A case of an 11-year-old boy with paediatric inflammatory multisystem syndrome associated with coronavirus disease, haemophagocytic lymphohistiocytosis, and systemic juvenile idiopathic arthritis (2024)

- A case of an 11-year-old.pdf[0.55 MB]

INTRODUCTION

Thecoronavirus disease 2019 (COVID-19) spread throughout theworld from thebeginning of2020, and on 11 March 2020 it was recognised as apandemic by theWorld Health Organisation (WHO) [1]. Alittle later, anew disease connected with SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) infection was described: paediatric multisystem inflammatory syndrome associated with coronavirus disease (PIMS) or multisystem inflammatory syndrome in children (MIS-C) [2]. PIMS results from immune dysregulation and is aconsequence ofaSARS-CoV-2 infection 2–4 weeks earlier (often asymptomatic or minimally symptomatic). PIMS is an acute and potentially dangerous inflammatory syndrome that may lead to cardiac complications [3]; therefore, it requires appropriate medical supervision. Due to similar symptoms to other diseases, differentiation may be difficult. There are many similarities to Kawasaki disease (KD) with an abnormal response oftheimmune system to aviral, bacterial, or unidentified environmental agent leading to vascular damage and possible cardiac complications [4]. Moreover, very rarely some patients with PIMS can develop macrophage activation syndrome (MAS) [5], which occurs most commonly with systemic- onset juvenile idiopathic arthritis (JIA) and is closely related, and is pathophysiologically very similar, to haemophagocytic lymphohistiocytosis (HLH) [6].
In this article we present acase report ofapatient who was twice diagnosed with PIMS, including PIMS with MAS, and who was later diagnosed with HLH and finally with JIA.

