
guarantor for this manuscript.
Declarations
Conflict of Interest None.
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bined clinical, pathologic, and molecular variables. J Clin Oncol.
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toma in childhood: Chang’s classification revisited. Int J Surg
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therapy for young children with medulloblastoma (SJYC07):
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trial. Lancet Oncol. 2018;19:768–84.
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11. Lannering B, Rutkowski S, Doz F, et al. Hyperfractionated versus
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Indian Journal of Pediatrics (November 2023) 90(11):1123–1126
https://doi.org/10.1007/s12098-023-04682-x
EDITORIAL
Transition of Care- The Time is Now!
Jagdish Chandra1,2 · Sucheta M. Joshi3
Received: 14 March 2023 / Accepted: 17 March 2023 / Published online: 18 August 2023
© The Author(s), under exclusive licence to Dr. K C Chaudhuri Foundation 2023
The survival of pediatric-onset chronic diseases has sig-
nificantly improved over the years. While general improve-
ment in life expectancy is a significant factor contributing to
improved survival, improvements in diagnostic techniques
including molecular diagnosis, as well as precision medi-
cine means that more children with chronic diseases, includ-
ing what were thought to be fatal conditions, are surviving
into adolescence and adulthood. In the absence of disease-
specific registries, data on long term survival of such dis-
eases in India is not precisely known. The world over,
survival of juvenile diabetes is well known. Children with
transfusion dependent thalassemia (TDT) are surviving lon-
ger into adulthood. A recent position statement of Thalas-
semia International Federation (TIF) on adult thalassemics
has discussed the potential of near normal survival of TDT
patients [1]. Children with cystic fibrosis are also living
into adulthood [2], while similar trends have been observed
in adolescents with epilepsy [3]. Adolescents with such
chronic medical conditions constitute a continuously grow-
ing pool of youth with special health care needs (YSHCN).
There is a need for the care of the YSHCN to be taken up by
adult care specialists and for a smooth and seamless transi-
tion of care from Pediatrics to Internal Medicine.
The term Transition is defined as a “change or shift from
one state, subject, place, etc. to another” [4]. In medicine,
transition is defined as “purposeful, planned process that
addresses the medical, psychosocial, educational and voca-
tional needs of adolescents and young adults with chronic
medical and physical conditions as they move from child-
centered to adult orientated healthcare systems” [5]. In
Jagdish Chandra
jchandra55@gmail.com
1
Department of Pediatrics, PGIMSR & ESIC Model Hospital,
Basaidarapur, New Delhi 110015, India
2
B 1007, Sea Show CGHS, Plot 14, Sector 19 B, Dwarka,
New Delhi 110075, India
3
Division of Pediatric Neurology, Department of Pediatrics,
Michigan Medicine, Ann Arbor, MI 48104, USA
practice this translates to movement from a child and fam-
ily-centered environment of pediatrics to a patient-centered
adult medicine setting. Transition is often used interchange-
ably with transfer of care; however the latter is the final
outcome, a single event where care is handed over from a
pediatric to adult provider.
The American Academy of Pediatrics states, “The goal of
transition in health care for YSHCN is to maximize lifelong
functioning and potential through the provision of high-
quality, developmentally appropriate health care services
that continue uninterrupted as the individual moves from
adolescence to adulthood” [6]. There are several reasons
why Transition of Care (TOC) for YSHCN- is needed.
With increased survival in chronic diseases, newer long
term complications and disabilities have emerged requiring
focused attention. For instance, among patients with TDT,
the incidence of iron overload related cardiomyopathy has
decreased. However, these patients are now at greater risk
of atherosclerotic cardiovascular disease due to prolonged
survival and associated impaired glucose metabolism [1].
Cystic fibrosis associated diabetes mellitus which occurs
in 2% in childhood, increases several folds in adolescence
and adulthood [7]. A large number of survivors of childhood
cancer will have other health issues with obesity, hyperten-
sion and hyperlipidemia being more common [8]. As these
children reach adult age, the knowledge of such complica-
tions and expertise to manage them are important for adult
care providers.
Another reason for TOC is to ensure ongoing treatment
adherence. Without proper TOC, adolescents are likely to
have non-adherence to treatment resulting in adverse out-
comes. Adolescents with Human-immunodeficiency virus
(HIV) infection on anti-retroviral therapy (ART) remain
largely asymptomatic and are full of energy which in itself
is the hallmark of adolescence. With this state of health and
mind, they do not feel need of taking ART anymore, and
are at risk for loss of treatment adherence and relapse of
disease [9]. Similarly, poor glycemic control and higher
emergency room visits among patients with type 1 diabe-
tes mellitus, transplant rejection among kidney transplant
13
1124
recipients and overall increased risk of loss of follow up are
described when TOC is not well addressed [10–13]. In addi-
tion, patient satisfaction which facilitates heightened adher-
ence is described when TOC is well planned. Positive youth
development programs have shown better health care self-
advocacy as well [14, 15]. Moreover, TOC is “to affirm that
just as children receive optimal primary care in a medical
practice experienced in the care of children, so too adults
benefit from receiving care from physicians who are trained
and experienced in adult medicine” [6].
Despite the well felt need of TOC, its implementation is
challenging, from the perspectives of pediatricians, physi-
cians as well as patients and families. Pediatric specialists
who care for children with chronic diseases follow these
patients through formative and critical years of childhood
and adolescence feel concerned about transition. They may
feel less comfortable referring their patients to an adult pro-
vider who is perceived as less familiar and less knowledge-
able about a childhood-onset condition. Families also have
a difficult time reconciling with a new provider after years
of trusted doctor-patient relationship with their pediatric
specialist. In this symposium, several authors have identi-
fied this issue as a barrier to TOC. Kanhere et al. as well as
Riar et al. have also identified cognitive challenges, legal
and economic issues as other issues that can impact TOC.
Indeed, for many YSHCN, these issues must be considered
while planning TOC as a subset of this population may need
assistance with financial planning, employment, indepen-
dent living. Lack or inadequate medical records are also
commonly cited barriers to TOC [16].
In developed countries including Canada, United States
and across Europe, transition programs have been designed
and are out into practice. There are studies from these sys-
tems not only on process and determinants of proper tran-
sition, but also towards evaluating different methods of
transition [6, 17, 18]. In India, discussion and studies on
health care transition (HCT) have only recently started
appearing [9, 19, 20].
TOC should focus on promoting skills in self-care, com-
munication, decision-making, assertiveness and advocacy
among YSHCN. Aspects of self-care and advocacy must
include having complete understanding of the disease, inde-
pendent living skills, self-medication, adherence, visiting
health professionals independent of their parents, involve-
ment in decision-making, and having knowledge of access-
ing the health service [21].
In the USA, ‘Got Transition’ has described 6 core ele-
ments of the process of TOC [22], starting with a transition
policy to completion of transfer of care:
i) Transition policy and guide—Develop, discuss and
share transition and care policy/ guide
13
Indian Journal of Pediatrics (November 2023) 90(11):1123–1126
ii) Tracking and monitoring—Track progress using a flow
sheet registry
iii) Readiness—Assess self-care skills and offer education
on identified needs
iv) Planning—Develop HCT plan with medical summary
v) Transfer of care—Transfer to adult-centered care and to
an adult practice, and
vi) Transition completion
To these 6 core elements, the Agency for Clinical Innova-
tion, Government of New South Wales, Australia has also
added identifying a local transition coordinator and commu-
nication with receiving team of physicians [23]. Educating
the receiving team of physicians should also be given due
importance [24]. The Canadian guidelines on TOC include
evaluation of the system as well [25].
While development of TOC policy is needed at national,
regional and state levels, it is important for hospitals to
develop local policies and practice guidelines around TOC.
Such policies help develop local programs for TOC, which
can be translated at larger levels. At a minimum, a TOC
policy should state (i) age of transition, (ii) transition initia-
tion and assessing readiness, (iii) nominated care providers
- both pediatrician and receiving physician, (iv) joint care
clinics, (v) care coordinator/ counsellor/ nurse(s).
There is varied opinion around the optimal age for transi-
tion. The US ‘Got Transition’ recommends initiating transi-
tion discussion at 12–14 y of age and complete all steps of
transition by 18–23 y [22]. Cut- off ages of 12 y, 13 y and
18 y are suggested by others, based on hospital policy. Some
have recommended a flexible approach, taking into account
not only chronological age but also emotional and develop-
mental maturity of the individual [26, 27]. Adolescent care
still falls under Pediatrics in most parts of the world, in such
systems, patients may be allowed to attend Pediatrics ser-
vices till 18 y age.
Assessment of transition readiness is also important to
understand needs of the patient and family, so that resources
around health care, education, psychosocial needs can be
individualized. There are validated tools available for such
screening, such as “Transition Readiness Assessment Ques-
tionnaire” (TRAQ)—a tool that is not disease specific, and
easy to administer [6, 28]. Disease specific tools have been
developed for conditions such as epilepsy [29]. Transition
tools can also be found at GotTransition.org [22].
There is also need for educating the adult providers in
the management of YSHCN. This is even more important
in context of pediatric-onset diseases which the adult physi-
cian may not be familiar with. Such education must remain
a longitudinal ongoing process where the pediatric special-
ist should be available for addressing any health care issues
that may arise [30, 31].
Indian Journal of Pediatrics (November 2023) 90(11):1123–1126
For proper TOC, the importance of joint care clinics has
been highlighted by Dabadie et al. [32]. These joint care
clinics aim at familiarizing the patients with the staff and
environment they are moving to. The meetings should be
attended by both the teams and care coordinators and nurses
as well. It is important to transfer the records and relevant
data regarding the patients’ illness at the time of actual
transfer or before that. To minimize the chances of loss of
follow up, a transition registry needs to be maintained [30].
In the current symposium, the importance and need for
TOC has been articulated across several Pediatric subspe-
cialties including patients with epilepsy, diabetes (and other
endocrine disease), celiac disease, cystic fibrosis, thalas-
semia, cancer survivors and nephrotic syndrome [33–39].
Common themes outlined by several authors include the
close long-term relationship between the pediatric provider,
patient and families, emphasizing this as a physician fac-
tor that could be a barrier to TOC. There is clear recogni-
tion of the need and importance of TOC for the adolescent
population broadly. As such the time to implement transi-
tion policies, provider education is now. Developing transi-
tion registries will help in informing processes around TOC.
As the system evolves in India, research into health related
outcomes is needed to determine best practices and develop
guidelines for successful transition of care for youth with
special health care needs.
Declarations
Conflict of Interest None.
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19. Basu S. Health care transition: Need of the hour. Indian J Pediatr.
2020;87:411–2.
20. Menon J, Peter AM, Nayar L, Kannankulangara A. Need and fea-
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https://doi.org/10.1007/s12098-023-04742-2
EDITORIAL
Anemia in Severe Acute Malnutrition: Ten Steps of Management Need
to be Fine‑Tuned
Jagdish Chandra1,2 · Praveen Kumar3
Received: 15 April 2023 / Accepted: 19 June 2023 / Published online: 12 July 2023
© The Author(s), under exclusive licence to Dr. K C Chaudhuri Foundation 2023
Introduction
Malnutrition remains an important public health problem
due to its associated high morbidity, mortality and seri-
ous long-term consequences [1]. Children with severe
acute malnutrition (SAM) i.e., children with weight for
length/ height less than -3SD and/ or mid upper arm cir-
cumference (MUAC) less than 115 mm in children 6–59
mo and/ or bilateral pitting pedal edema of nutritional
origin are at maximum risk of adverse health outcomes
and death [2].
As per UNICEF/ World Health Organization (WHO)/
World Bank Group Joint Child Malnutrition estimates,
144 million (21.3%) under 5 children are stunted, 47 mil-
lion (6.9%) under 5 children are wasted and 38.3 million
(5.6%) under 5 children are overweight in 2019 world-
wide [3]. India is one of the countries with very high
prevalence of severe acute malnutrition. As per National
Health and Family Survey-5 estimates, 7.7% of children
aged 6–59 mo in India are suffering from severe acute
malnutrition (SAM) at any point of time [4]. As nutri-
tion features strongly in the sustainable development
goals (SDG) with SDG target 2.2 aiming “end all forms
of malnutrition by 2030” including achieving by 2025, the
internationally agreed targets on stunting and wasting in
children under 5 y of age, we need to look for areas where
changes are needed [5].
* Jagdish Chandra
jchandra55@gmail.com
1
Department of Pediatrics, PGIMSR and ESIC Model
Hospital, Basaidarapur, New Delhi, India
2
B-1007, Sea Show CGHS, Plot 14, Sector 19B,
Dwarka, New Delhi 110075, India
3
Department of Pediatrics, LHMC and KSCH, New Delhi,
India
Anemia in Children with Severe Acute
Malnutrition
Anemia is a common clinical problem in children with SAM.
Children with SAM have several co-morbidities/ complica-
tions. These include pneumonia, acute diarrhea/ gastroenteri-
tis, sepsis and anemia. In recent studies on hospitalized chil-
dren with SAM, pneumonia occurred in 27.8 to 39%, diarrhea
in 26.5 to 61% while anemia was observed in 73.5% to 90%
[6–10]. True, all grades of anemia do not lead to immedi-
ate threat of life, which complications such as pneumonia or
gastroenteritis will pose. However, severe anemia has also
been reported as a very frequent co-morbidity. Thakur et al.
reported severe anemia in 67% of children and transfusion
requirement in 25% children with SAM [6]. Similar high
prevalence of severe anemia (24–70%) has been reported by
others [8, 10–13]. Presence of moderate to severe anemia
in SAM children with pneumonia, diarrhea, malaria etc. is
likely to further increase risk of mortality.
Wagnew et al. in a study from Ethiopia, reported that
SAM children with anemia had more than two times higher
hazard ratio for death [14] while Roy et al. from Bangla-
desh reported 4.2 times odds of death in SAM children with
anemia compared to those without anemia [15]. Gavhi et al.
compared adjusted odd’s ratio (aOR) of several factors for
mortality in children with SAM. They observed that pres-
ence of hypoglycemia had highest aOR (12.5) while aOR
for MUAC <11.5 cm, presence of poor appetite and anemia
were 3, 2.7 and 2.5 respectively [16].
There are several factors which influence the recovery
in cases with SAM. Presence of edema, age of the patients,
presence of diarrhea and other infections and anemia are
known determinants of recovery. A study by Gebremedhin
et al. from Ethipoia concluded, compared to younger chil-
dren, those above 24 mo were three times more likely to
recover from SAM while those with diarrhea were 78%
less likely to recover. Presence of anemia also had negative
effect with anemic children being 36% less likely to recover
13
Vol.:(0123456789)
1062 Indian Journal of Pediatrics (November 2023) 90(11):1061–1064

