ONLINE CLINICAL INVESTIGATIONS

Hyperferritinemia in Severe Dengue Infection:

Single-Center Retrospective Cohort Study
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Chidhambharam Lakshmanan,
OBJECTIVES: Hyperferritinemia in the critical phase of dengue infections may MD, DNB, FNB (PICU)1
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correlate with severe dengue (sd) disease, and our primary objective was to ex- Suchitra Ranjit, MD, FCCM1
amine the association between ferritin level on day 1 of PICU admission and
Rajeswari Natraj, DNB, IDPCCM1
2009 World Health Organization (WHO) criteria for sd. Our secondary objective
was outcome in relation to care. It is unclear whether immunomodulatory therapy Priyavarthini Venkatachalapathy,
MD, DNB, FNB (PICU)1
during the critical phase may restore immune homeostasis and mitigate disease
severity. Vasanth S. Kumar, MD, DNB, FNB
(PICU)1
DESIGN, SETTING, AND PATIENTS: Retrospective cohort study of children
Lucy Chai See Lum, MBBS,
with dengue 1 month to 16 years old with admission ferritin greater than or equal MRCP2
to 500 ng/mL requiring PICU admission. Demographics, clinical, and laboratory
parameters, presence of the 2009 WHO sd criteria and outcomes were analyzed.
Immunomodulatory therapy was used when there was persistent hyperinflamma-
tion beyond the critical phase of plasma leakage.
INTERVENTIONS: None.
MEASUREMENTS AND MAIN RESULTS: Fifty-five patients were admitted
in the critical phase of dengue with median (interquartile range) ferritin levels of
8,105 ng/mL (2,350–15,765 ng/mL). Patients with at least one WHO sd cate-
gory had higher ferritin levels compared to those without any sd criteria, with the
highest levels in eight patients with all three sd categories. In our cohort of 55,
52 patients (94%) recovered with standard supportive therapy. Recovery was
associated with decreased ferritin levels that occurred in parallel with improved
circulation and platelet counts; this included 22 of 24 patients with admission fer-
ritin levels greater than or equal to 10,000 ng/mL and two with ferritin greater than
1,00,000 ng/mL. Immunomodulation was used in three patients with unremitting
fever, persistent hyperferritinemia, and progressive multiple organ dysfunction be-
yond the critical phase, of whom two died.
CONCLUSIONS: Hyperferritinemia in the critical phase of sd is associated with
the number of 2009 WHO sd criteria present. Our data also indicate that many
patients with sd recover well with supportive care.
KEY WORDS: dengue; hyperferritinemia; hyperinflammation; supportive care

E
levated ferritin levels serve as acute phase markers and early biomarkers
of dengue viral severity, greater dengue viremia, and consequent more
extensive immune activation and pro-inflammatory cytokine release (1,
2). Patients with severe dengue (sd) infections and extreme elevations of fer-
ritin have greater degrees of thrombocytopenia, shock, and organ failure, with
elevated liver transaminases and coagulation disturbances being most frequent
(1–3). Most of these patients have a well-defined temporal evolution in disease Copyright © 2023 by the Society of
phases (4). The critical phase follows the febrile phase and is characterized by an Critical Care Medicine and the World
abrupt onset of plasma leakage with consequent hypovolemic shock, extravas- Federation of Pediatric Intensive and
cular fluid accumulation, thrombocytopenia, and organ dysfunction. During Critical Care Societies
this phase, elevated inflammatory markers, including hyperferritinemia, may DOI: 10.1097/PCC.0000000000003250

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 Lakshmanan et al

lymphohistiocytosis (DA-HLH) (5). We considered

day 1 as the first day of PICU admission because the
RESEARCH IN CONTEXT date of onset of the illness and defervescence could
not be obtained. Patients with coinfections (viral or
• Hyperferritinemia is associated with a short- bacterial), preexisting comorbidities such as chronic
lived pro-inflammatory state during the critical anemia, liver disease, chronic kidney disease, and
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phase of severe dengue (sd) and may have those receiving steroids with/without immunosup-
an association with one or more World Health
pressive therapies were excluded.
Organization (WHO) severity categories.
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Data collection included demographic data, relevant

