Immunomodulation in sepsis-induced macrophage activation syndrome in children

Ashna Kumar; Priyanka Choudhari; Anu Maheshwari; R Ackshya; Deonath Mahto

doi:10.4103/ipcares.ipcares_146_22

CASE SERIES

Year : 2023 | Volume : 3 | Issue : 1 | Page : 13-17

Immunomodulation in sepsis-induced macrophage activation syndrome in children

Ashna Kumar, Priyanka Choudhari, Anu Maheshwari, R Ackshya, Deonath Mahto
Department of Pediatrics, Lady Hardinge Medical College and Associated Kalawati Saran Children Hospital, New Delhi, India

Date of Submission	25-Jun-2022
Date of Decision	12-Dec-2022
Date of Acceptance	03-Feb-2023
Date of Web Publication	27-Feb-2023

Correspondence Address:
Dr. Anu Maheshwari
Department of Pediatrics, Lady Hardinge Medical College and Associated Kalawati Saran Children Hospital, New Delhi - 110 001
India

Source of Support: None, Conflict of Interest: None

DOI: 10.4103/ipcares.ipcares_146_22

Abstract

Background: Sepsis is a state of systemic inflammation due to an infectious etiology that may lead to multisystem dysfunction, hemodynamic instability, and even death. It has been postulated that there may be an underlying immunomodulatory process resulting from rapid and exaggerated activation of macrophages that results in a cytokine storm and the development of macrophage activation syndrome (MAS). Adding immunomodulation to standard therapy (antibiotics and supportive care) can improve the prognosis. Clinical Description: We present a series of three young children who presented with the clinical features of sepsis. All three showed poor clinical response to management with timely antibiotics and supportive care, even after 48–72 h of initiation. In addition, there was the development of thrombocytopenia and transaminitis. The suspicion of MAS prompted us to order ferritin, triglyceride, and fibrinogen levels and applies the 2016 diagnostic criteria for MAS. These were satisfied, thus establishing the diagnosis. Management: In all three cases, immunomodulatory agents (intravenous immunoglobulin with or without pulses of methylprednisolone) were added, after which there was a clinical improvement, normalization of biomarkers, and complete recovery. Conclusion: Early immunomodulatory therapy, in addition to antibiotics, is beneficial in the successful treatment of children presenting with sepsis-induced MAS, thus preventing further morbidity and mortality and improving outcomes.

Keywords: Immunomodulation, macrophage activation syndrome, secondary hemophagocytic lymphohistiocytosis, sepsis

How to cite this article:
Kumar A, Choudhari P, Maheshwari A, Ackshya R, Mahto D. Immunomodulation in sepsis-induced macrophage activation syndrome in children. Indian Pediatr Case Rep 2023;3:13-7

How to cite this URL:
Kumar A, Choudhari P, Maheshwari A, Ackshya R, Mahto D. Immunomodulation in sepsis-induced macrophage activation syndrome in children. Indian Pediatr Case Rep [serial online] 2023 [cited 2023 Sep 30];3:13-7. Available from: http://www.ipcares.org/text.asp?2023/3/1/13/370521

Sepsis is a state of systemic inflammatory reaction with dysregulated release of acute and chronic phase reactants due to a suspected or proven infectious etiology. The spectrum progresses from systemic inflammatory response syndrome to severe sepsis (sepsis combined with one or more organ dysfunction); hemodynamic instability, septic shock, or multiple organ dysfunction syndrome (MODS); and ultimately death, if left untreated.

Sepsis is a major cause of pediatric mortality and morbidity. A temporary global point prevalence study of sepsis in pediatric intensive care units reported 25% mortality, especially in children with MODS. Despite advances in treating and managing sepsis and its complications, this figure has remained more or less static till date, suggesting the presence of a hitherto unaddressed phenomenon. Some authors have postulated that this may be due to macrophage activation and the ensuing cytokine storm (i.e. a rapid and exaggerated release of cytokines and immune cell hyperactivation) that gets triggered by the infection.^[1],[2],[3] Hypothetically, patients with sepsis can be classified into three inflammatory phenotypes based on the underlying immune pathobiology: (i) dominant pro-inflammatory mechanisms; (ii) dominant anti-inflammatory mechanisms; and (iii) coexistent pro-inflammatory and anti-inflammatory mechanisms.^[4] The common end pathway leading to MODS may be due to macrophage activation.^[5] The present day management protocols of sepsis are primarily based on the source reduction of infection or eradicating infection with appropriate antibiotics and supportive care for the organ dysfunction (s). Recently, the role of immunomodulation for controlling the cytokine storm has been recognized as another important pillar of therapy if macrophage activation syndrome (MAS) is suspected.