[17]. Another study reported significant longer hospitaliza-
tion duration in anemic SAM children. In this study also,
SAM children without anemia had 1.36 times more chance
of recovery [18].
Ten Steps of Management for Children
with Severe Acute Malnutrition Requiring
Inpatient Care
The WHO in the year 1999 published guidelines for the
management of children with SAM. The guidelines provide
‘Ten Steps’ for management of children with SAM which
takes care of their common metabolic and physiological
changes, also known as reductive adaptations [19]. Sub-
stantial reductions in mortality rates have been achieved by
modifying treatment, taking into account the physiological
and metabolic changes occurring in severe malnutrition. In
the International Centre for Diarrhoeal Disease Research,
Bangladesh, after the introduction of a standardized proto-
col, based on the WHO guidelines, fatality rate decreased to
9% and subsequently to 3.9% from an earlier 17%. In South
Africa as well, the mortality rate decreased from 30–40% to
less than 15% [20].
In the ‘Ten Steps’ of management of severe malnutrition,
initial five steps address hypothermia, hypoglycemia, dehydra-
tion, dyselectrolytemia and infections. Sixth step is regarding
supplementation for correction of micronutrient deficiencies.
Micronutrients recommended to be supplemented include folic
acid, zinc, copper and iron. Supplementation of iron comes with
a warning that giving iron to start with may worsen the infec-
tion, hence iron supplementation to be started only when child

Table 1  Steps of SAM Steps Stabilizaon Phase Rehabilitaon

management: Fine-tuned to 11
steps 1-3 d 3-7 d 2-6 wk

1 Treat /Prevent
Hypoglycemia

2 Treat /Prevent
Hypothermia

3 Treat & Prevent

Dehydraon

4 Correct Electrolyte
Imbalance

5 Treat Infecons

6 Treat Severe Anemia

7 Correct Micronutrient
Deficiencies*
No Iron Iron
Iron Supplementaon

8 Start Cauous Feeding

9 Achieve Catch Up
Growth

10 Provide Sensory
Smulaon &
Structured Play Therapy

11 Prepare for discharge &

Follow-up

*
Investigate cause of moderate and severe anemia before starting supplementation and tailor therapy
according to serum ferritin, vitamin B12, folic acid levels

13
Indian Journal of Pediatrics (November 2023) 90(11):1061–1064
has started gaining weight [19, 20]. The document includes
recommendation for blood component therapy in children with
severe anemia if hemoglobin (Hb) is less than 4 g/dl in children
without cardiopulmonary compromise and <6 g/dl in presence
of cardiopulmonary compromise. However, this recommenda-
tion gets overlooked as it is not highlighted in ten steps. Second
issue is regarding duration of iron supplementation. For mild
and moderate anemia, iron supplementation is recommended
for 2 mo only. Work up for vitamin B12 deficiency and sup-
plementation is not mentioned. Further, under the section on
management of associated conditions, vitamin A deficiency,
dermatosis, parasitic infestations, continuing diarrhea and
tuberculosis is mentioned but anemia is not listed. In the sec-
tion on assessing the cases who fail to respond, assessment for
micronutrient deficiencies is listed. Anemia doesn’t get men-
tioned here as well [19, 20].
Guidelines on in-patient management of SAM in children
in India are largely based upon these WHO endorsed ‘Ten
Steps’ [21–23]. Going by the current understanding of ane-
mia in SAM as discussed above, we need to revisit the ‘Ten
Steps’ of SAM management and include the following to
address anemia better:
• First, though it is not stated as such but all cases with
SAM who are hospitalized get a blood specimen drawn
for estimation of serum electrolytes, kidney function test
(KFT) and complete blood counts to address the first
five steps. Hb report may be available within few hours.
It may clearly be stated upfront that all hospitalized chil-
dren with SAM should be assessed for severe anemia and
transfusion is given if indicated. Going by the details in
the guidelines, this is clearly intended though not stated
as such. This step may be embedded as step six (Table 1).
• Second, there is a need to look for deficiencies of spe-
cific hematopoietic micronutrients (iron, folic acid and
vitamin B12) at least in cases with moderate and severe
anemia. Diagnostic facilities have significantly improved
since the time these guidelines were initially published.
Knowing about specific deficiencies will allow tailor-
ing the therapy better. Deficiency of vitamin B12 among
anemic children with SAM is prevalent in certain areas
of our country [13, 24]. In such regions SAM children
should be provided with therapeutic doses of vitamin
B12 which will improve weight gain as well [25].
• Third, when the preparation of discharge from hospital
is being discussed, Hb should be estimated and supple-
mentation advised accordingly. Moreover, SAM children,
particularly those with anemia at entry point should be
advised to follow iron supplementation through Anemia
Mukt Bharat as has been recommended in recent guide-
lines on anemia [26].
• Further, the duration of iron supplementation in anemic chil-
dren should be 3–6 mo as replenishment of stores is also
1063
required. Many children do not attain normal Hb level with
3 mo’ iron supplementation or management of SAM [25,
27]. The authors’ group has recently reported persistence of
anemia in SAM children even after 12 wk of supplementa-
tion of micronutrients [25]. Persistence of anemia in over
50% cases has been reported in earlier studies as well [28].
Since anemia in SAM is linked to increased mortality and
poor recovery, it is advisable to strongly recommend looking
for anemia in cases with failure of treatment.
To conclude, ‘Ten Steps’ provide an easy to follow proto-
col for management of SAM. Adherence to the protocol has
led to substantial reduction in mortality due to SAM. How-
ever, as highlighted above, ‘Ten Steps’ have not adequately
emphasized management of anemia in children with SAM.
Now since these management guidelines are almost univer-
sally followed and have become standard of care of children
with SAM, it is desirable that importance of adequately
managing anemia and associated micronutrient deficiency
in these children is also addressed as suggested.
Declarations
Conflict of Interest None.
References
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nutrition study group. Maternal and child undernutrition and
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2. World Health Organisation. WHO Child Growth Standards and
the Identification of Severe Acute Malnutrition in Infants and
Children: Joint Statement by the World Health Organization and
the United Nations Children’s Fund. WHO. 2009. Available at:
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12 Mar 2023.
3. Levels and Trends in Child Malnutrition: UNICEF/WHO/The World
Bank Group Joint Child Malnutrition Estimates: Key Findings Edi-
tion. 2018. Available at: https://​www.​who.​int/​publi​catio​ns/i/​item/​
97892​40025​257. Accessed on 12 Mar 2023.
4. National Family Health Survey-5 (NFHS-5) 2019–21. Govern-
ment of India: Ministry of Health and Family Welfare. 2020.
Available at: https://​main.​mohfw.​gov.​in/​sites/​defau​lt/​files/​NFHS-
5_​Phase-​II_0.​pdf. Accessed on 19 Mar 2023.
5. Goal 2: Zero Hunger - United Nations Sustainable Development [Inter-
net]. 2015. Available at: https://​www.​un.​org/​susta​inabl​edeve​lopme​nt/​
hunger/. Accessed on 20 Apr 2020.
6. Thakur N, Chandra J, Pemde H, Singh V. Anemia in severe acute
malnutrition. Nutrition. 2014;30:440–2.
7. Shah S, Prajapati N. Anemia among SAM children and its effect
on outcome in nutrition rehabilitation centre at tertiary care centre
of Gujarat. MedPulse Int J Pediatr. 2020;16:21–4.
8. Arya AK, Kumar P, Midha T, Singh M. Hematological profile
of children with severe acute malnutrition: A tertiary care centre
experience. Int J Contemp Pediatr. 2017;4:1577–80.
13
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9. Meshram II, Arlappa N, Balakrishna N, Rao KM, Laxmaiah A, Brahmam
GNV. Trends in the prevalence of undernutrition, nutrient and food
intake and predictors of undernutrition among under five year tribal
children in India. Asia Pacific J Clin Nutr. 2012;21:568–76.
10. Garg M, Devpura K, Saini SK, Kumara S. A hospital based study
on co-morbidities in children with severe acute malnutrition. J
Pediatr Res. 2017;4:82–8.
11. Kumar R, Singh J, Joshi K, Singh HP, Bijesh S. Comorbidities
in hospitalized children with severe acute malnutrition. Indian
Pediatr. 2014;51:125–7.
12. Sharma SD, Sharma P, Jamwal A, Saini G. Demographic and
clinical profile of children with severe acute malnutrition – An
experience from nutritional rehabilitation centre in Jammu. Int J
Sci Study. 2019;7:38–42.
13. Goyal S, Tiwari K, Meena P, Malviya S, Asif M. Cobalamin and folate
status in malnourished children. Int J Contemp Pediatr. 2017;4:1480–4.
14. Wagnew F, Tesgera D, Mekonnen M, Abajobir AA. Predictors of
mortality among under- five children with severe acute malnutri-
tion, northwest Ethiopia: An institution based retrospective cohort
study. Arch Public Health. 2018;76:64.
15. Roy SK, Buis M, Weerasma R, et al. Risk factors for mortality
in severely malnourished children hospitalized with diarrhea. J
Health Popul Nutr. 2011;29:229–35.
16. Gavhi F, Kuonza L, Musekiwa A, Motaze NV. Factors associ-
ated with mortality in children under five years old hospital-
ized for severe acute malnutrition in Limpopo province, South
Africa, 2014–2018: A cross-sectional analytic study. PLoS ONE.
2020;15:e0232838.
17. Gebremedhin K, Ayele G, Boti N, Andarge E, Fikadu T. Predictors
of time-to-recovery from severe acute malnutrition treated in an
outpatient treatment program in health posts of Arba Minch Zuria
Woreda, Gamo Zone, Southern Ethiopia: A retrospective cohort
study. PLoS ONE. 2020;15:e0234793.
18. Wagnew F, Dejenu G, Eshetie S, Alebel A, Worku W, Abajobir
AA. Treatment cure rate and its predictors among children with
severe acute malnutrition in northwest Ethiopia: A retrospective
record review. PLoS ONE. 2019;14:e0211628.
19. World Health Organization. Management of severe malnutrition:
A manual for physicians and other senior health workers. Geneva:
World Health Organization; 1999.
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20. Ashworth A, Khanum S, Jackson A, Schofield C. Guidelines for
Inpatient Treatment of Severely Malnourished Children. WHO.
2003. Available at: https://​apps.​who.​int/​iris/​handle/​10665/​42724.
Accessed on 19 Mar 2023.
21. Bhatnagar S, Lodha R, Choudhury P, et al. IAP guidelines 2006
on hospital based management of severely malnourished children.
Indian Pediatr. 2007;44:443–61.
22. Dalwai S, Choudhury P, Bavdekar SB, et al. Indian Academy of
Pediatrics. Consensus statement of the Indian Academy of Pedi-
atrics on integrated management of severe acute malnutrition.
Indian Pediatr. 2013;50:399–404.
23. Facility Based Care of Severe Acute Malnutrition. National Health
Mission. Ministry of Health and Family Welfare. 2013. Available
at: https://w
​ ww.n​ hm.g​ ov.i​ n/i​ mages/p​ df/p​ rogra​ mmes/c​ hild-h​ ealth/​
IECma​teria​ls/​PARTI​CIPANT-​MANUAL_​FBCSA-​Malnu​triti​on.​
pdf. Accessed on 19 Mar 2023.
24. Anjana Murthy K, Malladad A, Kariyappa M. Estimation of
serum Folate and Vitamin B12 levels in children with severe acute
malnutrition. Int J Contemp Pediatr. 2020;7:1013–6.
25. Khanna S, Kumar P, Sharma S, Chandra J, Sinha R. Nutritional
and hematological profile of children with severe acute malnutri-
tion rehabilitated with or without vitamin B12. Int J Commun
Med Pub Health. 2022;9:882–6.
26. Chandra J, Dewan P, Kumar P, et al. Diagnosis, treatment and
prevention of nutritional anemia in children: Recommendations of
the joint committee of pediatric hematology-oncology chapter and
pediatric and adolescent nutrition society of the Indian academy
of pediatrics. Indian Pediatr. 2022;59:782–801.
27. Yewale YN, Dewan B. Treatment of iron deficiency anemia in
children: A comparative study of ferrous ascorbate and colloidal
iron. Indian J Pediatr. 2013;80:385–90.
28. Kangas ST, Salpeteur C, Nikiema V, et al. Vitamin A and iron
status of children before and after treatment of uncomplicated
SAM. Clin Nutr. 2020;39:3512–9.
Publisher's Note Springer Nature remains neutral with regard to
jurisdictional claims in published maps and institutional affiliations.
Indian Journal of Pediatrics (November 2023) 90(11):1069–1070
https://doi.org/10.1007/s12098-023-04748-w
EDITORIAL COMMENTARY
Exploring the Association between G6PD Activity and Retinopathy
of Prematurity: A Promising Connection or a Wild Goose Chase?
Thirunavukkarasu Arun Babu1 · Ballambattu Vishnu Bhat2
Received: 19 June 2023 / Accepted: 21 June 2023 / Published online: 7 July 2023
© The Author(s), under exclusive licence to Dr. K C Chaudhuri Foundation 2023
Retinopathy of prematurity (ROP) is a vasoproliferative dis-
ease characterized by abnormal growth of blood vessels in
the developing retina of premature infants receiving exces-
sive oxygen therapy [1]. This can lead to various complica-
tions, including abnormal vascular shunts, neovasculariza-
tion, and even retinal detachment resulting in significant
ocular morbidity. Understanding its pathophysiology is cru-
cial to comprehend this complex disease in order to develop
evidence based interventions.
Normally, the relative hypoxic environment in fetus
stimulates the release of vascular endothelial growth fac-
tor (VEGF), promoting retinal vessel growth. When pre-
mature infants are exposed to high oxygen levels causing
increased reactive oxygen species (ROS), VEGF produc-
tion decreases, resulting in the cessation of vessel growth
and the formation of an avascular retina. Prolonged oxygen
exposure leads to vasoconstriction and vessel obliteration,
leaving the peripheral retina without adequate blood supply.
Over time, the avascular retina becomes ischemic, leading to
late VEGF production resulting in neovascularization [1, 2].
Glucose-6-phosphate dehydrogenase (G6PD) is an enzyme
that plays a crucial role in converting glucose-6-phosphate
to glucose and generating reduced glutathione (GSH), an
important antioxidant which directly neutralises excess ROS
implicated in the pathogenesis of ROP [2, 3].
In a case-control study by Paulpandian et al. published
in Indian Journal of Pediatrics, the researchers aimed to
explore the relationship between G6PD activity and ROP
[4]. They hypothesized that lower levels of G6PD enzyme
activity would increase the risk of ROP, as no previous
studies had examined this association. The study found that
* Ballambattu Vishnu Bhat
drvishnubhat@yahoo.com
1
Department of Pediatrics, All India Institute of Medical
Sciences (AIIMS), Mangalagiri, Andhra Pradesh, India
2
Department of Pediatrics, Aarupadai Veedu Medical College
and Hospital, Vinayaka Mission’s Research Foundation-DU,
Pondicherry 607 403, India
infants with ROP had slightly higher median G6PD activity
compared to those without ROP, although the difference was
not statistically significant. However, there was a trend of
increasing G6PD activity with more severe forms of ROP.
The researchers also found that both G6PD activity and ges-
tation independently predicted the development of ROP on
multivariable analysis.
This unexpected finding of higher G6PD activity being
associated with ROP, contrary to the initial hypothesis, was
explained by the researchers as a significant association that
is less likely to be due to chance, considering the observed
dose-responsiveness among different severity levels of ROP.
The study design used a case-control methodology, which
allowed for a comparison of G6PD activity between infants
with and without ROP while controlling for potential con-
founding factors.
However, there are few limitations to consider. The sam-
ple size was relatively small, which may affect the generaliz-
ability of the findings. A larger sample size would provide
more statistical power and strengthen the conclusions. Addi-
tionally, the study focused only on inborn boys, so the appli-
cability of the results to entire population may be limited.
Due to the case-control study design, severe cases of ROP
and those who received blood transfusions, which likely
included cases with more advanced stages of ROP, were
excluded, and milder forms of ROP were lost during follow-
up. This exclusion may have led to an overrepresentation of
moderate cases of ROP that required treatment. Additionally,
the authors were unable to measure the variation between
different observers when staging ROP, all of which could
have resulted in selection bias among the participants. The
article would benefit from a more thorough discussion of the
potential mechanisms underlying the observed association
between G6PD activity and ROP.
Although there is limited knowledge regarding normal
G6PD levels at different gestational ages in neonates, pre-
vious studies have shown an inverse linear relationship
between G6PD levels and gestation, with the highest levels
found in infants born before 29 wk of gestation, gradually
13
Vol.:(0123456789)
1070
decreasing by term gestation [3, 5]. In the current study, the
average gestational age of “controls” were almost two weeks
more than the “cases” and this difference was statistically
significant. Therefore, caution should be exercised when
interpreting the current results.
Nevertheless, this study provides valuable insights into
the potential association between G6PD activity and ROP,
shedding light on the role of oxidative stress in the devel-
opment of this condition. Despite contradicting previous
knowledge, it adds an interesting twist to the complex under-
standing of ROP's pathophysiology. Further exploration of
this association is warranted to fully comprehend the role of
G6PD activity in the development of ROP.
Declarations
Conflict of Interest None.
13
Indian Journal of Pediatrics (November 2023) 90(11):1069–1070
References
1. Strube YNJ, Wright KW. Pathophysiology of retinopathy of pre-
maturity. Saudi J Ophthalmol. 2022;36:239-42.
2. Couroucli XI. Oxidative stress in the retina: implications for retin-
opathy of prematurity. Curr Opin Toxicol. 2018;7:102-9.
3. Mesner O, Hammerman C, Goldschmidt D, Rudensky B, Bader D,
Kaplan M. Glucose-6-phosphate dehydrogenase activity in male
premature and term neonates. Arch Dis Child Fetal Neonatal Ed.
2004;89:F555-7.
4. Paulpandian R, Dutta S, Das R, Katoch D, Kumar P. Retinopathy
of prematurity and glucose-6-phosphate dehydrogenase activity: a
case-control study. Indian J Pediatr. 2023. https://d​ oi.o​ rg/1​ 0.1​ 007/​
s12098-​023-​04604-x.
5. Ko CH, Wong RP, Ng PC, et al. Oxidative challenge and glucose-
6-phosphate dehydrogenase activity of preterm and term neonatal
red blood cells. Neonatology. 2009;96:96-101.
Publisher's Note Springer Nature remains neutral with regard to
jurisdictional claims in published maps and institutional affiliations.
Indian Journal of Pediatrics (November 2023) 90(11):1165
https://doi.org/10.1007/s12098-023-04758-8