• During recovery, ferritin levels trend downwards, clinical examination and laboratory parameters, and
emphasizing its role as a severity marker rather the presence of WHO severity markers. In general, fer-
than mediator of severe disease.
ritin levels and platelet counts were repeated between
• It is unclear whether immunomodulation during days 3 to 5 of PICU admission. We also recorded data
the critical phase of sd is required to mitigate about organ function (respiratory/liver/renal), mark-
disease severity. ers of hemolysis, duration of PICU stay, PICU-free
days (30 - number of days in ICU, death within 30 days
be observed (1, 2). The critical phase is typically brief, was assigned zero ICU free days) and outcomes, and
lasting for 24–48 hours in the majority, following which compared important clinical outcomes in those with
most sd patients enter the recovery phase and improve admission ferritin less than 10,000 versus greater than
completely (4). During recovery, the hyperferritinemia or equal to 10,000 ng/mL.
also trends downwards, emphasizing ferritin’s role as In our PICU, our practice is to manage patients
a severity marker in a self-limited pro-inflammatory needing supportive therapy according to the WHO
state (1). Dengue Guidelines including carefully titrated fluid
In this report, we describe a retrospective co- replacement, organ support, and blood transfusions,
hort of 55 children who needed PICU admission for where ever indicated (4). Antibiotics are not routinely
dengue and associated hyperferritinemia. Our pri- prescribed in this viral syndrome unless bacterial coin-
mary objective was to examine the association be- fection is suspected/confirmed. The decision to initiate
tween ferritin level on day 1 of PICU admission and immunomodulatory therapy such as IV immunoglob-
2009 World Health Organization (WHO) criteria for ulin (IVIG) and/or steroids was taken at the discretion
sd. The secondary objective was outcome in relation of the attending clinician in patients with an unusu-
to care. ally severe clinical trajectory beyond the critical phase,
among whom new/coinfections had been excluded.
Indications included persistent new/unremitting fever,
MATERIALS AND METHODS
persistent or progressive hyperferritinemia, thrombo-
This single-center retrospective study did not require cytopenia, and/or organ dysfunction during the ex-
parent informed consent, and approval was waived pected recovery phase.
by the Apollo Hospital Ethics Committee (ACH- Data were entered in Excel 2013 sheets (Microsoft,
C-S-007/05-22), South India. The study was carried Indianapolis, IN) and were analyzed using SPSS soft-
out in accordance with The Helsinki Declaration of ware Version 25.0 (IBM, Armonk, NY). Categorical
1975 and the ethical standards of the Apollo Hospital variables and continuous variables were summarized
Ethics Committee. The cohort was derived from PICU as frequency (percentage) in mean (sd) or median (in-
admissions over two epochs: August to December terquartile range [IQR]), respectively. For comparative
2019 and 2021. We included children 1 month to 16 analysis, chi-square or Fisher exact test was performed
years old with laboratory-confirmed dengue requiring for categorical and Student t test or Mann-Whitney U
PICU admission and who had ferritin levels greater test for continuous variables, respectively.
than or equal to 500 ng/mL at admission. This was the A p value of less than 0.05 was considered signif-
cutoff level of ferritin used in a systematic review and icant for the primary outcome. For secondary out-
meta-analysis on dengue-associated hemophagocytic comes, the measures and reporting depended on the

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 Online Clinical Investigations

type of variable. For categorical variables, we consid- duration of fever, fluid resuscitation in first 24 hours,
ered the odds ratio as an effect measure and reported and outcomes in the cohort. While 41 of 55 patients
along with 95% CIs. For continuous variables, the dif- (75%) were afebrile at admission, at least one WHO
ference in medians was calculated as an effect measure criterion for sd was documented in 47 of 55 patients.
and reported along with 95% CIs using the Hodges- Among these 47 patients, severe plasma leakage
Lehmann estimator. Further, in order to correct for (SPL) leading to shock and/or respiratory distress was
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multiple comparisons, a type 1 error (alpha value) of observed in 46 of 55 patients (84%) (Fig. 1, A and B).
less than 0.005 was considered significant after adjust- Five patients required vasoactive-inotropic support for
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ment by Bonferroni correction. shock, and of the 20 subjects with fluid accumulation,
respiratory support was initiated with high-flow nasal
RESULTS oxygen in 15 and invasive ventilation in five patients.
Other criteria for sd, such as organ involvement and se-
We identified 55 of 76 patients with laboratory- vere ongoing bleeding, were seen in 16 of 55 (29%) and
confirmed dengue infections who were admitted 10 of 55 (18%), respectively. Patients with one or more
to the PICU and had ferritin levels greater than or category for sd as defined in the 2009 WHO dengue
equal to 500 ng/mL. Table 1 summarizes the demo- classification had significantly higher ferritin levels com-
graphic details including severity scores, PICU course, pared to those without any. Furthermore, the median