MAS is a term that has conventionally been used by rheumatologists due to its association with various rheumatoid disorders. However, it is now recognized that MAS can be triggered by other conditions, including sepsis. Another name for MAS is secondary hemophagocytic lymphohistiocytosis (HLH) because of the similarity in clinical manifestations with primary HLH, i.e. constitutional symptoms, organ dysfunction (cytopenias, transaminitis, and coagulopathy), and biomarkers of the cytokine storm (increased ferritin and triglycerides and decreased fibrinogen). The establishment of diagnosis is by the application of diagnostic criteria; the 2004 criteria for HLH are gradually being replaced by the more recent 2016 guidelines for MAS [Table 1].^[6] MAS is associated with high mortality if specific therapy is not instituted in time. We have summarized three studies of children with sepsis and MAS who received immunomodulation and their outcomes in [Table 2].

Table 1: Studies on macrophage activation syndrome in children with sepsis

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Table 2: Comparison of diagnostic criteria for hemophagocytic lymphohistiocytosis and macrophage activation syndrome, with application of latter in all three children

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It is imperative that clinicians learn to recognize MAS in a child with sepsis and treat it as life-threatening emergency. This can be challenging as the clinical deterioration that manifests is difficult to differentiate from disease progression, complications, nosocomial sepsis, etc., due to overlapping clinical features, unless a high index of suspicion is kept. In this case series, we present three children with sepsis in whom we suspected MAS due to inadequate clinical response to timely and appropriate initiation of antibiotics and provision of supportive care and share details of further management.

Case 1

Clinical description

An 11-day-old preterm boy was referred to our hospital for persistent respiratory distress (RR) since birth and fever for 7 days. On reviewing the medical records, we learned that there was a significant antenatal history of maternal hypothyroidism and pregnancy-induced hypertension, though complete details were unavailable. The baby had been born at 31 weeks + 3 days gestation by an emergency cesarean section. There was no history of any sepsis setting, and the mother did not receive antenatal steroids for enhancing lung maturity. The APGAR score was 8 at both 1 and 5 min, and he weighed 1.9 Kg (appropriate for gestational age). The baby developed RR soon after birth and was transferred to the nursery, where he received endotracheal surfactant and was put on continuous positive airway pressure (CPAP). A diagnosis of RR syndrome was made based on the clinical course and investigations. The baby was referred to us due to the persistent requirement of CPAP even after 6 days. There was no history of any seizures, altered sensorium, decreased urine output, jaundice, or bleeding from any site. The family history was not contributory.

On admission, the baby appeared sick. He was tachypneic with a respiratory rate of 78 breaths/min and had subcostal and intercostal retractions. The heart rate was 140 beats/min. The temperature and capillary refill time (CFT) were normal. Multiple abscesses were noted on the right ring finger, anterior chest wall, and lower back, which ranged in size from 4 to 10 mm in diameter. There were no pallor, cyanosis, jaundice, or petechiae. Salient systemic findings were bilateral crepitations and bronchial breathing on the right hemithorax, normal cardiovascular findings, and the absence of hepatosplenomegaly. The cry was weak, but neonatal reflexes and spontaneous movements were present. A clinical diagnosis of late-onset neonatal sepsis was kept. Symptomatic management was initiated in the form of broad-spectrum antibiotics (meropenem and vancomycin), intravenous (IV) fluids, and incision and drainage of the abscesses. The child was placed on bubble CPAP and started on enteral feeding.