BOOK REVIEW

Essentials of Tuberculosis in Children: Rakesh Lodha, SK Kabra,

Vimalesh Seth (eds)

ISBN: 978-93-5465-762-7; Pages 492; Price: ₹ 2495

Published by Jaypee Brothers Medical Publishers (P) Ltd., New Delhi, India; 5­ th Edition: 2023;

Divya Nandakumar1 · Winsley Rose1

Received: 30 June 2023 / Accepted: 30 June 2023 / Published online: 19 July 2023
© The Author(s), under exclusive licence to Dr. K C Chaudhuri Foundation 2023

Tuberculosis (TB) is a major public health concern; tubercu-
losis in children is of special significance as it is a marker for
recent TB transmission, and because young children are at a
greater risk of developing life-threatening forms of TB dis-
ease. This book offers an updated and comprehensive overview
of tuberculosis in children. It covers many facets of tubercu-
losis in children including epidemiology, microbiology and
immune-pathogenesis, the clinical spectrum of disease, the
diagnostic methods and management in fair detail. The inclu-
sion of multiple figures and radiological images for illustra-
tion, tables to organize the content in the many chapters and
the highlights at the end of each chapter increase the appeal
of the book.
The section on clinical spectrum of tuberculosis deals
extensively with different clinical aspects of tuberculosis in
children. Some of the more difficult aspects of tuberculosis
such as neurotuberculosis are dealt with in greater detail with
the inclusion of multiple case studies that clarifies much of
the nuances in the diagnosis and management of neurotuber-
culosis. In addition to the chapters on common manifestations,
there is also a chapter that deals with unusual manifestations
such as that of the eye, ear, heart, kidney, breast etc. This sec-
tion also describes the diagnostic modalities and management
issues depending on the organ system involved.
Given the paucibacillary nature of tuberculosis in children,
establishing a definitive diagnosis is a major challenge. Con-
siderable detail has been presented in the diagnostic section
including a separate chapter on airway specimen collection. The
use of imaging in diagnosis has also been explained with mul-
tiple useful illustrative images. The advent of newer diagnostic
tests for the diagnosis of TB infection and disease have also
been covered. There is considerable detail on first and second
line anti-tuberculer drugs that improves the understanding of
their mechanisms of action, pharmacokinetics, adverse effects
and drug interactions. The management strategies and impor-
tantly, the rationale for these strategies have also been dealt with
in an understandable manner.
There are a few repetitions such as those in the chapters
on anti-tuberculous drugs and chapters on the clinical spec-
trum and diagnosis and management, some of which are
unavoidable. More details on the complications of BCG vac-
cination especially in the context of immune-compromised
conditions, paradoxical reactions and their management, and
treatment of drug resistant TB in children would have made
the book more complete.
Overall, the book has been well written and offers the cli-
nician with a good overall and in-depth view of tuberculosis
in children that can be used by practising pediatricians,
postgraduate students and infectious disease trainees.
Publisher's Note Springer Nature remains neutral with regard to
jurisdictional claims in published maps and institutional affiliations.