TABLE 1.
Demography, PICU Course, and Outcomes
Demography and Clinical Features No. of Patients, Clinical Variables, and Values

Included patients 55
Agea 6 yr 11 mo (38–122 mo)
Female gender 25
Pediatric Risk of Mortality-3 scores 11 (6–14)a
Pediatric Logistic Organ Dysfunction-2 scores 6 (1–11)a
Fever duration (d) 4.5 (3.7–5)a
Number needing organ support 10
Invasive ventilation: 5
Vasopressor-inotrope: 5
Renal replacement: 3
Plasma exchange: 2 (four patients required > 1 organ support)
Lowest platelet count (mm ) 3
21,000 (13,000–39,000)a
Presence of dengue shock, n (%) (consequent to severe 33/55 (60)
plasma leakage)
Resuscitation fluid received in:
 First 6 hr (mL/kg) 17 (12–26)a
 First 24 hr (mL/kg) 38 (19–67)a
Number who received immunotherapy, n 3/55
IV immunoglobulin: 2
Steroid: 2
One patient received both
Duration of PICU stay (d) in survivors 4 (2.5–5.5)a
Survival, n (%) 53 (98)
a
Median (interquartile range).

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 Lakshmanan et al

With respect to admis-

sion ferritin levels, therapy
and outcomes, the me-
dian admission ferritin
was 8,105 ng/mL (IQR,
2 ,3 5 0 –1 5 ,7 6 5 ng /mL)
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in the entire cohort and

6,090 ng/mL (IQR, 2,270–
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15,153 ng/mL) in 52 of 55
patients who recovered
with supportive therapy.
Twenty-two of 24 patients
with admission ferritin
levels greater than or equal
to 10,000 ng/mL recovered
with supportive therapy,
including two patients
with ferritin levels greater
than 1,00,000 ng/mL. A re-
peat ferritin level (checked
at the discretion of the
treating intensivist) in 31
of 55 patients between day
3–5 of admission showed
the following: in 28 of 31
patients, the hyperfer-
ritinemia demonstrated
decreasing trends in par-
allel with improved clin-
Figure 1. Overlap between World Health Organization Severe Dengue criteria. A, Features of ical and circulatory status,
severe dengue (sd) in 47 patients. B, Relationship of shock ± respiratory distress in 46 patients platelet levels and organ
with severe plasma leakage.
function.
ferritin levels increased with incremental categories of The PICU course was markedly different in three
sd, and the highest median ferritin level—32,820 ng/mL patients in our cohort of 55. These three patients were
(IQR, 21,545–44,937 ng/mL) were seen in eight of 55 admitted late in the critical phase with protracted shock
patients (14.5%) with all three WHO sd categories (Fig. and massive fluid collections, among whom the admis-
2). On univariate analysis of secondary outcomes by sion ferritin levels were 8,744, 36,950, and 42,460 ng/
effect size and 95% CI, we identified an association be- mL. These three children failed to show improvement
tween day 1 ferritin greater than or equal to 10,000 ng/ with supportive therapy but rather continued to expe-
mL and few secondary outcomes (Table 2). Of the 12 rience persistent fever, progressive organ failure, and
patients investigated for suspected intravascular he- one patient had continued catastrophic hemorrhage.
molysis, this entity was confirmed in only one patient Although the fulminant clinical picture was com-
based on raised lactate dehydrogenase (LDH), anemia, mensurate with the sequelae of protracted shock, the
and peripheral smear showing red cell fragments (6). attending clinician elected to provide immunotherapy
Moreover, we found a poor association between features comprising IVIG and steroids in view of worsening
of hemolysis (a combination of raised LDH and red cell organ failure and a poor response to supportive therapy.
fragments on smear) and ferritin levels greater than or Two of three late presenters with hyperferritinemia
equal to 10,000 ng/mL (Fisher exact test p = 0.83). and organ failure had a relentlessly unfavorable course

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 Online Clinical Investigations