CASE REPORT

In September 2021, an 11-year-old boy was transferred to theDepartment ofPaediatrics and Paediatric Endocrinology from adistrict hospital due to PIMS.
In thehistory, 8 days before theadmission to our department, thepatient developed ablotchy rash, first on thethighs, then all over thebody (Figure 1). After 2 days, theboy began to be febrile up to 39°C; thenext day symptoms such as swelling and pain in theankle and wrist joints was observed. Theprimary care physician diagnosed pharyngitis.
On thefifth day offever, due to thelack ofimprovement, theboy was referred to thehospital. PIMS was diagnosed in thedistrict hospital based on theclinical picture and laboratory tests. Theresults showed high parameters ofinflammation – significantly elevated levels oftroponins, aminotransferases, ferritin, and D-dimers (Table 1 0). No RNA oftheSARS-CoV-2 virus was detected in anasal swab using thereverse transcription-polymerase chain reaction (RT-PCR) test. Antibodies against SARS-CoV-2 in theIgG class were reactive, and therheumatoid factor (RF) concentration was insignificant. Thetreatment included methylprednisolone (2 mg/kg), immunoglobulin infusion was started, and athird-generation cephalosporin. On thesecond day oftreatment thepatient was transferred to our department.
On admission to our department, attention was drawn to ared, blotchy, confluent rash on theskin ofthetrunk and limbs, reddening ofthehands and feet (Figure 2), peeling epidermis in theelbow (Figure 3), knee, and ankle areas, chapped red lips, conjunctival hyperaemia, tongue covered with awhite coating, tachycardia (130/min), and hydrocele oftheright testicl*. Thepatient reported pruritus. We found out from themedical history that theboy had not been vaccinated against COVID-19. Laboratory tests showed high parameters ofinflammation, increased activity ofaminotransferases and increased concentrations ofγ-glutamyltranspeptidase (GTP), while bilirubin and alkaline phosphatase (AP) concentrations were normal. We found increased levels oflactate dehydrogenase (LDH), ferritin, troponins, and D-dimers as well as disturbances in thelipid profile (Table 1 I). Abdominal ultrasound showed no abnormalities. Theconsulting cardiologist evaluated normal coronary vessels, and thecontractility oftheheart was in thelower limit ofnormal (ejection fraction [EF] = 57–60%). Thetreatment included methylprednisolone (2 mg/kg/day), transfusion ofimmunoglobulin, continuation oftreatment with use ofthird-generation cephalosporin, and hepatoprotective drugs as well as acetylsalicylic acid. No bacteria were found in theblood culture. Escherichia coli ESBL+ was found in therectal swab.
In thefirst 3 days oftreatment, thepatient was significantly weakened and reported severe pruritus. Then thegeneral condition ofthechild improved, his fever stopped, and adecrease in theparameters ofinflammation was observed.
On theninth day ofhospitalisation, during thereduction ofsteroid therapy, thepatient began to be febrile again, theparameters ofinflammation that had already decreased started to increase again, and increased activity ofaminotransferases and increased concentrations ofGTP were reported, while bilirubin and AP were within thenormal range (Table 1 II). Imaging tests were performed – chest X-ray showed no abnormalities, while abdominal USG showed an enlarged liver with enlarged lymph nodes in thehilum. Acardiological consultation was carried out – no changes in thecoronary vessels were found, and thecontractility oftheheart was in thelower limit. Piperacillin with tazobactam and fluconazole were added to thetreatment; due to asignificant increase in D-dimers nadroparin was added; methylprednisolone pulses were used for 5 consecutive days. Ahaematological consultation was performed, followed by abone marrow biopsy. Themyelogram showed no features ofabone marrow proliferative disease or haemophagocytosis, and rich cell marrow was described, with aclearly stimulated granulocyte system, as in autoinflammatory disease, without signs ofhaemophagocytosis (assessed after steroid therapy). Agastroenterological consultation was also carried out, according to which thediagnosis ofhypertransaminasaemia was extended: in theCOMBI test we found weakly elevated titre ofANA antibodies (1 : 320) with afine-grained glow and few nuclear dots, but there was no significant antibody titre in theANA Profil (ANA examination was after infusion ofimmunoglobulin). No infection with HAV, HBV, or HCV viruses was found. Thefirst test (qualitative) indicated thepresence ofEpsteina-Barr virus (EBV) DNA, but thesecond test (quantitative) did not detect thepresence ofEBV DNA while thealanine aminotransferase concentration was over 2000 U/l. On this basis, EBV infection was ruled out as acause ofhepatitis.
On thefourth day ofadministration ofpulses with methylprednisolone, theboy’s condition improved, his fever stopped, theskin lesions began to subside, he stopped feeling pruritus, and peeling oftheepidermis on thefingers was observed. Normalisation oflaboratory test results was noticed, but thepatient was discharged with persistently elevated levels ofC-reactive protein (CRP), GTP, LDH, and ferritin and elevated transaminases. Due to persistent myocardial contractility at thelower limit ofnormal value, theconsulting cardiologist recommended enalapril and aresting lifestyle as well as acheck-up in 4 weeks.
After 4 weeks, theboy was admitted to our ward for control tests and arrangement offurther management. On admission, attention was drawn to discoloration in places ofprevious scratches and hydrocele oftheright testicl*; otherwise, no abnormalities were found. Laboratory tests showed significantly increased activity ofaminotransferases and increased concentrations ofGTP, LDH, ferritin, and D-dimers (Table 1 III). Cardiologically, thecondition was stable. Due to thesuspicion ofautoimmune hepatitis, theboy was transferred to theDepartment ofPaediatric Gastroenterology. Transferrin isoforms, α-1-antitrypsin, urine and serum copper, and ANCA antibodies were determined. In cholangio-MR, theimage ofthebile ducts was normal. Liver biopsy showed degenerative hepatocytes, low-grade lymphocytic inflammatory infiltrates, no fibrosis, and normal bile ducts. Theunequivocal cause ofhypertransaminasaemia was not identified, and thepatient remains under thecare ofa*gastroenterologist. During hospitalisation thepatient experienced pain in theright testicl*. Based on ultrasound image, torsion oftheright appendage was suspected and right hydrocele surgery was performed.