* Winsley Rose
winsleyrose@cmcvellore.ac.in
1
Department of Pediatrics, Christian Medical College,
Vellore, Tamil Nadu 632002, India

13
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Indian Journal of Pediatrics (November 2023) 90(11):1154
https://doi.org/10.1007/s12098-023-04761-z

SCIENTIFIC LETTER

Cardiac Outcomes in a Cohort of Children with MIS‑C

Tanu Singhal1 · Tanuja Karande2 · Prashant Bobhate2 · Preetha Joshi3

Received: 29 April 2023 / Accepted: 30 June 2023 / Published online: 13 July 2023
© The Author(s), under exclusive licence to Dr. K C Chaudhuri Foundation 2023

To the Editor: We aimed to study cardiac outcomes of chil-
dren with Multisystem inflammatory syndrome (MIS-C) at
our centre. We included all children diagnosed with MIS-C
at our centre in 2020-2021. The diagnosis and treatment was
as per standard guidelines [1]. All patients underwent ECHO
at baseline, 48-72 h, 2 wk, 4-6 wk and if abnormal, every
3-6 mo. The patients were followed up till December 2022.
Twenty-seven patients were diagnosed with MIS-C (10
in 2020 and 17 in 2021) with ages between 1-17 y (mean
7 y). Fifteen had a Kawasaki disease phenotype while 12
had a toxic shock phenotype. Nineteen patients received
intravenous immunoglobulin (IVIG) and steroids and eight
only steroids. The baseline ECHO was abnormal in 15 (55%)
patients. The ECHO abnormalities included reduced ejection
fraction (REF) in 10, coronary artery dilatation (Z score >2)
in 7 and both in 3 patients. The lowest EF was 35% and Z
score ranged from 2-2.5. All children survived and all were
followed up till December 2022. The REF function normal-
ized at 2 wk in 5 (50%) and at 3, 6, 12 and 18 mo in 1 each.
Only 1 patient had low voltage QRS complex at 18 mo. The
coronary artery dilatation resolved by 2 wk in 4 patients and
by 6 wk, 3 and 12 mo in 1 each.
The incidence of baseline cardiac abnormalities in our
cohort (55%) is similar to that reported in a recent systematic
review [2]. The findings of our study are similar to other
cohorts which have reported normalization of ECHO abnor-
malities by 6 mo in most patients [3]. However, some studies
have reported residual abnormalities in global longitudinal
strain (GLS) and cardiac MRI in 20-50% of patients at 6 mo
follow up [4]. The long term consequences of these findings
remains to be seen.
Declarations
Conflict of Interest None.
References
1. Indian Academy of Paediatrics. Multi-system Inflammatory Syn-
drome in Children (MIS-C): Statement by Indian Academy of
Pediatrics (April 2021). Available at: https://​iapin​dia.​org/​pdf/​
yOQBzD ​ mtbU4​ R05M_I​ AP%2​ 0Covi​ d%2​ 019%2​ 0mana​ gemen​ tGui​
delin​es%​20for%​20Ped​iatri​cian%​20V1.1%​20Apr%​2027_​2021%​
20%​282%​29.​pdf. Accessed on 16 Apr 2023.
2. Arantes Junior MAF, Conegundes AF, Branco Miranda BC,
et al. Cardiac manifestations in children with the multisystem
inflammatory syndrome (MIS-C) associated with SARS-CoV-2
infection: systematic review and meta-analysis. Rev Med Virol.
2023;33:e2432.
3. Yasuhara J, Masuda K, Watanabe K, et al. Longitudinal car-
diac outcomes of multisystem inflammatory syndrome in chil-
dren: a systematic review and meta-analysis. Pediatr Cardiol.
2023;44:892–907.
4. Benvenuto S, Simonini G, Della Paolera S, et al. Cardiac MRI in
midterm follow-up of MISC: a multicenter study. Eur J Pediatr.
2023;182:845–54.
Publisher's Note Springer Nature remains neutral with regard to
jurisdictional claims in published maps and institutional affiliations.

* Tanu Singhal
tanusinghal@yahoo.com
1
Department of Pediatrics, Kokilaben Dhirubhai Ambani
Hospital and Medical Research Institute, Mumbai, India
2
Department of Pediatric Cardiology, Kokilaben Dhirubhai
Ambani Hospital and Medical Research Institute, Mumbai,
India
3
Department of Pediatric Intensive Care, Kokilaben Dhirubhai
Ambani Hospital and Medical Research Institute, Mumbai,
India

13
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Indian Journal of Pediatrics (November 2023) 90(11):1164
https://doi.org/10.1007/s12098-023-04762-y

CORRESPONDENCE

Treatment of Alopecia Universalis in a Child with Down Syndrome

Evangeline Abenoja1 · Hanof Ahmed2,3,4 · Gomathy Sethuraman1

Received: 16 May 2023 / Accepted: 30 June 2023 / Published online: 3 August 2023
© The Author(s), under exclusive licence to Dr. K C Chaudhuri Foundation 2023

To the Editor: A 2-y-old Down syndrome (DS) boy had
sudden-onset of hair loss that started at the age of 1 y. He
initially had patchy hair loss on the scalp, which later pro-
gressed to involve the entire scalp and other parts of the body
including the eyebrows and eyelashes. Examination revealed
alopecia universalis (AU) (Supplementary Fig. S1A) and
scrotal tongue. Karyotyping confirmed the diagnosis of DS.
He was treated with topical mometasone lotion 0.1%, 5
drops on the scalp once daily, tacrolimus ointment 0.03%
in the evening and minoxidil lotion 2% twice daily. Sixty
percent hair regrowth was observed within four months
(Supplementary Fig. S1B). At the end of six months there
was near complete regrowth of hair including the eyebrows
(Supplementary Fig. S1C, D). After 9 mo, frequency of topi-
cal application was tapered down to alternate days and then
biweekly. Within 3 mo parents noticed 2 small patches of
partial alopecia. At which point parents were advised for
alternate days of medication and he responded within few
weeks. He is on regular follow-up and continues to show
sustained improvement.
Children with DS and AU are often treated with systemic
agents such as steroids, methotrexate, cyclosporin or JAK
inhibitors, either alone or in combination [1–4]. Even with
systemic therapy, response is variable and there is always a
relapse [4]. Other limiting factors include side effects and
high cost. Hence, we treated the child with a combination
of topical mometasone and tacrolimus along with minoxidil
2%. Interestingly, the child had excellent response and sig-
nificant regrowth of hair within four months with sustained
improvement and good tolerability. A minor relapse upon
tapering frequency was quickly addressed with subsequent
improvement.
In conclusion, children with severe AU in DS can be
treated with combination topical therapy as a safe, cost-
effective and efficacious treatment before considering other
systemic treatment options.
Supplementary Information The online version contains supplemen-
tary material available at https://​doi.​org/​10.​1007/​s12098-​023-​04762-y.
Declarations
Conflict of Interest None.
References
1. Sethuraman G, Malhotra AK, Sharma VK. Alopecia universalis in
Down syndrome: response to therapy. Indian J Dermatol Venereol
Leprol. 2006;72:454–5.
2. Cranwell WC, Lai VW, Photiou L, et al. Treatment of alopecia
areata: an australian expert consensus statement. Australas J Der-
matol. 2019;60:163–70.
3. Bokhari L, Sinclair R. Treatment of alopecia universalis with topi-
cal Janus kinase inhibitors–a double blind, placebo, and active
controlled pilot study. Int J Dermatol. 2018;57:1464–70.
4. Schepis C, Barone C, Lazzaro Danzuso GC, Romano C. Alopecia
areata in Down syndrome: a clinical evaluation. J Eur Acad Der-
matol Venereol. 2005;19:769–70.
Publisher's Note Springer Nature remains neutral with regard to
jurisdictional claims in published maps and institutional affiliations.

* Gomathy Sethuraman
gsethuraman@aiims.edu; aiimsgsr@gmail.com
1
Division of Dermatology, Sidra Medicine, Doha, Qatar
2
Department of Dermatology & Venereology, Hamad Medical
Corporation, Doha, Qatar
3
School of Medicine, Weill Cornell Medicine-Qatar, Doha,
Qatar
4
King’s College London, London, UK

13
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Indian Journal of Pediatrics (November 2023) 90(11):1073–1074
https://doi.org/10.1007/s12098-023-04767-7
EDITORIAL COMMENTARY
Hemodynamically Significant Patent Ductus Arteriosus (HsPDA)
in a Preterm Infant – An Innocent Bystander or a Predilection for Disaster?
Bharathi Balachander1 · Ballambattu Vishnu Bhat2
Received: 23 June 2023 / Accepted: 3 July 2023 / Published online: 21 July 2023
© The Author(s), under exclusive licence to Dr. K C Chaudhuri Foundation 2023
A hemodynamically significant patent ductus arteriosus
(HsPDA) in a preterm infant remains an object of contro-
versy as far as the decision for screening, treatment, and
modality of treatment. The heart of the controversy is
the fact that preterm PDA has been implicated in several
clinical outcomes. These include chronic lung disease
(CLD), necrotising enterocolitis (NEC), intraventricu-
lar haemorrhage (IVH), pulmonary haemorrhage and
acute kidney injury (AKI) [1]. However, treatment of
the HsPDA has not shown a reduction in any of these
morbidities. This has been supported by the fact that
conservative management with watchful expectancy has
resulted in successful closure without adverse effects
[2]. The trials on HsPDA, however, have had some lim-
itations, namely the heterogeneity in the definition of
HsPDA and lack of a standardized approach to measur-
able hemodynamic effects causing clinical instability [3].
The most common definitions of HsPDA use the size of
the PDA in combination with one or more parameters of
pulmonary over-circulation or systemic hypo-perfusion.
The left atrium to aortic root ratio >1.4 with diastolic
flow reversal in the abdominal aorta is the commonly
used parameter. These parameters individually are not
specific to a HsPDA and must be taken in combination
and the best approach widely remains unknown.
In short, preterm HsPDA is a spectrum that can tran-
sition from physiological normality to a devastating
problem causing varying effects on major organs. This
has led the physician treating the infant, at the bedside
* Ballambattu Vishnu Bhat
drvishnubhat@yahoo.com
1
Department of Neonatology, St John’s Medical College,
Bangalore, Karnataka, India
2
Medical Research and Publications, Aarupadai Veedu
Medical College & Hospital, Vinayaka Mission’s Research
Foundation-DU, Kirumampakkam, Pondicherry 607403,
India
to stand at a crossroads between the wait-and-watch
approach vs. the treatment approach. The big question
is “What is worse? The disease or the treatment? [4]”
The study by Zhang et al. published in Indian Journal
of Pediatrics, is a randomized trial that looks at a com-
bination of cardio-pulmonary effects of the HsPDA [5].
Physiologically, an objective measurement of HsPDA
on the lung is an important consideration for the treat-
ment of the same. In the study by Zhang et al., it was
found that lung ultrasound was used as a tool to guide the
continuous positive airway pressure (CPAP) setting, and
indirectly, surfactant administration and HsPDA treat-
ment were not based on a single screenshot but rather
serial monitoring that indicated worsening. The results
showed that the study group required more aggressive
interventions namely higher CPAP settings, earlier use of
ibuprofen, and more infants getting ibuprofen for HsPDA
closure. However, this translated into better outcomes
such as less use of invasive ventilation and reduced mod-
erate-severe bronchopulmonary dysplasia (BPD).
The study has limitations as pointed out by the author,
namely that the sample size was small and a per-protocol
analysis was used. Additionally, an older definition of
BPD was used and it remains to be seen if the results
would alter if a recent definition of BPD was used. But
the idea of using serial monitoring of HsPDA and using
cardio-pulmonary ultrasound as an add-on is novel and
would provide more convincing evidence to the clinician
at the bedside to decide on treatment. It would probably
aid to balance between the harms caused by the disease
vs. treatment. However, it needs to be explored in larger
trials to provide more evidence for this approach.
Declarations
Conflict of Interest None.
13
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1074 Indian Journal of Pediatrics (November 2023) 90(11):1073–1074

References dysplasia: reexamining a randomized controlled trial. J Pediatr.

2009;154:873–6.
5. Zhang Z, Lou X, Hua L, Jia X, Xu L, Zhao M. Cardiopulmo-
1. Noori S, McCoy M, Friedlich P, et al. Failure of ductus arteriosus
nary ultrasound-guided treatment of premature infants with
closure is associated with increased mortality in preterm infants.
respiratory failure and patent ductus arteriosus: A randomized,
Pediatrics. 2009;123:e138–44.
controlled trial. Indian J Pediatr. 2023. https://​doi.​org/​10.​1007/​
2. Hundscheid T, Onland W, Kooi EMW, et al. Expectant manage-
s12098-​023-​04489-w.
ment or early ibuprofen for patent ductus arteriosus. New Engl J
Med. 2023;388:980–90.
Publisher's Note Springer Nature remains neutral with regard to
3. Smith A, EL-Khuffash A. Patent ductus arteriosus clinical trials:
jurisdictional claims in published maps and institutional affiliations.
lessons learned and future directions. Child (Basel). 2021;8:47.
4. Clyman R, Cassady G, Kirklin JK, Collins M, Philips JB. The
role of patent ductus arteriosus ligation in bronchopulmonary