Management and outcome

Investigations showed hemoglobin (Hb) of 11.6 gm%; total leukocyte count (TLC) of 25,000/mm³ with differential leukocyte count (DLC) of N72, L22, M6, and platelet count of 25,000/mm³. The C-reactive protein (CRP) was 111 mg/L, and procalcitonin was also raised (>10 ng/ml). A lumbar puncture to rule out meningitis was deferred in view of the thrombocytopenia. The chest X-ray showed bilateral streaky infiltrates. The baby showed clinical improvement in the initial 72 h. On the 4^th day, he developed new abscesses over his scalp. This was associated with feeding intolerance, vomiting, abdominal distension, worsening of respiratory distress (RR 72/min with chest retractions), and the requirement of increased CPAP support to maintain oxygen saturation (SpO₂) saturation. On repeating investigations, we found that the platelet counts had decreased to 7000/mm³ and the CRP had risen to 209.7 mg/L. The pus and blood culture reports became available and revealed the growth of Methicillin-resistant Staphylococcus aureus. In view of clinical worsening despite sensitivity to the antibiotics being given, thrombocytopenia and rising CRP, MAS was suspected and workup was sent accordingly.

The ferritin level was 1038 ng/ml, serum glutamic-oxaloacetic transaminase (SGOT) 68 U/L, triglycerides 361 mg/dl, and fibrinogen 280 mg/dl. Our suspicion was confirmed by satisfaction of the diagnostic criteria of MAS [Table 1], and IV immunoglobulin (IVIG) was administered (2 g/kg). The baby improved clinically, and hematological parameters started to normalize within 48 h. He was gradually weaned off oxygen over the next 7 days and discharged after 3 weeks of IV antibiotics. At the 3-month follow-up visit, the infant showed good weight gain, and his hematological parameters were still normal, excluding the possibility of primary HLH.

Case 2

Clinical Description

A 1-month-old boy presented with a history of fever, lethargy, and refusal to feed for 3 days. There was no history of any seizures, respiratory difficulty, progressive pallor, abdominal distention, vomiting, diarrhea, jaundice, or bleed from any site. The baby was being fed cow's milk with double dilution by a bottle, and the mother felt that the baby was not gaining weight satisfactorily. The baby had been born at term at home by a vaginal delivery conducted by a trained birth attendant. The birth weight was 2.8 kg. Antenatal records were not available, but according to the mother, she was immunized, and the pregnancy had been uneventful. There was no family history of unexplained infant death or similar complaints in the siblings.

On admission, the baby appeared sick and lethargic. He was hypothermic (temperature 34°C), with a heart rate of 150/min, respiratory rate of 56/min, the absence of chest retractions, and prolonged CFT in the setting of normal volume brachial pulses. The SpO₂ was 94% on room air. The baby weighed 2 kg. He did not have any pallor, icterus, cyanosis, sclerema, or any rash. The umbilicus was normal. The anterior fontanelle was at the level and of normal size, but the cry was weak, spontaneous movements were less, and Moro's reflex, though symmetrical was blunted. The rest of the systemic examination was normal. The blood sugar level by a heel prick was in the hypoglycemic range (28 mg/dl). A diagnosis of late-onset neonatal sepsis with suspected meningitis, moderate hypothermia, possible shock, hypoglycemia, and failure to thrive was kept based on the clinical phenotype.

Management and outcome

The baby was kept under a radiant warmer and treated for hypothermia and hypoglycemia as per standard protocol. Inotropic support was not required. A sepsis screen as well as blood and urine cultures were sent. He was started on broad spectrum antibiotics (Cefotaxime and Amikacin). A lumbar puncture was performed after thermal and hemodynamic stabilization. Initial investigations showed Hb of 9.2 gm%, TLC of 19,000/mm³ with differential of N60, L34, M6, and platelet count of 73,000/mm³. The CRP was 64 mg/l and procalcitonin >10 ng/ml. The lumbar puncture was suggestive of pyogenic meningitis with 100 cells (80% polymorphs), cerebrospinal fluid (CSF) sugar 20 mg/dl (concurrent blood sugar: 67 mg/dl), and protein 126 mg/dl. An ultrasound skull was done to rule out intraventricular bleeding in view of thrombocytopenia was normal.

