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CASE REPORT
Year : 2022  |  Volume : 23  |  Issue : 2  |  Page : 129-132

Langerhans cell histiocytosis presenting as post-COVID-19 multisystem inflammatory syndrome: A rare case report


Department of Dermatology, Venereology and Leprology, S. Nijalingappa Medical College, Bagalkote, Karnataka, India

Date of Submission24-Jul-2021
Date of Decision17-Nov-2021
Date of Acceptance19-Nov-2021
Date of Web Publication30-Mar-2022

Correspondence Address:
Dr. Varsha R Koti
Department of Dermatology, Venereology and Leprology, S. Nijalingappa Medical College and HSK Research Hospital, Bagalkote, Karnataka
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ijpd.ijpd_114_21

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  Abstract 


Langerhans cell histiocytosis is a rare clonal disease of monocyte-macrophage system characterized with uncontrolled proliferation and accumulation of immature dendritic cells. Acute disseminated form of this disease known as Letterer-Siwe disease is life threatening. Here, we report such a case who presented as multisystem inflammatory syndrome following COVID-19 infection.

Keywords: COVID-19, dermoscopy, Langerhans cell histiocytosis, Letterer-Siwe disease, multisystem inflammatory syndrome


How to cite this article:
Sudhakar Rao K M, Koti VR, Ankad BS. Langerhans cell histiocytosis presenting as post-COVID-19 multisystem inflammatory syndrome: A rare case report. Indian J Paediatr Dermatol 2022;23:129-32

How to cite this URL:
Sudhakar Rao K M, Koti VR, Ankad BS. Langerhans cell histiocytosis presenting as post-COVID-19 multisystem inflammatory syndrome: A rare case report. Indian J Paediatr Dermatol [serial online] 2022 [cited 2022 May 17];23:129-32. Available from: https://www.ijpd.in/text.asp?2022/23/2/129/341454




  Introduction Top


Langerhans cell histiocytosis (LCH), previously known as "Histiocytosis X" is a rare disease characterized by an abnormal proliferation of immature dendritic cells in the skin and visceral organs.[1] It manifests as isolated self-healing skin/bone lesions to life-threatening multi-system disease.


  Case Report Top


A 10-month-old orphan male infant presented to the pediatric department with a history of fever and generalized swelling of the body for 4 days. He was referred to the dermatology department as he had a history of itchy and oozing lesions over the scalp, bilateral eyebrows, neck, trunk, groin, and limbs for 6 months for which he had received various topical treatments, but with partial improvement. History of poor feeding and irritability was present for 6 months. On general physical examination, the patient was febrile with tachycardia. Pallor, icterus, and pitting pedal edema were present. Bilateral, nontender, firm, single left cervical and multiple right occipital lymphadenopathy of size 2 cm × 2 cm and 0.5 cm × 0.5 cm size, respectively, were present. Puffiness of the face with peri-orbital edema, distension of abdomen with edema of scrotum, and lower limb edema was present. Abdomen was distended with visible veins and everted umbilicus. Hepatomegaly (6 cm below costal margin) and splenomegaly (2.5 cm below costal margin) with mild ascites were present. Examination of the cardiovascular, respiratory and central nervous system were normal. Cutaneous examination revealed erythematous papules, plaques with scaling and crusting over the scalp, medial aspect of eyebrows, lower abdomen, and entire back [Figure 1]a, [Figure 1]b, [Figure 1]c, [Figure 1]d. Erythematous discharging erosions involving the folds of the neck and groin were present [Figure 1]e and [Figure 1]f. Palms and soles showed petechial rash with crusted erosions [Figure 1]g and [Figure 1]h. Nails and mucosa were normal. With the above history and clinical examination, our provisional diagnosis was LCH and multisystem inflammatory syndrome-children (MIS-C). Routine laboratory investigations revealed hemoglobin 6.5 g%, platelet count 95,000/mm3 at admission, which subsequently dropped to 30,000/mm3 the following week. Total bilirubin was 8.8 mg% with direct bilirubin of 6.2 mg%. Albumin was 2.2 g/dL with reduced albumin to globulin ratio and albuminuria. Alkaline phosphatase was 424U/L. C-reactive protein and serum ferritin levels were raised. Ultrasonography of the abdomen showed minimal ascites with periportal cuffing. X-ray of the skull was normal. COVID-19 screening real-time reverse-transcriptase polymerase chain reaction (RT-PCR), immunoglobulin M (IgM) were negative but IgG positive which led to the diagnosis of MIS-C post-COVID. The child was managed with intravenous immunoglobulin (Ig) 2 g/kg body weight in divided doses for 5 days, injection human albumin for hypoabluminemia and packed red blood cells to correct anemia. Dermoscopy of the lesion on the trunk showed red blotches and brown structureless areas [Figure 2]. A skin biopsy from a crusted erythematous papule showed stratum corneum covered with crusts containing pyknotic neutrophilic microabscess and plasma globules. Dermis showed dense inflammatory infiltration encroaching the overlying atrophic epidermis obscuring dermo-epidermal junction. Inflammatory infiltrate was composed of cells with eosinophilic cytoplasm with reniform nucleus, numerous eosinophils, and extravasation of RBCs [Figure 3]. Immunohistochemistry showed positivity to CD1a and S100 stains of multiple Langerhan's cell infiltrating the epidermis [Figure 4]. Based on the clinicopathological and immunohistochemistry findings, we confirmed acute disseminated form of LCH (Letterer-Siwe disease) presenting as post-COVID-19 MIS-C. Vitals, inflammatory markers improved with IVIg, while skin lesions, hepatomegaly, splenomegaly, abdominal distension persisted and hence the infant was referred to higher center for chemotherapeutic management.
Figure 1: Multiple erythematous papules with crusting in few lesions over scalp (a), medial aspect of eyebrows (b), lower abdomen (c), and entire back (d). Erythematous discharging erosions involving the folds of the neck (e) and groin (f). Purpuric lesions involving palms (g) and soles (h). Note the puffiness of face (b), abdominal distension (c) and scrotal swelling (f)