13
Indian Journal of Pediatrics (November 2023) 90(11):1065–1066
https://doi.org/10.1007/s12098-023-04772-w
EDITORIAL COMMENTARY
Predicting Fluid Responsiveness in Children with Shock: POCUS Can Guide
Shubham Charaya1 · Suresh Kumar Angurana1
Received: 4 July 2023 / Accepted: 10 July 2023 / Published online: 2 August 2023
© The Author(s), under exclusive licence to Dr. K C Chaudhuri Foundation 2023
Children with septic shock often have fluid deficit, decreased
vascular tone, and myocardial dysfunction [1]. Therefore, fluid
resuscitation and vasoactive agents are important components
of septic shock management. However, it has been demon-
strated that fluid bolus led to improvement in cardiac output
in only 40–50% of patients; it was sustained in <10% patients
at 60 min [1, 2]. Moreover, fluid boluses have been shown
to worsen cardiac function and endothelial glycocalyx injury;
cause arterial vasodilatation and worsening of hemodynamics;
higher need of mechanical ventilation; and increased mortal-
ity [1, 3]. Therefore, it is pertinent to administer fluid bolus
to only those who are fluid responsive and fluid tolerant. The
ideal method to determine fluid responsiveness is still elusive.
Point-of-care ultrasound (POCUS) is increasingly used in
Pediatric intensive care settings as ultrasound machines are
available in many units; it is real-time, easy to perform and
interpret, and simple eye-balling can provide ‘yes’ or ‘no’
answers; it has short learning curve; and it is without the
risk of radiations. Study by Banothu et al. published in IJP
is an important addition to determine the fluid responsive-
ness by using POCUS in children with shock [4]. Authors
enrolled 37 mechanically ventilated children [median age 60
(36–108) mo] with shock admitted in PICU and measured
inferior vena cava distensibility index (ΔIVC), respiratory
variation in peak aortic blood flow velocity (∆Vpeak), and
stroke volume index (SVI) before and after 10 ml/kg fluid
bolus. After a fluid bolus, 62% (n = 23) children were fluid
responsive (increase in SVI by ≥10%). Fluid responders
had higher median (IQR) ΔIVC [26% (16.9–36.5) vs. 17.2%
(8.4–21.9), p = 0.018] and mean (SD) ΔVpeak [13.9%
(6.1) vs. 8.4% (3.9), p = 0.004)] than non-responders.
ΔIVC and ΔVpeak had similar ability to predict fluid
responsiveness [ROC area 0.73 (0.56–0.9), p = 0.01; and
0.78 (0.63–0.94), p = 0.002, respectively]. The best cut-off
* Suresh Kumar Angurana
sureshangurana@gmail.com
1 tive (PREDICT). Cardiac index changes with fluid bolus therapy
Department of Pediatrics, Advanced Pediatric Centre,
Postgraduate Institute of Medical Education and Research
(PGIMER), Chandigarh, India
of ΔIVC and ΔVpeak to predict fluid responsiveness were
23% and 11.3%, respectively [4].
Banothu et al. [4] demonstrated that in hands of Pediatric
intensivists, both ΔIVC and ΔVpeak are good predictors of
fluid responsiveness among mechanically ventilated chil-
dren with shock. However, the optimum cut-off for ΔIVC
and ΔVpeak for predicting fluid responsiveness is still elu-
sive due to wide range observed in different studies [4–6].
Also, there is a need to take into account several factors that
confound the measurement of ΔIVC (skill of the operators,
cardiac function, abnormal intrathoracic pressure, intra-
abdominal hypertension); and ΔVpeak (skills of the operator,
tidal volume, rhythm abnormality, heart rate/ventilatory rate
ratio, and the timing of measurement) [4]. The role of IVC
variability among spontaneously breathing children or those
on mechanical ventilation with pressure support mode need
to be evaluated.
As excess of fluid boluses are harmful; there is need to
have a best parameter to determine the fluid responsiveness
so that fluid can be administered to only those who need it.
In absence of such single parameters, combination of inputs
from clinical details, hemodynamic parameters, and POCUS
may help clinicians in decision making to administer fluid
bolus to children with shock.
Declarations
Conflict of Interest None.
References
1. Ranjit S, Kissoon N, Argent A, et al. Haemodynamic support for
paediatric septic shock: a global perspective. Lancet Child Adolesc
Health. 2023. https://​doi.​org/​10.​1016/​S2352-​4642(23)​00103-7.
2. Long E, Babl FE, Oakley E, Sheridan B, Duke T, Pediatric
Research in Emergency Departments International Collabora-
in children with sepsis-an observational study. Pediatr Crit Care
Med. 2018;19:513–8.
13
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1066 Indian Journal of Pediatrics (November 2023) 90(11):1065–1066

3. Maitland K, Kiguli S, Opoka RO, et al. Mortality after fluid
bolus in african children with severe infection. N Engl J Med.
2011;364:2483–95.
4. Banothu KK, Sankar J, Pathak M, et al. Utility of inferior vena cava
distensibility and respiratory variation in peak aortic blood flow
velocity to predict fluid responsiveness in children with shock.
Indian J Pediatr. 2023. https://​doi.​org/​10.​1007/​s12098-​023-​04585-x.
5. Carioca FL, de Souza FM, de Souza TB, et al. Point-of-care ultra-
sonography to predict fluid responsiveness in children: a system-
atic review and meta-analysis. Paediatr Anaesth. 2023;33:24–37.
6. Sethasathien S, Jariyasakoolroj T, Silvilairat S, Srisurapanont M.
Aortic peak flow velocity as a predictor of fluid responsiveness in
mechanically ventilated children: a systematic review and meta-
analysis. Pediatr Crit Care Med. 2023;24:e352-61.
Publisher’s Note Springer Nature remains neutral with regard to
jurisdictional claims in published maps and institutional affiliations.

13
Indian Journal of Pediatrics (November 2023) 90(11):1155
https://doi.org/10.1007/s12098-023-04779-3

SCIENTIFIC LETTER

Hyperosmolar Hyperglycemic State: A Rare Presentation of Neonatal

Diabetes Mellitus
Siva Vyasam1 · Bisman Singh1 · Arun George2 · Muthuvel Rajangam1 · Devi Dayal2 · Suresh Kumar Angurana1

Received: 4 June 2023 / Accepted: 12 July 2023 / Published online: 2 August 2023
© The Author(s), under exclusive licence to Dr. K C Chaudhuri Foundation 2023

To the Editor: A 7-wk-old boy was admitted with fever,
loose stools, vomiting, and seizures. His father and mater-
nal grandmother were diagnosed with young-onset diabetes
mellitus. Examination and investigations revealed acidotic
breathing, normal hemodynamics and systemic examina-
tion, blood glucose 991 mg/dL, metabolic acidosis (pH 7.18,
­PaO2 38 mmHg, ­PaCO2 52 mmHg, bicarbonate 17 mmol/L),
urea 111 mg/dL, creatinine 0.7 mg/dL, sodium 183 mmol/L,
potassium 5.9 mmol/L, negative blood ketones, and cal-
culated effective osmolarity 421 mOsm/kg. Diagnosis of
Neonatal Diabetes Mellitus (NDM) with Hyperosmolar
Hyperglycemic State (HHS) was made. Treatment included
fluid resuscitation (N/4 5% dextrose for 72 h), insulin infu-
sion (0.02 U/kg/h), antiseizure medications, and mechani-
cal ventilation. Over next 48 h, there was improvement in
clinical and metabolic parameters when intravenous fluid
was stopped, subcutaneous insulin was started, and he was
extubated. As he remained euglycemic, subcutaneous insulin
was discontinued after 7 d. Further investigations revealed
HbA1c 7.7% (normal <6.5%), C-peptide levels 0.52 ng/mL
(normal 1.1–4.4 ng/mL), normal ultrasonography of pan-
creas, and negative next-generation sequencing for 36 genes
associated with monogenic diabetes. Follow up till 13-mo of
age shows normal development, normal blood sugar values,
and HbA1c of 6%.
NDM is a rare disorder present in infants <6 mo and
caused by mutations in genes that affect pancreatic beta-cell
function (ATP-sensitive potassium channel genes KCNJ11
and ABCC8) [1]. Elevated HbA1c and low C-peptide sug-
gest NDM. Some cases of NDM may respond to oral sulfo-
nylureas, making genetic testing more crucial. HHS is a rare
complication of NDM and it is characterized by very high
blood sugar, mild acidosis, low ketones, and high osmolarity.
The management includes fluid resuscitation and insulin [2].
Pathogenic mutations may be positive in around 50–60% of
cases. NDM is transient in half of the cases with remission
within 1–18 mo followed by relapse in childhood or adult-
hood [2–4].
Declarations
Conflict of Interest None.
References
1. De Franco E, Flanagan SE, Houghton JAL, et al. The effect of
early, comprehensive genomic testing on clinical care in neonatal
diabetes: an international cohort study. Lancet. 2015;386:957–63.
2. Foughty ZC, Moryan-Blanchard K, Henkel EB, Gahm C. Hyper-
osmolar hyperglycemic coma in an infant with neonatal diabetes
mellitus. Am J Emerg Med. 2022;54:327.e5-e7.
3. Korula S, Ravichandran L, Paul PG, et al. Genetic heterogeneity
and challenges in the management of permanent neonatal diabetes
mellitus: a single-centre study from south India. Indian J Endo-
crinol Metab. 2022;26:79–86.
4. Jain V, Satapathy A, Yadav J, et al. Clinical and molecular charac-
terization of children with neonatal diabetes mellitus at a tertiary
care center in northern India. Indian Pediatr. 2017;54:467–71.

Publisher’s Note Springer Nature remains neutral with regard to

* Suresh Kumar Angurana jurisdictional claims in published maps and institutional affiliations.
sureshangurana@gmail.com
1
Division of Pediatric Critical Care, Department
of Pediatrics, Advanced Pediatrics Centre (APC),
Postgraduate Institute of Medical Education and Research
(PGIMER), Chandigarh 160012, India
2
Division of Pediatric Endocrinology, Department
of Pediatrics, Advanced Pediatrics Centre (APC),
Postgraduate Institute of Medical Education and Research
(PGIMER), Chandigarh 160012, India

13
Vol.:(0123456789)
Indian Journal of Pediatrics (November 2023) 90(11):1161
https://doi.org/10.1007/s12098-023-04785-5
CORRESPONDENCE
Evaluation of Modified Extended Sick Neonate Score to Predict
In‑Hospital Mortality among Newborns Admitted to Resource‑Poor
Settings in Rural India: Authors’ Reply
Ajay Jayasheel1 · Barathy Chandrasegaran2 · Vellanki Bramha Kumar3 · N. Shivaramakrishna Babji3
Received: 9 July 2023 / Accepted: 13 July 2023 / Published online: 14 September 2023
© The Author(s), under exclusive licence to Dr. K C Chaudhuri Foundation 2023
To the Editor: We thank the authors for raising relevant
queries on our article [1]. This study was done in NICU of
Mamata Medical College and Hospital, Khammam, Telan-
gana. The aim was to find an appropriate score useful in
rural settings without requirement of extensive equipment
or laboratory tests. Hence, we chose the title [2]. The article
does not mention anywhere that this study is done at a rural
setting. The study was conducted to devise a score based on
two existing neonatal scores, Extended Sick Neonate Score
(ESNS) and Modified Sick Neonatal Score (MSNS) which
have good sensitivity and specificity at admission [3, 4].
Identifying severity of illness at admission helps in prior-
itising care for sick neonates in resource-poor settings and
managing appropriate referrals to higher centres. Further
studies are needed to evaluate this score for monitoring pur-
pose later during the course of stay in NICU.
There is a difference in sensitivity of score (86.27%)
from this study and sensitivity of the calculated sample
size. Moreover, the sample size comes to approximately 520
when considering the sensitivity of ESNS score as 85.9%,
with 3% absolute precision and 95% confidence interval.
Therefore, the required sample size may vary based on this
study’s estimate. This is one of the limitations of this study.
The recording of all these components is routinely done
in NICU at admission as part of our protocol. Two junior
residents and one senior resident are present all the time
* N. Shivaramakrishna Babji
shivababji123@gmail.com
1
Department of Pediatrics, Navodaya Medical College,
Raichur, Karnataka, India
2
Department of Pediatrics, Indira Gandhi Medical College
and Research Institute, Puducherry, India
3
Department of Pediatrics, Mamata Medical College
and Hospital, House no. 207, Penna Quarters, Mamata
Hospital Campus, Giriprasadnagar, Khammam,
Telangana 507002, India
in our NICU, which makes it feasible to record these com-
ponents at the earliest. In case of pulse oximetry, record-
ing both preductal and postductal values was only to look
for any gross variation among the two. This score doesn’t
include mean BP as a parameter. So, we compared it with
MSNS score since it doesn’t have mean BP as a component
unlike ESNS which requires mean BP values.
Funding The project was self-funded. No external agency had funded
the project.
Declarations
Ethics Approval This study was approved by the Research Ethics Com-
mittee and was carried out following the principles contained within
the 1964 Declaration of Helsinki and as revised in 2013.
Consent for Publication Written informed consent was not taken from guard-
ians/ parents, as the study objectives were not related to patients' identities.
Conflict of Interest None.
References
1. Sameer K, Patel DV, Nimbalkar SM. Evaluation of modified
extended sick neonate score to predict in-hospital mortality among
newborns admitted to resource-poor settings in rural India: Cor-
respondence. Indian J Pediatr. 2023. https://​doi.​org/​10.​1007/​
s12098-​023-​04786-4.
2. Jayasheel A, Chandrasegaran B, Kumar VB, Babji NS. Evaluation
of modified extended sick neonate score to predict in-hospital
mortality among newborns admitted to resource-poor settings in
rural India. Indian J Pediatr. 2023;90:341–7.
3. Ray S, Mondal R, Chatterjee K, Samanta M, Hazra A, Sabui TK.
Extended sick neonate score (ESNS) for clinical assessment and
mortality prediction in sick newborns referred to tertiary care.
Indian Pediatr. 2019;56:130–3.
4. Mansoor KP, Ravikiran SR, Kulkarni V, et al. Modified sick
neonatal score (MSNS): a novel neonatal disease severity scor-
ing system for resource-limited settings. Crit Care Res Pract.
2019;2019:9059073.
Publisher's Note Springer Nature remains neutral with regard to
jurisdictional claims in published maps and institutional affiliations.
13
Vol.:(0123456789)
Indian Journal of Pediatrics (November 2023) 90(11):1160
https://doi.org/10.1007/s12098-023-04786-4