Notwithstanding the
extreme hyperferri-
tinemia and severity of
the clinical presentation,
the period of clinical
instability was short-
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lived in the majority. We

observed that 52 of 55
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patients (94.5%) who

presented early during
the critical phase recov-
ered fully with timely
supportive care, in-
cluding 22 of 24 patients
with admission ferritin
levels greater than or
equal to 10,000 ng/mL,
a level considered to be
highly sensitive and spe-
cific for HLH (9). Among
patients who presented
Figure 2. Ferritin levels (median and interquartile range) depending on number of World Health early, we could demon-
Organization (WHO) criteria for severe dengue. *p ≤ 0.05. strate downward trends
in the elevated fer-
and died, the first on day 6 because of uncontrolled ritin levels along with
gastrointestinal bleeds; the second died 48 hours after improved clinical parameters, further emphasizing fer-
requested transfer to another facility. ritin’s role as a short-lived severity marker rather than
a mediator of an uncontrolled inflammation state in
DISCUSSION this condition (1, 2). However, in patients with delayed

The key to good outcomes in sd may be standard sup-

portive care, including early recognition and metic-
ulously titrated restoration of the circulation with IV
fluids and blood transfusion when necessary (4, 7).
AT THE BEDSIDE
Extensive immune activation is a hallmark of sd (1),
and we identified a relationship between 2009 WHO • Incremental rise in 2009 WHO sd category
categories for sd and ferritin level on day 1 of PICU greater than or equal to 1, versus not, is asso-
admission and could demonstrate higher ferritin lev- ciated with higher ferritin levels.
els with incremental involvement of sd categories. We • The majority of our sd patients presenting early
observed that during the recovery period, the ferritin during the critical phase recovered using PICU
levels trended downwards in the majority, in parallel supportive therapies.
with improved platelet levels, organ function, and cir- • It is likely that not all hyperferritinemic syn-
culatory status. dromes are the same, and outcomes associ-
The 2009 WHO dengue case classification com- ated can be remarkably different. Uncertainty
prised non-sd and sd. sd is defined by three categories: remains in regard to use of immunomodulation
SPL, severe organ impairment, and severe bleeding (4). therapy for sd, and following the recovery tra-
jectory in relation to phase of the disease may
Patients with sd may manifest one or more of these
be helpful.
categories, SPL being the most common, particularly
in children less than 15 years old (4, 8).
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 Lakshmanan et al

TABLE 2.
Comparison of Clinical Outcomes Between Patients With Ferritin Values Below and
Greater Than 10,000 ng/mL
Ferritin < 10,000 ng/mL, Ferritin ≥ 10,000 ng/ Effect Size
Clinical Outcomes n = 31, n (%) mL, n = 24, n (%) (95% CI), p
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Shock 19 (61) 14 (58) 0.9 (0.3–2.6)b, 0.8

Severe hemorrhage 2 (6) 8 (33) 7.3 (1.4–38.3)b, 0.01
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Need for noninvasive ventilation/high- 7 (26) 12 (50) 3.2 (1.1–10.9)b, 0.03

flow nasal cannula
Need for invasive ventilation 1 (3) 4 (17) 6.0 (0.6–57.7)b, 0.08
Organ dysfunctiona (liver/kidney/CNS) 5 (16) 11 (46) 4.4 (1.3–15.3)b, 0.01
PICU days, median (IQR) 3 (2–4.5) 5 (3.8–6) 1.8 (0.5–3.0)c, 0.004d
PICU-free days, median (IQR) 27 (25.5–28) 25 (24–26.2) 1.8 (0.5–3.0)c, 0.003d
Length of hospital stay, d, median 4 (3–5.5) 6 (5–8) 2 (1–3)c, 0.003d
(IQR)
Mortality 1 (3) 1 (4) 1.3 (0.1–21.9)b, 0.8
IQR = interquartile range.
a
Presence of anyone organ dysfunction defined as per World Health Organization 2009 Dengue Guidelines.
b
Odds ratio (95% CI).
c
Difference in medians (95% CI) by Hodges-Lehmann (nonparametric) estimator.
d
p < 0.005 is significant by Bonferroni correction.