After 48 h of management, the baby did not show any clinical improvement and hypoglycemia persisted (necessitating a glucose infusion rate of 8 mg/kg/min), though the temperature and hemodynamic status were maintained. Minimal enteral feeds were started. Repeat investigations revealed leukopenia with a TLC of 3400 (N60, L30, M5), worsening of thrombocytopenia (platelet count: 20,000/mm³), and increase in CRP (138 mg/l). We upgraded antibiotics to meropenem and amikacin after sending repeat blood cultures. We also decided to work up for fungal sepsis in view of the failure to thrive; however, urine analysis was normal, with the absence of yeast cells. MAS was also suspected in view of the inadequate response to antibiotics and worsening hematological parameters. The following laboratory values were obtained: ferritin >2000 ng/ml, SGOT 401 U/L, triglycerides 282 mg/dl, and fibrinogen 169 mg/dl. Thus, the criteria for MAS were satisfied [Table 1]. The infant was given IVIG (2 g/kg), followed by injectable methylprednisolone (@10 mg/kg) for 3 days. Following the steroid pulse, the baby became euglycemic and clinically stable within 72 h and was shifted to full feeds. The laboratory parameters normalized after 1 week. All cultures were sterile. The feeds were gradually increased, and he started gaining weight. The baby was discharged after completing 2 weeks of antibiotics. On follow-up after 2 months, the infant was well with adequate weight gain, and the ferritin level was 178 ng/ml.

Case 3

Clinical Description

An 18-month-old boy was brought to the emergency in shock with a history of loose stools, vomiting, and fever for a day and decreased oral acceptance for a few hours. The stool frequency was 6–8 per day, and there was no history of blood or mucous. The child had vomited twice since onset. The fever was not documented but described as moderate grade and without chills. The child was passing urine normally. There was no history of abdominal distension, jaundice, cough, coryza, RR, rashes, eye redness, altered sensorium, or seizures. The mother was giving properly prepared oral rehydration solution in adequate volume since the onset of diarrhea, which the child had been accepting well despite the vomiting till a few hours. There was no history of accidental ingestion of any unknown substance and no other family member had similar symptoms. He was a developmentally normal child with no previous history of hospitalization. The family history was not contributory in terms of similar illness, unexplained infant deaths, febrile convulsions, or epilepsy.

At presentation, the weight was 13 Kg, and there was no visible wasting in the child. Other parameters were not taken in view of his clinical status. There were no signs of dehydration, though the pulses were feeble, his peripheries were cold, he had tachycardia (heart rate: 210/min.), and his blood pressure was not recordable. We suspected septic shock because there were no signs of dehydration. The respiratory rate was 50/min with a saturation of 92% on room air. The general physical examination was normal, and there was no clinical sign of any toxidrome. During evaluation in the emergency ward, the child had three episodes of generalized tonic–clonic seizures (GTCS), which were managed as per the standard protocol (blood sugar 125 mg/dl). Following this, the Glasgow Coma Scale was 5/15 on the basis of which he was intubated and started on ventilator support. The pupils were of normal size and reacting to light. The remaining central nervous system examination in a comatose child did not reveal any focal neurological deficit or evidence of increased intracranial tension. The cardiovascular system and remaining systemic examination were normal. We made a diagnosis of acute gastroenteritis with septic shock. Unknown poisoning though considered less likely could not be ruled out completely.

Management and outcome

The child was resuscitated with fluids and inotropes as per protocol and started on broad-spectrum antibiotics (ceftriaxone and amikacin). The preliminary investigations showed Hb of 6.6 g/dl (blood indices and peripheral smear indicative of hypochromic microcytic anemia), TLC was 48,000/mm³ with neutrophilia (DLC N82, L18), and platelet count of 131,000/mm³. The serum electrolytes, calcium (total and ionized) levels, and liver and kidney function tests were all within normal limits excluding metabolic causes of the GTCS. An electrocardiogram was ordered to rule out paroxysmal supraventricular tachycardia, which showed no evidence of arrhythmia. After initial stabilization, a lumbar puncture was performed; the CSF analysis was acellular, and the biochemistry (sugar and proteins) was normal. There was a progressively declining trend of platelets to 58,000/mm³ and 25,000/mm³ over the next 48 h.