CORRESPONDENCE

Evaluation of Modified Extended Sick Neonate Score to Predict In‑Hospital

Mortality among Newborns Admitted to Resource‑Poor Settings in Rural
India: Correspondence
K. Sameer1 · Dipen V. Patel1 · Somashekhar M. Nimbalkar1

Received: 14 June 2023 / Accepted: 13 July 2023 / Published online: 2 August 2023
© The Author(s), under exclusive licence to Dr. K C Chaudhuri Foundation 2023

To the Editor: We read with interest an article by Jayasheel
et al. on the Modified Extended Sick Neonate Score (ESNS)
[1]. We compliment the authors for making the score work-
able without compromising its sensitivity and specificity.
We would like certain clarifications.
Though the study was conducted at a tertiary care hospi-
tal, readers would wish to know the study site. Tertiary care
centres have better provisions of man power and equipment
[2]. This makes the title misleading, as it addresses to the
newborns admitted to resource-poor settings in rural India.
Authors wrote that this score would find worsening condition
of the neonates. Can a risk scoring done only for one time on
admission find worsening condition? The 31% sensitivity for
sample size is too less even when contrasted to their own results.
The 10 components of the score require documentation at
admission. As certain components require prior standardiza-
tion, how would have this been possible to document in 15 min
in a retrospective study? For example, they have assessed heart
rate using stethoscope over one minute and usually, Moro’s
reflex and Ballard scoring are done as a part of detailed
examination. They measured pulse oximeter readings from
two limbs. Were both documented in old records and which
reading they considered? It would be interesting to know that
in a retrospective study how they could get details of all the
components in majority of the patients.
In the Supplementary File (provided as a link) in an article
by Jayasheel et al., the calculations of number of participants
“enrolled” and “missing” is not proper [1]. In discussion sec-
tion, comparison of mean total scores is done with mean scores
of a different one, which is not ideal [3].
Acknowledgements Prof. Ajay G. Phatak and Mayur K. Shinde, Cen-
tral Research Services, Pramukhswami Medical College, Shree Krishna
Hospital, Bhaikaka University, Karamsad, Anand, Gujarat, 388325.
Declarations
Conflict of Interest None.
References
1. Jayasheel A, Chandrasegaran B, Kumar VB, Babji NS. Evaluation
of modified extended sick neonate score to predict in-hospital
mortality among newborns admitted to resource-poor settings in
rural India. Indian J Pediatr. 2023;90:341–7.
2. Bajaj JS, Srivastava RK. Report of the working group on tertiary
care institutions for 12th five year plan (2012-2017). Ministry of
Health and Family Welfare, Government of India, Planning Com-
mission. 2011;23073678:23379197. Available at: https://​pmssy-​
mohfw.​nic.​in/​files/​WG_​2tert​iary.​pdf. Accessed on 8 Jun 2023
3. Mia RA, Etika R, Harianto A, Indarso F, Damanik SM. The
use of score for neonatal acute physiology perinatal extention II
(SNAPPE II) in predicting neonatal outcome in neonatal intensive
care unit. Paediatr Indones. 2005;45:241–5.
Publisher's Note Springer Nature remains neutral with regard to
jurisdictional claims in published maps and institutional affiliations.

* Dipen V. Patel
dipen_patel258@yahoo.co.in
1
Department of Neonatology, Pramukhswami Medical
College, Shree Krishna Hospital, Bhaikaka University,
Karamsad, Anand 388325, Gujarat, India

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Vol:.(1234567890)
Indian Journal of Pediatrics (November 2023) 90(11):1158
https://doi.org/10.1007/s12098-023-04790-8

SCIENTIFIC LETTER

Serum Ferritin Level, a Prognostic Marker of Morbidity and Mortality

in Pediatric Intensive Care Unit in Correlation with PRISM III Score
Nishant Tawari1,2 · Shobha Sharma1 · Neil Castellino1 · Nandkishore Kabra3

Received: 7 March 2023 / Accepted: 14 July 2023 / Published online: 28 July 2023
© The Author(s), under exclusive licence to Dr. K C Chaudhuri Foundation 2023

To the Editor: We conducted this study at a tertiary pediatric
intensive care unit (PICU) with an aim to find out correlation
between serum ferritin levels and the severity of illness and
risk of mortality as defined by PRISM 3 score [1].
As we know that serum ferritin is an acute phase reactant
and elevated serum ferritin level is not unusual in a sick child
(mild or severe) [2]. Hence, to establish ferritin as a predic-
tive marker of illness severity, it needs to be correlated with
established scoring system. We chose PRISM 3 score, as it
provides better guidance in discriminating the severity of
the patient’s condition.
In this study, total 413 patients were enrolled after consid-
ering inclusion and exclusion criteria. Out of 413 patients,
10 died in PICU. Non-survivors had significant higher mean
ferritin (3461.6 ng/mL; p <0.0001) as compared to survivors
(670.77 ng/mL). Serum ferritin ≥300 ng/mL was associ-
ated with a 43.35 times (p <0.0001) more risk of death than
patients having serum ferritin <300 ng/mL. Many studies
like the study conducted by Dermirkol et al. show that serum
ferritin level is directly or indirectly related to mortality [3].
PRISM 3 score were independently associated with mor-
tality and also had moderate correlation with serum ferritin
value (Spearman’s coefficient 0.63; p <0.0001). Patients
with high serum ferritin levels at admission had higher
PRISM 3 score, longer duration of stay in hospital and mor-
bidities. These results were independent of iron deficiency
anemia. This finding is similar to the study conducted by
Ghosh et al. [4].
With the help of Fisher’s exact test and Spearman’s coef-
ficient we found that high serum ferritin level is associated
with poor outcome in PICU patients which is not affected by
presence or absence of iron deficiency anemia and hence, it
can be used as a predictive marker of morbidity and mortal-
ity along with current prognostic scores.
Declarations
Conflict of Interest None.
References
1. Pollack MM, Patel KM, Ruttimann UE. PRISM III: an updated
pediatric risk of mortality score. Crit Care Med. 1996;24:743–52.
2. Weiss G. Modification of iron regulation by the inflammatory
response. Best Pract Res Clin Haematol. 2005;18:183–201.
3. Demirkol D, Yildizdas D, Bayrakci B, et al. Turkish Second-
ary HLH/MAS Critical Care Study Group. Hyperferritinemia in
the critically ill child with secondary hemophagocytic lympho-
histiocytosis/sepsis/multiple organ dysfunction syndrome/mac-
rophage activation syndrome: what is the treatment? Crit Care.
2012;16:R52.
4. Ghosh S, Baranwal AK, Bhatia P, Nallasamy K. Suspecting
hyperferritinemic sepsis in iron-deficient population: do we
need a lower plasma ferritin threshold? Pediatr Crit Care Med.
2018;19:e367–73.
Publisher's Note Springer Nature remains neutral with regard to
jurisdictional claims in published maps and institutional affiliations.

* Nishant Tawari
drnstawari@gmail.com
1
Department of Pediatrics, Surya Children’s Medicare Pvt.
Ltd, Mumbai, India
2
Flat 401, Keshav Kala Apartment, Diksha Bhoomi Road,
Rahate Colony, Nagpur, Maharashtra 440020, India
3
Department of Pediatrics‑ Neonatology, Surya Children’s
Medicare Pvt. Ltd, Mumbai, India

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Indian Journal of Pediatrics (November 2023) 90(11):1075–1076
https://doi.org/10.1007/s12098-023-04791-7
EDITORIAL COMMENTARY
Wearables – A Revolution in Neonatal Monitoring?
Sindhu Sivanandan1
Received: 11 July 2023 / Accepted: 14 July 2023 / Published online: 16 August 2023
© The Author(s), under exclusive licence to Dr. K C Chaudhuri Foundation 2023
Wireless monitoring equipment is a wearable device that
monitors the vital signs of the neonate and transmits real-
time data from the infant's body to a central monitoring sta-
tion. The wearable device offers many advantages over tradi-
tional monitoring systems, including increased mobility for
the neonate and the provider, the ability to monitor remotely
in areas with limited access to healthcare and continuous
monitoring. These devices offer improved comfort for the
newborn and their parents as they are small, wearable and
non-invasive allowing unrestricted parental care in a more
natural and stress-free environment.
Numerous studies have focused on evaluating the accu-
racy, reliability, and efficacy of wireless monitoring devices
in neonates [1]. In this issue of IJP, Aggarwal et al. evalu-
ated the efficacy and safety of a novel wireless monitor, the
Nemocare Raksha (NR), an internet of things (IoT)–enabled
smart wearable device to continuously monitor four vital
signs (heart rate, respiration rate, body temperature and oxy-
gen saturation) for 6 h in neonates admitted to the pediatric
ward [2]. The device weighs just 20 g and could be applied
to the neonate’s foot. The data from the device is transmitted
wirelessly to an Android tablet and cloud server for seamless
remote access to the health providers. The NR device had
good safety with no discomfort, skin changes or local rise in
temperature. The device showed a good level of agreement
for heart rate and oxygen saturation among the four param-
eters measured. Since this was the first study to evaluate
the safety and efficacy of NR, the device was used in stable
neonates for a shorter period of time and at hospital settings.
The scalability of this device depends on further testing in
sick neonates and at community settings.
ANNE monitoring system is another wireless vital sign
monitoring system that uses small, light sensors attached
to the neonate’s skin [3]. The device was tested in preterm
* Sindhu Sivanandan
drsindhusivanandan@gmail.com
1 have been marketed to parents for use in the home for well
Department of Neonatology, Kauvery Hospital, Radial Road,
Kovilambakkam, Chennai 600117, India
and term neonates and demonstrated safety and efficacy in
vital signs when compared to standard monitoring. Another
innovation is a smart chest belt made of textile called
“NeoWear” to monitor respiratory rate and detect apnea [4].
The BEMPU bracelet is a smart wearable device used to
detect hypothermia in neonates. Tanigasalam et al. showed
that BEMPU could monitor body temperature continuously
and had an accuracy of 95.8% in detecting hypothermia [5].
Many other wireless monitors built into socks, onesies, but-
tons, leg bands, and diaper clips have been developed to
monitor neonatal vital signs. Most devices have undergone
only preliminary testing in controlled hospital settings and
limitations in their accuracy have been noted [6].
Despite benefits, the limitations of wireless devices need
to be considered especially when used in remote settings.
Wireless devices are susceptible to interference from other
electronic devices and sources of electromagnetic fields,
which can affect accuracy of data transmission. The dis-
tance between the device and central station may lead to
connectivity issues or signal loss, resulting in incomplete or
delayed data transmission. Wireless devices rely on batteries
for power which may need frequent recharging or replace-
ment. Factors such as sensor placement, device calibration
and motion artefacts affect signal quality and accuracy of
measurements. Hence regular device maintenance, calibra-
tion, and quality assurance protocols are necessary. The
wireless transmission of sensitive medical data raises con-
cerns about data security and privacy. Robust encryption
and authentication mechanisms are mandatory to protect
data from unauthorized access or interception. Continuous
monitoring over prolonged periods can generate enormous
data that becomes difficult to interpret without algorithms to
automatically process and interpret data. Finally, the adop-
tion of wireless neonatal monitoring devices may involve
significant costs, including the device cost, installation of
central monitoring station, data transmission and training
of healthcare staff.
In recent years many smart phone integrated wearables
infants. There are no medical indications for electronic
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1076
monitoring of healthy infants at home and the application
of inaccurate devices or for inappropriate indications or
improper interpretation of data can lead to potentially dev-
astating consequences [6]. Future research should address
the limitations and continuously improve the technology to
enhance the safety and effectiveness of wireless neonatal
monitoring devices.
Declarations
Conflict of Interest None.
References
1. Rao S, Thankachan P, Amrutur B, Washington M, Mony PK. Con-
tinuous, real-time monitoring of neonatal position and temperature
13
Indian Journal of Pediatrics (November 2023) 90(11):1075–1076
during Kangaroo Mother Care using a wearable sensor: a techno-
feasibility pilot study. Pilot Feasibility Stud. 2018;4:99.
2. Aggarwal R, Gunaseelan V, Manual D, Sanker M, Prabaaker S.
Clinical evaluation of a wireless device for monitoring vitals in
newborn babies. Indian J Pediatr. 2023. https://​doi.​org/​10.​1007/​
s12098-​022-​04459-8.
3. Chung HU, Kim BH, Lee JY, et al. Binodal, wireless epidermal
electronic systems with in-sensor analytics for neonatal intensive
care. Science. 2019;363:eaau0780.
4. Cay G, Solanki D, Al Rumon M, et al. NeoWear: An IoT-connected
e-textile wearable for neonatal medical monitoring. Pervas Mob
Comput. 2022;86:101679.
5. Tanigasalam V, Bhat BV, Adhisivam B, Balachander B, Kumar H.
Hypothermia detection in low birth weight neonates using a novel
bracelet device. J Matern Fetal Neonatal Med. 2019;32:2653–6.
6. Bonafide CP, Jamison DT, Foglia EE. The emerging market
of smartphone-integrated infant physiologic monitors. JAMA.
2017;317:353–4.
Publisher's Note Springer Nature remains neutral with regard to
jurisdictional claims in published maps and institutional affiliations.
Indian Journal of Pediatrics (November 2023) 90(11):1163
https://doi.org/10.1007/s12098-023-04792-6