Again, thepatient was admitted to our department after 2 months due to fever with arash. Three weeks earlier, due to contact with aperson infected with SARS-CoV-2, theboy had RT-PCR test for COVID-19, which turned out to be positive; thepatient was asymptomatic. Three weeks after theconfirmed infection, thepatient became febrile and developed agarland rash all over thebody and papular lesions on thehands and feet. Thechild complained ofpain in thewrists and ankles and sore throat. Physically, apart from rash changes, there was ascar after thetesticular hydrocele operation, swollen tonsils, and clearly red labial redness. In laboratory tests attention was drawn to increased parameters ofinflammation (Table 1 IV). Theswab for SARS-CoV-2 was negative (RT-PCR), thepresence ofreactive antibodies to SARS-CoV-2 in theIgG class was found, but IgM antibodies were non-reactive. Treatment included antibiotics, antipyretics, hydration, and ongoing medications. In next days thepatient had ahigh fever, intensification ofskin and mucosal lesions, and peripheral oedema appeared (Figure 4, 5), shortness ofbreath with saturation drops below 90%, decrease in thealveolar murmur over thelungs was observed, as well as abdominal pain, loose stools, and oliguria. Deterioration oflaboratory test results was noted (Table 1 V). We received information about theabsence ofbacteria in theblood culture. Growth ofKlebsiella pneumoniae ESBL+ bacteria in nasal and throat swabs was confirmed. Lymphocyte typification was performed, and thepercentage ofB and NK lymphocytes was reduced. Abnormalities in laboratory tests were increasing. Thechest X-ray showed inflammatory changes, and chest computed tomography (CT) showed confluent densities ofthelung parenchyma ofa“milky glass” nature and atelectasis-inflammatory changes. On abdominal ultrasound, theliver and spleen were enlarged, with enlarged lymph nodes in thehilum oftheliver. Thecardiologist found sinus tachycardia, myocardial contractility at thelower limit (EF = 52%), and ventricular septal hypokinesis. Thedoctor recommended theaddition ofmetoprolol and spironolactone. PIMS was diagnosed, methylprednisolone pulses were administered, immunoglobulins and albumin with adiuretic were transfused, heparin and drugs were administered according to cardiological recommendations, and meropenem was added.
After 4 days oftreatment, due to thelack ofimprovement, an interleukin 1 inhibitor was introduced (2  100 mg). In thefollowing days, thepatient’s general condition improved, his fever subsided, skin lesions and peripheral oedema disappeared, pulse and diuresis normalised, and auscultatory changes over thelungs disappeared. Laboratory parameters also improved with normalisation ofmorphology parameters and CRP concentration. During whole hospitalisation in our department theboy was never diagnosed with anaemia or hyponatraemia.
During thereduction ofthedoses ofthebiological drug and glucocorticosteroid (oral prednisone was used), theboy became feverish again, skin changes appeared – arash ofavariable, polymorphic nature was observed. Increases in inflammation and other biochemical parameters were again revealed (Table 1 VI). Test ANA showed no presence ofautoantibodies. Thepresence ofp-ANCA, c-ANCA, and ASCA antibodies was not detected. HIV infection was excluded, as well as HBV and HCV infection. Antibody titres against Coxsackie B2, B3, and B4 viruses were negative. Abone marrow biopsy was performed showing signs ofstimulated granulocytic system and phagocytosis. After specialist consultations in thefield ofhaematology, rheumatology, and immunology, it was established thepatient did not meet thecriteria for HLH, and theclinical picture may suggest MAS in thecourse ofPIMS. Theinitial dose ofanakinra was returned, and methylprednisolone pulses were used. Theboy’s condition, as well as theresults oflaboratory tests, improved again. However, during thereduction ofsteroid and anakinra doses, theboy’s condition deteriorated once more, he developed ahigh fever, and inflammation parameters increased. Steroid therapy was modified (dexamethasone), cyclosporine was added, and improvement was achieved. Due to thefeatures ofhaemophagocytosis in themyelogram, theboy was transferred to thePaediatric Haematology and Oncology Department.
In theDepartment ofHaematology, after further tests and observation, thediagnosis ofHLH without involvement ofthecentral nervous system was confirmed. Haemophagocytosis in thebone marrow was confirmed, thetests showed leukopaenia, anaemia, and thrombocytopaenia; significant hyperferritinaemia and hypofibrinogenaemia were found. Additionally, low level ofNK-cells – 2% oflymphocytes, reduced perforin expression in NK-cells – 43.74%, and CD8 lymphocytes – 15.74% as well as high concentration ofsoluble receptor for IL-2 – 6383 U/ml were found. Treatment was started according to theHLH 2004 protocol (initially dexamethasone and cyclosporine and then etoposide), which was continued for thefollowing weeks. Control chest CT was normal. During thecourse oftreatment thepatient had rashes, intertrigo lines, and swellings ofthewrist and interphalangeal joints (Figure 6, 7). During thelast hospitalisation in theDepartment ofHaematology, at thetime ofdiscontinuation ofglucocorticoids according to theprotocol, thechild developed afever, swelling oftheankle joints, and an intense, confluent rash all over thebody (Figure 8). Due to thesuspicion ofsystemic juvenile idiopathic arthritis, theboy was transferred to theDepartment ofPaediatric Rheumatology.
On admission to theRheumatology Department, theboy was diagnosed with bluish-red confluent skin lesions, epidermis peeling on theauricles, inflammation ofthecorners ofthemouth, Cushingoid silhouette, hair loss on thehead, and oedema oftheleft wrist joint. Tuberculosis was excluded, HLA-B27 antigen was negative. No presence ofANA, ANCA, anti-CCP, anticardiolipin antibodies, anti-B-2 glycoprotein antibodies, or RF was found. Thediagnosis ofJIA was confirmed, and treatment included methylprednisolone, cyclosporine was continued, and then treatment with tocilizumab was started, resulting in theresolution ofjoint swelling, pruritus, and skin lesions.
Currently, thepatient continues treatment with tocilizumab and is under thecare ofa*gastroenterologist, haematologist, and cardiologist. Based on genetic testing, theboy was diagnosed with Gilbert’s syndrome. In thelast cardiological check-up, myocardial contractility was normal (66%), and theimage ofthecoronary arteries was normal.Theentire medical history is presented in thetimeline in Figure 9.