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Figure 2: Dermoscopy (Dermlite DL3N, Polarised Mode) of Langerhans cell histiocytosis lesions showing vascular blotches (black arrow) and yellowish-brown structureless areas (yellow arrow)

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Figure 3: (a) Skin biopsy showing infiltration of the dermis by dense inflammatory cells, impinging on the epidermis. Lakes of erythrocytes present (black arrow) (H and E, ×40). (b) Closer view shows cells with reniform nucleus surrounded by eosinophilic cytoplasm (green circle) and few eosinophils (yellow circles) (H and E, ×100)

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Figure 4: Immunohistochemistry showed CD1a (a) and S100 (b) positivity of multiple Langerhan's cells infiltrating the epidermis

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  Discussion Top


Paul Langerhans in 1868 first described the epidermal dendritic cells which are now known as Langerhans cells. LCH is a rare clonal disease of monocyte-macrophage system characterized with uncontrolled proliferation and accumulation of CD1a+/CD207+ immature dendritic cells as a result of continuous immune stimulation.

LCH is divided into three types: Letterer−Siwe disease, Hand-Schuller-Christian disease, and eosinophilic granuloma. Letterer−Siwe disease is a multifocal multisystem disease occurring predominantly in children <2 years. It is characterized by cutaneous lesions, hepatomegaly, splenomegaly, ganglionic hypertrophies, bone lesions involving the skull, long bones, and mandible. Cutaneous manifestations in the form of recurrent pyoderma lesions with crusting, scaling, vesicles, pustules, and purpuric eruption occurring in crops over the scalp, face, trunk, and intertriginous areas mimicking seborrheic dermatitis are seen, consistent with our case. Intraoral hemorrhage, gingivitis, loose teeth, floating teeth or ectopic teeth can be seen.[2] Other organs which could be involved include lymph nodes, bone marrow, central nervous systems and lungs. The differential diagnosis for LCH includes other histiocytic disorders (Rosai−Dorfman disease and Erdheim-Chester disease), dendritic neoplasm, lymphoma, and LC sarcoma.

The diagnosis of LCH is based on histopathological pattern showing lesional histiocytes with reniform or lobulated nucleus with unremarkable eosinophilic cytoplasm. Other specialized investigations such as immunohistochemistry where Langerhans cells show positive for markers CD1a and S-100. The presence of birbeck granules on electron microscopy could not be performed in our patient due to financial constraints and poor resource settings.

Dermoscopy of LCH shows vascular blotches that correspond to dermal hemorrhage and brown dots or yellow structureless areas to the epidermal infiltration and necrosis by Langerhans cells,[3] which was consistent in our case.

The case definition of MIS-C includes six criteria: Serious illness leading to hospitalization, an age of <21 years, fever (body temperature, >38.0°C) or report of subjective fever lasting at least 24 hours, laboratory evidence of inflammation, multisystem organ involvement (involving at least two systems), and laboratory confirmed syndrome–related coronavirus-2 infection (positive SARS CoV-2 RT-PCR or antibody test during hospitalization) or an epidemiologic link to a person with COVID-19.[4] The clinical pointers in favor of MIS-C in our case were fever, anasarca, petecial rashes over palms and soles leading to hospitalization, lymphadenopathy, hepato-splenomegaly, pancytopenia, elevated markers of inflammation, and COVID-19 IgG antibody positivity. Our case fulfilled most of the criteria for MIS-C, and hence, the baby was treated with IVIg by the pediatricians due to the ongoing pandemic. Meanwhile, the skin biopsy reports (of histopathological examination and immunohistochemistry for S100 and CD1a) were awaited. The overlapping features of MIS-C and LCH are multisystem involvement with organomegaly, pancytopenia, lymphadenopathy, fever, erythematous macules to papules, vesicles, and purpuric eruptions as observed in our case.