presentation and prolonged severe shock, supportive immunomodulation might be helpful to mitigate se-
therapy may be ineffective. This appeared to be the vere disease (13). Hyperferritinemia has also been
case in three of 55 patients who presented late in pro- described in association with extensive cell damage
tracted shock and continued to have unrelenting mul- and ischemia-reperfusion injury (14), and these mech-
tiple organ failure and hyperferritinemia, of whom two anisms may have contributed to the higher ferritin lev-
patients died, despite receiving immunomodulation. els seen in our patients with two or more categories of
The hyperferritinemic syndrome is a recently sd, including three of 55 late presenters.
described entity encompassing four conditions char- Intravascular hemolysis, while infrequent in the
acterized by high levels of ferritin and includes macro- setting of dengue (15, 16), may contribute to elevated
phage activation syndrome, adult-onset Still’s disease, ferritin levels. There is no single laboratory test that is
catastrophic antiphospholipid syndrome, and septic specific for hemolysis (17) and a combination of raised
shock (10). In this syndrome, extreme hyperferritinemia LDH, red cell fragments on smear, or the presence of
is a harmful mediator of pro-inflammatory cytokines urinary hemosiderin may be helpful in establishing
that contribute to the development of a cytokine storm the diagnosis (6) and in our cohort, we found a poor
and worse prognosis, and immunomodulatory therapy association between features of hemolysis and ferritin
(IVIG, steroids) has been found to be successful (10). levels greater than or equal to 10,000 ng/mL.
However, hyperferritinemia in sd may have sev- Interestingly, hyperferritinemia may also be a de-
eral mechanisms, although not all have been fully fence mechanism, and in vitro studies suggest that
elucidated. The best-known mechanism suggests that ferritin binds to high-molecular-weight kininogen
ferritin is a product of highly active Dengue virus di- thereby blocking the release of bradykinin which is
sease reflecting greater dengue viremia and culmi- a potent vasodilator that contributes to capillary leak
nating in a pro-inflammatory cytokine release and is (18). This phenomenon may be helpful in the context
highest in the critical phase (1, 3, 11). The hyperferri- of sd, although not specifically studied in this setting.
tinemia during this phase is helpful to call out dengue Finally, hyperferritinemia that progresses or persists
severity (10, 12), although some reports suggest that beyond the critical phase, that is, several days after

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 Online Clinical Investigations

initial defervescence, may have very different connota- the highest levels in those with all three criteria, and
tions including DA-HLH, which, although rare, can be it is unclear whether immunomodulatory therapy may
fatal if untreated and needs full work-up and standard confer additional benefits.
therapy (19, 20). Tan et al (21) and others suggest that
the diagnosis of DA-HLH be considered in patients
with persistently high and unremitting fever greater
ACKNOWLEDGMENTS
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than 7 days and persistent cytopenia in association We gratefully acknowledge the contributions of Mrs.
with hyperferritinemia that is out of proportion to and Sadhana Kannan, MSc Biostatistics, Department of
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occurs beyond the critical phase of plasma leakage (5). Statistics, Clinical Research Secretariat (Advanced
It is likely that not all hyperferritinemic syndromes Centre for Treatment, Research and Education in
are the same, and outcomes associated can be remark- Cancer), Tata Memorial Centre, Mumbai, all our col-
ably different. Understanding/identifying the un- leagues including Dr. Indira Jayakumar, and all our en-
derlying processes of different hyperferritinemias is thusiastic PICU Fellows, all PICU nurses and Physician
essential before implementing rescue treatments. For Assistant Ms. Santhalakshmi.
the clinician treating a child with sd, observing the
progression of the disease, trends in ferritin levels and
1 Department of Pediatric ICU, Apollo Children’s Hospital,
recovery trajectory in relation to the phase of the di- Chennai, India.
sease may be helpful, rather than relying on a single 2 Department of Pediatrics, University of Malaya Medical
ferritin value, irrespective of the value. Center, Kuala Lumpur, Malaysia.
Limitations of our study include the retrospective The authors have disclosed that they do not have any potential
observational nature of our study from a single center. conflicts of interest.
Furthermore, our cohort consists of only children For information regarding this article, E-mail: lct120190@gmail.
com
less than 16 years old. Ferritin levels in adults might
This study was performed at Pediatric ICU, Apollo Children’s
have different connotations as they are less likely to
Hospital, Chennai, India.
have SPL but rather present with a higher frequency
of organ impairment and severe bleeding, perhaps re-
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