DISCUSSION

Thecase report shows thesevere clinical course ofseveral diagnosed diseases that occurred in our patient. Subsequently, thediagnosis ofPIMS was made, then PIMS-MAS, and later HLH and JIA.
There are many similarities between thedescribed diseases, both in clinical symptoms and in their complicated network ofrelationships and pathomechanisms. In thecase ofour patient we based our diagnosis ofPIMS and MAS associated with PIMS on Polish Paediatric Society guidelines [7]. Thediagnosis ofhaemophagocytic lymphohistiocytosis was based on the2004 updated HLH criteria, which requires 5 out of8 ofthecharacteristics [8], and thediagnosis ofJIA was based on theInternational League ofAssociations for Rheumatology criteria modified in 2001 (Edmonton) [9]. Each ofthediseases recognised in our patient are characterised by fever, and in each ofthem we can observe high concentrations ofinflammation parameters, including ferritin. In MAS and HLH, among thecommon criteria, we also find hypertriglyceridaemia, and in both we can find areduced number ofplatelets. It should be noted that also thedrugs used in each ofthementioned diseases are partially overlapped. Moreover, in our patient, during both PIMS and HLH, at thetime ofreducing thedoses ofglucocorticosteroids, recurrence ofsymptoms was observed (Figure 9). It can be concluded that although each ofthediseases is aseparate disease entity, thementioned disorders are partially associated with similar mechanisms. Additionally, when thinking about each ofthementioned diseases, other causes should always be ruled out, which often leads to difficulties in making clear and unequivocal diagnosis. Moreover, in thediagnosis ofMAS, so far associated mainly with JIA, from themoment oftheCOVID-19 pandemic, causes such as SARS-CoV-2 should also be taken into account as an important triggering factor. For this reason, in thetreatment ofMAS syndrome in our patient, therecommendations for PIMS management were followed before thediagnosis ofJIA was established.
PIMS developed in about 1/1000 children infected with SARS-CoV-2, and its mortality rate was 1.5–2% despite treatment, at thebeginning ofCOVID-19 pandemic [10]. Currently, according to aCDC report from 30 August 2023, PIMS is suppressed [11]. There are several definitions ofPIMS in different countries [12, 13]; however, all recommendations take into account the6 main criteria [7]. Moreover, characteristic constellation ofabnormalities in laboratory tests can be helpful in establishing thediagnosis: usually very high rates ofinflammation parameters (CRP above 100 mg/l), lymphopaenia, mild anaemia, hypoalbuminaemia, hyponatraemia, and high levels ofmarkers ofheart damage: BNP or NT-proBNP, troponin I [3, 10]. In our patient, there was no initial anaemia or hyponatraemia during PIMS recognition.
It is worth to mention that at thebeginning PIMS was termed “Kawasaki disease-like”, as some patients with PIMS also met thecriteria for thediagnosis ofKD. Diagnostic criteria for KD were prepared by AHA in 2017 [4].
Very rarely some patients with PIMS can develop MAS. Prior to theCOVID-19 pandemic, MAS was mainly diagnosed in children with JIA or systemic lupus erythematosus [6]. Diagnosis ofMAS in children with JIA is based on criteria adopted by EULAR, ACR, and thePaediatric Rheumatology International Trials Organisation (PRINTO) [14]. Our patient met MAS recognition criteria as associated with PIMS during thesecond PIMS diagnosis (Table 1 V).
Haemophagocytic lymphohistiocytosis is arare, life-threatening immune syndrome characterised by uncontrolled activation ofcytotoxic lymphocytes and macrophages. Thepathogenesis ofsecondary HLH remains unclear; however, themost common infectious agent that triggers HLH is EBV [15]. Several features reported in severe COVID-19 and features included in theHLH-2004 diagnostic criteria are common. Therefore, SARS-CoV-2 can be also considered apotential trigger ofHLH [16]. Hyperferritinaemia is themost characteristic symptom; also in our patient asignificant increase was visible.

CONCLUSIONS

It is important to be aware that all thediseases listed here can lead to serious health consequences, including death. During thediagnosis and treatment ofthepatient, thework ofan interdisciplinary team ofspecialists is often necessary for proper diagnosis and treatment. We do not have long-term follow-up ofmany patients after PIMS, so theimmunological consequences ofthese diseases are not fully understood, and afurther period ofpatient observation is needed. It would be reasonable to carry out genetic diagnostics in thedirection ofimmunodeficiency syndromes to provide an answer to thequestion ofwhy our patient’s COVID-19 infection caused such serious consequences.
We hope that thedescription ofour case will show thediagnostic difficulties and serve to develop studies on thepathomechanisms ofimmune system diseases.

Disclosures

• Institutional review board statement: Not applicable.
• Assistance with the article: None.
• Financial support and sponsorship: None.
• Conflicts of interest: None.

REFERENCES