SCIENTIFIC LETTER

Safety and Tolerability of Remdesivir in Infants and Children

with COVID-19
Tanu Singhal1 · Juhi Mehrotra1 · Santanu Sen1

Received: 30 April 2023 / Accepted: 17 July 2023 / Published online: 4 August 2023
© The Author(s), under exclusive licence to Dr. K C Chaudhuri Foundation 2023

To the Editor: COVID-19 is a mild illness in children and
generally requires only symptomatic therapy. Antiviral
therapy may be considered in children with COVID-19
pneumonia or those with risk factors for disease progres-
sion [1]. Remdesivir and monoclonal antibodies are the
only approved treatments for children [1]. There is limited
data on the safety and tolerability of remdesivir in children.
We included all children below 18 y with confirmed
SARS-CoV-2 infection at our centre who received at least 1
dose of remdesivir from 2020-2022. Remdesivir was given
after taking due consent as per standard doses [1]. Infor-
mation regarding demographics, indications for remdesivir,
adverse effects and outcomes was analysed.
A total of 21 children (15 boys) with age ranging from 1 mo
to 18 y (mean age 8 y) were included in the study. The indica-
tions for remdesivir were 4 children with moderate COVID-19
pneumonia (age related tachypnea with/without hypoxia), 4
children with computerized tomographic (CT) but no clinical
evidence of pneumonia, 2 ventilated infants with nosocomial
COVID-19 infection following post complex cardiac surgery
and 11 children with mild COVID-19 infection with risk fac-
tors including post hematologic stem cell transplant recipients
(n = 5), hematologic malignancy on chemotherapy (n = 5) and
neonate with congenital heart disease (n = 1).
All children received the full course except two where
therapy was interrupted due to transient elevation of liver
enzymes/early discharge (1 each). No cases of sinus brady-
cardia were observed. Two patients with COVID-19 pneu-
monia and hypoxia also received steroids. Nineteen children
improved and were discharged. Two infants with COVID-19
infection following congenital heart surgery died but causal
relationship with COVID-19 could not be established.
Our study adds to growing evidence of safety and toler-
ability of remdesivir in infants and children with COVID-19
[2–4]. However in the absence of a control group no conclu-
sions about efficacy can be made.
Declarations
Conflict of Interest None.
References
1. Galindo R, Chow H, Rongkavilit C. COVID-19 in children: clini-
cal manifestations and pharmacologic interventions including vac-
cine trials. Pediatr Clin North Am. 2021;68:961–76.
2. Goldman DL, Aldrich ML, Hagmann SHF, et al. Compassionate
use of remdesivir in children with severe COVID-19. Pediatrics.
2021;147:e2020047803.
3. Samuel AM, Hacker LL, Zebracki J, et al. Remdesivir use in pedi-
atric patients for SARS-CoV-2 treatment: single academic center
study. Pediatr Infect Dis J. 2023;42:310–4.
4. Ong RYL, Seah VXF, Chong CY, et al. A cohort study of COVID-
19 infection in pediatric oncology patients plus the utility and
safety of remdesivir treatment. Acta Oncol. 2023;62:53–7.
Publisher’s Note Springer Nature remains neutral with regard to
jurisdictional claims in published maps and institutional affiliations.

* Tanu Singhal
tanusinghal@yahoo.com
1
Department of Pediatrics, Kokilaben Dhirubhai Ambani
Hospital and Medical Research Institute, Mumbai, India

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Indian Journal of Pediatrics (November 2023) 90(11):1157
https://doi.org/10.1007/s12098-023-04793-5

SCIENTIFIC LETTER

Neonatal Scrub Typhus: A Case Series

Revati Deglurkar1 · Ambalakkuthan Murugesan1 · Nishad Plakkal1

Received: 19 May 2023 / Accepted: 17 July 2023 / Published online: 2 August 2023
© The Author(s), under exclusive licence to Dr. K C Chaudhuri Foundation 2023

To the Editor: Scrub typhus, a rickettsial infection caused
by Orientia tsutsugamushi is endemic in south India [1].
However, presentation in neonates is rare. We describe the
clinical profile of 7 neonates admitted to a tertiary care
NICU between January 2022 and March 2023 with fever,
later diagnosed to have scrub typhus based on a positive
RT-PCR (56 kDa gene). The mean gestational age was
38.1 (1.6) wk, and birthweight 3000 (629) g. Median age at
symptom onset was 21 d (range: 2–30). All seven cases had
fever and thrombocytopenia, while 85% (6/7) had hepato-
splenomegaly. Seventy-one percent (5/7) had transamini-
tis, 57% (4/9) required respiratory support, 43% (3/7) had
multi-organ dysfunction, 29% (2/7) had shock, and one had
disseminated intravascular coagulation (DIC). One of them
also had evidence of transplacentally acquired infection,
the neonate being symptomatic at 36 h of life with posi-
tive scrub typhus PCR in both mother and baby. The same
neonate also had meningitis and received treatment for 10
d. All neonates were initially started on empirical antibiot-
ics for neonatal sepsis, which were changed to doxycycline
after suspicion/confirmation of scrub typhus. One neonate
received azithromycin in addition to doxycycline due to poor
response. One neonate who had Multiple organ dysfunction
syndrome (MODS) at admission succumbed despite initia-
tion of doxycycline. The other six responded to treatment
and were discharged. Response to treatment was heralded
by defervescence of fever, regression of organomegaly, and
improvement in vital parameters in all cases except the one
who eventually succumbed. Twenty-two cases of neonatal
scrub typhus have been reported so far in literature, with a
mortality rate of 18% [2, 3]. Eschar has been reported in 18%
of published cases, but no neonate in our series had eschar.
Fever, hepatosplenomegaly and thrombocytopenia in a neo-
nate should arouse suspicion of scrub typhus in endemic
areas. Early initiation of doxycycline improves outcomes [4].
Declarations
Conflict of Interest None.
References
1. Kore VB, Mahajan SM. Recent threat of scrub typhus in India: a
narrative review. Cureus. 2022;14:e30092.
2. Samad TEA, Kamalarathnam CN. Clinical profile of scrub typhus
in newborns. Indian Pediatr. 2020;57:579.
3. Deglurkar R, Thangavel NP, Murugesan A, Plakkal N. Scrub
typhus due to vertical transmission in a neonate: rare presentation
of a common tropical infection. BMJ Case Rep. 2023;16:e253172.
4. Rathi N, Kulkarni A, Yewale V, For Indian Academy of Pediat-
rics Guidelines on Rickettsial Diseases in Children Committee.
IAP guidelines on rickettsial diseases in children. Indian Pediatr.
2017;54:223–9.
Publisher's Note Springer Nature remains neutral with regard to
jurisdictional claims in published maps and institutional affiliations.

* Ambalakkuthan Murugesan
murugesan89@gmail.com
1
Department of Neonatology, Jawaharlal Institute
of Postgraduate Medical Education and Research,
Gorimedu, Puducherry 605006, India

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Indian Journal of Pediatrics (November 2023) 90(11):1159
https://doi.org/10.1007/s12098-023-04796-2

SCIENTIFIC LETTER

Usefulness of FilmArray Meningitis/Encephalitis Panel Using Serum

Samples in Neonates and Infants
Yuji Fujita1 · Manabu Miyamoto1 · Shinya Yoshihara1 · Yuhi Takagi1 · Shigemi Yoshihara1

Received: 6 July 2023 / Accepted: 17 July 2023 / Published online: 28 July 2023
© The Author(s), under exclusive licence to Dr. K C Chaudhuri Foundation 2023

To the Editor: ­FilmArray® is a multiplex polymerase chain
reaction (PCR) system widely used recently to detect patho-
gens, including SARS-CoV-2, in samples such as nasopharyn-
geal swabs, blood, and cerebrospinal fluid (CSF). The notable
features of the ­FilmArray® are the simplified inspection pro-
cedure, the short inspection time, and the minimal sample
volume required (approximately 200 µL of blood or CSF sam-
ples). ­FilmArray® meningitis/encephalitis panel includes vari-
ous pathogenic organisms, especially Cytomegalovirus, Herpes
simplex virus (HSV), and Human Parechovirus (HPeV), which
are viruses that cause serious infections in neonates and infants
and should be identified early.
In Cytomegalovirus and HSV detection, PCRs using blood
samples are commercially available; however, a large amount
of blood sample is required, which is often difficult to obtain,
especially from premature neonates. HPeV cannot be detected
using commercial-based blood PCR in Japan. HPeV migrates
from the blood to the CSF [1]; hence, it can be detected via
­FilmArray® meningitis/encephalitis panel using CSF samples.
Collecting CSF samples is more challenging than obtaining
blood samples. We aimed to investigate these viruses in serum
samples using the F­ ilmArray® meningitis/encephalitis panel.
HSV was examined in one neonate with disseminated
HSV-1 infection [2], and the blood PCR result was positive.
Cytomegalovirus was examined in two premature infants
with acquired Cytomegalovirus infection, and their blood
PCR or antigenemia results were positive. Furthermore, two
neonates or infants with HPeV infection had positive CSF
PCR results using this panel. Serum samples collected at
diagnosis were used for this investigation, and the results
revealed that all patients were serum positive for the virus.
Early administration of acyclovir or ganciclovir and avoid-
ance of unnecessary antibiotic administration can be achieved
because results are quickly obtainable. To our knowledge,
no study has reported on F­ ilmArray® meningitis/encephalitis
panel using serum samples. However, ­FilmArray® that can
detect these viruses in the blood is expected.
Acknowledgements We would like to thank Editage (www.​edita​ge.​
com) for the English language editing.
Declarations
Conflict of Interest None.
References
1. Aizawa Y, Izumita R, Saitoh A. Human parechovirus type 3
infection: an emerging infection in neonates and young infants.
J Infect Chemother. 2017;23:419–26.
2. Takagi Y, Fujita Y, Otaka T, et al. Postpartum neonatal dis-
seminated herpes simplex virus-1 infection in which herpes
simplex virus-1 was detected in mother’s breast milk. Indian
J Pediatr. 2023;90:510–2.
Publisher’s Note Springer Nature remains neutral with regard to
jurisdictional claims in published maps and institutional affiliations.