MIS-C was ruled out as the cutaneous lesions persisted, organomegaly, pancytopenia, lymphadenopathy did not resolve with IVIg, oxygen saturation was within normal limits, lung fields were clear, COVID-19 IgG positive, and with histopathological and IHC reports, a diagnosis of LCH was made in our case.

The pathogenesis of COVID 19 involves the cytokine release syndrome on account of an overtly reactive immune system that reacts in an unregulated manner. It presents with increased T-cell expression with release of pro-inflammatory cytokines involving dendritic cells, macrophages which includes interleukin-1 (IL-1), IL-6, tumor necrosis factor (TNF) alpha, interferon (IFN) gamma, etc. IL-6 triggers severe inflammation and cause acute injury to multiple organs. IFN gamma causes over production of monocyte chemokines and enhance levels of pro-inflammatory cytokines. TNF alpha is a primary mediator of immune regulation and inflammatory response.[5] MIS-C have persistent IgG antibodies with enhanced ability to activate monocytes and cause greater activation of T cells.[6] Similarly, LCH also exhibited T cell activation, higher levels of IL-1, TNF alpha, IL-10 and IFN gamma, Granulocyte monocyte- colony stimulating factor (GM CSF). This cytokine storm favors recruitment of Langerhans cell progenitors, their survival, rescue from apoptosis and maturation into effector cells in contributing to pathological accumulation of LCH cells.[7] Hence, MIS-C has a synergistic effect in rapid progression and exacerbation of signs and symptoms of LCH, as seen in our case with new onset of organomegaly, vasculitis, and pancytopenia. Therefore, MIS-C with LCH has a poor prognosis due to rapid deterioration of disease.

Therapy is based on whether high risk or low risk organs are involved and whether the disease involved a single system or multiple systems. According to modified Lahey criteria,[8] our patient had anemia, thrombocytopenia, hepatomegaly with dysfunction, and splenomegaly, hence had high risk organs involvement, which has a very poor prognosis. Furthermore, extensive purpuric lesions on palms and soles which is a reputedly lethal sign, was seen in our case.[9] For multifocal multisystem LCH, the Histiocyte Society suggests treatment duration of 12 months reduces the risk of reactivation compared with 6 months of treatment.[10] Prednisone and vinblastine combination has proven to be an effective treatment with minimal toxicity and hence is the standard initial therapy. The patient was referred to higher center for chemotherapy.

To conclude, we document LCH presenting as MIS-C following COVID-19 infection. The COVID-19 pandemic has brought the state of impossibility in the management due to little knowledge about its etiopathogenesis; therefore, the diagnosis holds utmost importance as management differs in both these conditions whose clinical presentations are akin. Further studies are needed to confirm the overlapping inflammatory pathogenesis which was substantiated in this report.

Declaration of consent

The authors certify that they have obtained all appropriate consent forms, duly signed by the parent(s) of the patient. In the form the parent(s) has/have given his/her/their consent for the images and other clinical information of their child to be reported in the journal. The parents understand that the names and initials of their child 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.



 
  References Top

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Singh T, Satheesh CT, Appaji L, Aruna Kumari BS, Mamatha HS, Giri GV, et al. Langerhan's cell histiocytosis: A single institutional experience. Indian J Med Paediatr Oncol 2010;31:51-3.  Back to cited text no. 1
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Centers for Disease Control and Prevention. Emergency Preparedness and Response: Multisystem Inflammatory Syndrome in Children (MIS-C) Associated with Coronavirus Disease 2019 (COVID-19). Health Advisory. Available from: https://emergency.cdc.gov/han/2020/han00432.asp. [Last accessed 2021 Nov 15].  Back to cited text no. 4
    
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Emile JF, Wechsler J, Brousse N, Boulland ML, Cologon R, Fraitag S, et al. Langerhans' cell histiocytosis. Definitive diagnosis with the use of monoclonal antibody O10 on routinely paraffin-embedded samples. Am J Surg Pathol 1995;19:636-41.  Back to cited text no. 8
    
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Nezelof C, Frileux-Herbet F, Cronier-Sachot J. Disseminated histiocytosis X: Analysis of prognostic factors based on a retrospective study of 50 cases. Cancer 1979;44:1824-38.  Back to cited text no. 9
    
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Gadner H, Minkov M, Grois N, Pötschger U, Thiem E, Aricò M, et al. Therapy prolongation improves outcome in multisystem Langerhans cell histiocytosis. Blood 2013;121:5006-14.  Back to cited text no. 10
    


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  [Figure 1], [Figure 2], [Figure 3], [Figure 4]



 

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