Even after appropriate antibiotics, fluid resuscitation, and inotropes, the shock was nonresponsive and there was no clinical response within 48 h. Blood, urine, and CSF cultures were negative. In view of the clinical profile and worsening platelet counts, MAS was suspected. The ferritin level was 802 ng/ml, SGOT 41 IU/L, creatine phosphokinase 4038 U/L, triglycerides 320 mg/dl, and fibrinogen 210 mg/dl, fulfilling the criteria of MAS [Table 1]. IVIG was given (2 g/kg) followed by three pulses of methylprednisolone (@ 30 mg/kg/day). Following this, the shock and overall clinical condition improved within 72 h. The ventilator settings remained minimal, and we were able to extubate the patient after 5 days. He was discharged with normal laboratory parameters after completing 14 days of antibiotics. Neuroimaging of the brain performed after discharge ruled out any structural lesion. The cause of seizures was kept as probably secondary to sepsis or complex febrile seizures.

Discussion

It has been suggested that, in MAS, the underlying etiopathogenesis is the cocktail of cytokines, notably tumor necrosis factor alpha and various interleukins (IL), i.e., IL-6, IL-1β, and IL-18 that are produced by the activated macrophages/monocytes. This triggers off the cascade of inflammatory pathways that ultimately culminates in a cytokine storm.^[10] It also results in the production of the biomarkers of MAS that are included in the diagnostic criteria. Ferritin is secreted by the activated macrophages; inflammation induces the activation of vascular lipoprotein lipase, leading to increased triglyceride, as well as SGOT values; and depleting fibrinogen levels is caused by the consumptive coagulopathy.

Ferritin values of more than 500 ng/ml have been associated with 60% mortality in pediatric sepsis. In fact, the mortality among the three aforementioned inflammatory phenotypes was reportedly the highest when hyperferritinemic MAS developed.^[11] The prognostic implication of serum fibrinogen value in outcomes of sepsis is also well known, with values <150 mg/dl being indicative of adverse outcomes.

Since the pathophysiology of MAS is primarily due to a hyper-inflammatory state, treatment comprises therapeutic agents that can slow down the inflammatory storm. The immune effector cells get modulated by the interaction of the Fc portion of Ig with the Fc receptors of these cells. This controls and normalizes the cytokine cascade. There has been a gradual transition in the management protocols of MAS with less potent and safer immunomodulating drugs such as IVIG and pulses of methylprednisolone instead of the chemotherapeutics and/or dexamethasone (that was used when the 2004 diagnostic criteria of HLH and management protocols were being followed).^[7] A study by Demirkol et al. in 2012 showed 100% survival of 65% Turkish patients with active infection, MODS, and hyperferritinemia after treatment with IVIG-based treatment.^[7] Another Turkish study by Haytoglu et al. in 2017 showed 83% survival for patients with hyperferritinemia-associated sepsis/MODS treated with less immunosuppressive therapy.^[9] Rajajee et al., in a retrospective study involving 40 Indian children with HLH, demonstrated good outcomes (disappearance of fever, clinical improvement, normalization of cell counts, and event-free survival of 12 months) in 86.4% of children treated with IVIG plus steroids.^[8]

In this report, we have described three children with sepsis-induced MAS (including a neonate) who were successfully treated after the diagnosis was suspected and confirmed. This was done by application of the 2016 consensus criteria, which are less stringent than the earlier criteria [Table 1]. In terms of ease of office practice and in the case of sepsis, splenomegaly is no longer mandatory (often not seen in all children with sepsis), and neither is there a need to get the soluble CD25 levels done (not an easily accessible test and expensive). The need for demonstrating hemophagocytosis by invasive tests also becomes less relevant, since the diagnostic criteria get satisfied by the presence of ≥2 criteria in the presence of elevated ferritin in a febrile patient with an underlying predisposing condition (in this case sepsis). In terms of management, we chose IVIG and methylprednisolone in view of the benefits shown in the literature search mentioned earlier.^[6],[10] Methylprednisolone was avoided in the preterm neonate, as we felt the risks did not justify any potential benefit to adding it to IVIG.

The message that we wish to deliver from this case series is that clinicians should suspect MAS in a clinical setting of sepsis, if the general condition does not seem to respond despite appropriate treatment within 48–72 h, and/or laboratory parameters show progressive thrombocytopenia and/or transaminitis. Screening for MAS can be easily done by additional investigations such as ferritin, fibrinogen, and triglycerides that are usually not ordered routinely. If the diagnostic criteria of MAS get satisfied, timely administration of easily available specific therapy can reverse the inflammatory state, prevent irreversible organ damage, and improve the prognosis.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form the patients have given their consent for their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

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