* Yuji Fujita
fujitay@dokkyomed.ac.jp
1
Department of Pediatrics, Dokkyo Medical University, 880
Kitakobayashi, Mibu, Shimotsuga, Tochigi 321‑0293, Japan

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Indian Journal of Pediatrics (November 2023) 90(11):1156
https://doi.org/10.1007/s12098-023-04798-0

SCIENTIFIC LETTER

An Unusual Manifestation of a Common Tropical Infection

Aman Elwadhi1 · Prateek Kumar Panda1 · K. C. Neha1 · Diksha Gupta1 · Indar Kumar Sharawat1

Received: 9 July 2023 / Accepted: 17 July 2023 / Published online: 2 August 2023
© The Author(s), under exclusive licence to Dr. K C Chaudhuri Foundation 2023

To the Editor: A 15-y-old girl presented with acute onset
high-grade fever associated with chills and rigor for 3 d.
There was no history of cough, sore throat, burning mictu-
rition, pain abdomen, headache, or any other complaints.
Examination revealed purple-colored, non-pruritic rashes
over face, extremities, and trunk and an eschar over the
right leg. Rest of the examination was normal. Investigations
revealed thrombocytopenia and mildly elevated transami-
nase. Serological tests revealed high Orientia tsutsugamushi
IgM antibody titers. Workups for other tropical illnesses
were non-contributory. A diagnosis of scrub typhus was
made and she was started on intravenous ceftriaxone. She
became afebrile within 2 d, but after one week she developed
holocranial, progressively worsening headache, vomiting,
and blurring of vision. She had bilateral grade-4 papilledema
and bilateral ­6th cranial nerve palsy. Magnetic resonance
imaging of the brain showed tortuous and distended optic
nerve sheaths and partial empty sella, without any parenchy-
mal abnormalities. The cerebrospinal fluid examination was
normal except elevated opening pressure (60 cm of water). A
diagnosis of idiopathic intracranial hypertension (IIH) was
made and she was started on acetazolamide.
The exact cause of IIH is not fully understood, but cer-
tain viruses and other microorganisms and medications may
play a role in triggering the condition. These microorgan-
isms are believed to initiate an immune response in the cen-
tral nervous system, leading to inflammation and increased
intracranial pressure [1]. Scrub typhus is a common tropi-
cal infection and reported nervous system manifestations
include meningoencephalitis, encephalopathy, cerebellitis,
cerebral infarction, cranial nerve palsies, acute disseminated
encephalomyelitis, transverse myelitis, and Guillain Barre
syndrome [2–4]. IIH has not been reported so far with scrub
typhus infection. There is a wide geographic presence of
scrub typhus in India, hence, sensitizing clinicians regard-
ing the myriad of presentations is of utmost importance. It
is imperative to suspect scrub typhus among other tropical
febrile illnesses and to start specific treatment at the earliest
to decrease morbidity and mortality.
Declarations
Conflict of Interest None.
References
1. Wakerley BR, Mollan SP, Sinclair AJ. Idiopathic intracranial
hypertension: ipdate on diagnosis and management. Clin Med
Lond Engl. 2020;20:384–8.
2. Kim DE, Lee SH, Park KI, Chang KH, Roh JK. Scrub typhus
encephalomyelitis with prominent focal neurological signs. Arch
Neurol. 2000;57:1770–2.
3. Karanth SS, Gupta A, Prabhu M. Pure cerebellitis due to scrub
typhus: a unique case report. Trop Doct. 2013;43:41–2.
4. Kim JH, Lee SA, Ahn TB, et al. Polyneuropathy and cerebral
infarction complicating scrub typhus. J Clin Neurol. 2008;4:36–9.
Publisher’s Note Springer Nature remains neutral with regard to
jurisdictional claims in published maps and institutional affiliations.

* Indar Kumar Sharawat

sherawatdrindar@gmail.com
1
Division of Pediatric Neurology, Department of Pediatrics,
All India Institute of Medical Sciences, Rishikesh,
Uttarakhand 249203, India

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Indian Journal of Pediatrics (November 2023) 90(11):1071–1072
https://doi.org/10.1007/s12098-023-04802-7
EDITORIAL COMMENTARY
Blood Pressure Monitoring for Predicting Mortality in Neonatal Sepsis
Deepak Chawla1
Received: 14 July 2023 / Accepted: 19 July 2023 / Published online: 17 August 2023
© The Author(s), under exclusive licence to Dr. K C Chaudhuri Foundation 2023
When evaluating a neonate presenting with clinical features
or risk factors of sepsis, a clinician faces many questions - 1)
is the probability of sepsis sufficiently high so as to warrant
investigating and starting antibiotic therapy? 2) what is the
likely causative organism and to which antibiotics it would be
sensitive? 3) how severe is sepsis and will it progress to cause
organ dysfunction (e.g., shock) and death? If the probability
of sepsis is sufficiently high to cross the test-treatment thresh-
old (an arbitrary and usually subconscious value but present
nevertheless) set by the clinician, the neonate will undergo
laboratory investigations and be administered empirical anti-
biotic therapy. While awaiting the results of the laboratory
workup, the clinician and family grapple with the question of
the risk of progression and death. One of the most important
predictors of the adverse outcome in neonatal sepsis is blood
culture-positive sepsis. Neonates with culture-positive sepsis
are at about 30 times greater relative risk of death than neo-
nates without sepsis [1]. However, only a small proportion
of neonates who are evaluated for sepsis or even die with
the diagnostic label of sepsis have culture-positive sepsis.
In addition, culture positivity is not known till 12–72 h after
incubating the blood sample. Until then, the clinician has to
rely on the clinical status of the neonate.
Neonates with sclerema, shock, acidosis, and respira-
tory failure at the time of presentation are at greatest risk of
dying. However, risk assessment is also needed in neonates
who do not have these ‘severe’ features at the presentation
and are hemodynamically stable. Neonates at a greater risk
of dying can be monitored more frequently for early detec-
tion and management of complications or referred to an
appropriate center if the facilities for monitoring and man-
agement are unavailable. In a study published in this issue of
the journal, Saini et al. attempt to investigate if blood pres-
sure monitoring can be used to assess the risk of death [2].
* Deepak Chawla
drdeepak@gmch.gov.in
1 tem may have altered consciousness or seizures at presentation but
Department of Neonatology, Government Medical College
Hospital, Chandigarh, India
Authors posit that due to endotoxemia, neonates with severe
sepsis may have lower blood pressure even in the absence of
shock. Non-invasive blood pressure, an objective vital sign
routinely recorded in neonatal units, can be easily monitored
if found to have prognostic utility.
Although authors report a significant association between
mortality and blood pressure during 0–54 h of assessment, the
performance of blood pressure as a prognostic marker does not
look to be promising. First, although the values of systolic blood
pressure are statistically lower at many time points, a large degree
of overlap of values between survivors and non-survivors would
reduce the discriminating ability [3]. There would not be an
accurate cut-off value or categories of blood pressure (raw or
Z-score) to quantify the risk of death. Second, the study shows
that neonates with culture-proven sepsis and no sepsis (labeled
as clinical sepsis in the study) had similar systolic blood pressure
values. Culture-positivity is one of the most significant prognos-
tic markers and it seems that blood pressure during the first few
hours of presentation is not able to differentiate between neo-
nates with and without culture-positive sepsis. Third, the study
excludes neonates with culture-negative but probable sepsis. Of
neonates who present with clinical features of sepsis, this cohort
constitutes a significant fraction, the rest being neonates with
culture-positive sepsis (10–25%) and neonates without any sepsis
(25–50%). The neonates with probable sepsis are managed in the
same way till the culture report is available and excluding these
neonates will reduce the applicability of a prognostic marker. It is
possible that neonates with probable sepsis have blood pressure
values lower than in the neonates with no sepsis but higher than
in the neonates with culture-positive sepsis. Including neonates
with probable sepsis, as would be a correct approach, may further
reduce the prognostic accuracy of blood pressure.
Neonatal sepsis, although a single diagnostic label, is an
umbrella term for the syndrome of infection that can present in var-
ied ways in neonates of different gestations and with different organ
systems being variably affected. Neonates with predominant lung
involvement may have a lower oxygen saturation but preserved
blood pressure. Neonates with a predominant central nervous sys-
not low blood pressure. Term neonates with sepsis may be able to
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1072 Indian Journal of Pediatrics (November 2023) 90(11):1071–1072

preserve normal blood pressure for a longer duration than very pathogens in neonates born in tertiary care centres in Delhi, India:
preterm neonates with sepsis. Therefore, it is likely that a single A cohort study. Lancet Global Heal. 2016;4:e752–60.
2. Saini SS, Shrivastav AK, Sundaram V, Dutta S, Kumar P.
marker evaluating only the cardiovascular system will not be a Early blood pressure changes in neonatal sepsis and the risk
good predictor of the severity of infection in an unselected cohort of mortality. Indian J Pediatr. 2023. https://​doi.​org/​10.​1007/​
of neonatal sepsis and a more ‘inclusive’ approach is needed [4]. s12098-​023-​04597-7.
3. Kumar R, Indrayan A. Receiver operating characteristic (ROC)
curve for medical researchers. Indian Pediatr. 2011;48:277–87.
4. Richardson DK, Corcoran JD, Escobar GJ, Lee SK, for The Cana-
dian NICU Network, The Kaiser Permanente Neonatal Minimum
Declarations Data Set Wide Area Network, and The SNAP-II Study Group.
SNAP-II and SNAPPE-II: simplified newborn illness severity and
Conflict of Interest None. mortality risk scores. J Pediatr. 2001;138:92–100.

Publisher's Note Springer Nature remains neutral with regard to

jurisdictional claims in published maps and institutional affiliations.
References
1. Investigators of the Delhi Neonatal Infection Study (DeNIS) Col-
laboration. Characterisation and antimicrobial resistance of sepsis

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Indian Journal of Pediatrics (November 2023) 90(11):1067–1068
https://doi.org/10.1007/s12098-023-04804-5
EDITORIAL COMMENTARY
Neurodevelopmental Outcomes in Infants of Mothers with Gestational
Diabetes: Are We Missing the Boat?
Divyani Garg1 · Suvasini Sharma2
Received: 17 July 2023 / Accepted: 19 July 2023 / Published online: 9 August 2023
© The Author(s), under exclusive licence to Dr. K C Chaudhuri Foundation 2023
The intrauterine environment during pregnancy can poten-
tially impact neurodevelopmental outcomes in children, by
modulating fetal brain development. There has been some
data to link gestational diabetes mellitus (GDM) with lower
performance on various cognitive and memory measures,
when tested at varying ages of the child, ranging from 1 y
to school-going age group [1, 2]. However, the results are
not consistent, with other studies showing no association
between neurodevelopmental outcomes and occurrence of
GDM or elevated blood sugar during pregnancy [3].
The study by Bersain et al. attempts to bridge this gap
by assessing even younger children, to evaluate the impact
of GDM on very early neurodevelopmental outcomes [4].
In this cross-sectional study, the authors compared two
groups of infants- those born to mother with GDM (but not
pre-gestational diabetes) and mothers without GDM. The
Development Quotient (DQ) was assessed at 3­ 1/2 mo of age
using Developmental Assessment Scale for Indian Infants
(DASII). Fifty-two infants were assessed in each group.
Infants born to mothers with GDM scored lower on mean
motor DQ [101 (1.41) vs. 109.5 (10.6); p <0.001], mean
mental DQ [84 (9.89) vs. 88 (8.48); p = 0.03], and composite
DQ [92.5 (5.65) vs. 98.75 (9.54); p = 0.001] compared to
infants born to non-diabetic mothers. No association was
observed between maternal obesity or HbA1c levels in the
diabetic group.
Hence, neurodevelopmental outcomes were affected at
a very early age (­ 31/2 mo) in infants born to mothers with
GDM. This observation might raise the question whether
more stringent measures for diabetes control are required
* Suvasini Sharma
sharma.suvasini@gmail.com
1
Department of Neurology, All India Institute of Medical
Sciences, New Delhi, India
2
Division of Neurology, Department of Pediatrics, Lady
Hardinge Medical College and Associated Kalawati Saran
Children’s Hospital, New Delhi 110001, India
for optimum neurodevelopmental outcomes during preg-
nancy. However, the mean ­HbA1c in this group was 5.05
(0.21)%, which indicates excellent glycemic control.
Despite this, neurodevelopmental outcomes were affected,
suggesting that factors extraneous to glycemic control may
be operational in determining the infant’s neurological
development. The infants born to mothers with GDM also
had significantly lower weight and length compared to the
control group, connoting that not only maternal but also
fetal factors need to be studied as possible determinants of
neurodevelopmental outcomes. A case-control study may
provide answers to these queries. It would also be useful to
include infants of mother with pre-gestational diabetes and
assess an association between pre-gestational glycemic con-
trol and neurodevelopmental outcomes to further strengthen
or decimate this association.
Another important concern in these children is regard-
ing long-term developmental outcomes. It would be useful
to follow up this specific cohort prospectively and reassess
their neurodevelopmental outcomes at regular intervals to
see if this lag persists, accelerates, decelerates or a ‘catch
up’ phenomenon happens. In a previous study from India, 32
infants born to mothers with GDM were reassessed at 9–10
y and were counterintuitively observed to have better scores
in long-term retrieval/storage, learning and verbal ability,
and no difference in other cognitive measures compared to
controls [5]. Hence, a follow-up study may be able to clarify
what happens to these children over time. Overall, the study
by Bersain et al. should certainly trigger concern towards
early rehabilitation of affected infants while simultaneously
engendering appropriately designed studies to provide fur-
ther answers.
Declarations
Conflict of Interest None.
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1068 Indian Journal of Pediatrics (November 2023) 90(11):1067–1068

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