Clinical case

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Introduction

Mastocytosis is a clonal disease of mast cells. The frequency reaches 1:10000 of the population [1]. In adults, mastocytosis most often proceeds for a long time and is benign, and in children, as a rule, it regresses within several years [1, 2].

Mast cells are normally resident in connective tissue and proliferate under the influence of stem cell growth factor. The activating signal is transmitted by the receptor tyrosine kinase KIT. Somatic mutation in the C-KIT proto-oncogene leads to hyperproduction of the activating KIT receptor molecule, which causes excessive proliferation of mast cells. Up to 86% of children with mastocytosis have a somatic mutation in the C-KIT gene [3]. In addition to mast cells, the proliferation of melanocytes also depends on the KIT pathway, thus most likely causing typical pigment rashes [4]. Despite proven clonal growth, the aggressive course of mastocytosis in children, unlike adults, is extremely rare [5].

In aggressive course of the disease, chemotherapeutic approaches are similar to the strategy in adults. The variant with C-KIT mutation is crucial: if the С-KIT D816V is not detected, imatinib is effective [6, 7]. When the C-KIT D816V is revealed, cladribine and interferon alpha are used as the main drugs showing similar efficacy reaching about 50% [8]. New tyrosine kinase inhibitors (avapritinib and midostaurin) are also effective [9, 10]. Currently, allogeneic hematopoietic stem cell transplantation (HSCT) is recognized as the only curative method of aggressive mastocytosis. Appropriate experience with children is limited, however, there are reports on curative effect of HSCT [11].

The most frequent symptoms of mastocytosis are caused by permanent or periodical degranulation, i.e., release of various cytokines and biologically active substances from cytoplasmic granules of the mastocytes. The intensity of degranulation determines the variety of complaints: from their absence to severe itching, bullous rash, anaphylactoid reactions, abdominal pain requiring daily pharmacotherapy [12]. The release of cytokines is provoked by certain medications, bathing, mood swings and other factors [13]. The main therapeutic actions are aimed at avoidance of provoking factors, reducing the degranulation reaction and neutralizing the effect of histamine release. Due to the fact that the prognosis for non-aggressive forms of mastocytosis is generally favorable, and the disease regresses spontaneously in most patients, the main goal of attending physician is to improve the quality of life and ensure psychological welfare of the child and parents before the disease resolves. In this respect, we present a clinical case of skin mastocytosis with later developing osteoblastoma in an infant.

Case report

Figure 1. Newborn baby with severe course of urticaria pigmentosa, a clinical feature of skin mastocytosis

Figure 2. Histamine crisis in a child with skin mastosytosis. Redness of the skin, vesicular eruptions at the nasolabial triangle, at the tip and back of the nose, in the suborbital areas, on the back of the hand and wrist

Figure 3. The patient is 10 years old. Residual manifestations of mastocytosis on the skin

The boy was born full-term, weight 3190, body length 51 cm, head circumference 33 cm. At birth, there was a polymorphic rash on the baby's skin, including the formation of blisters (Fig. 1). Urticaria pigmentosa was clinically diagnosed.

In addition to the typical skin changes, mastocytosis was manifested by constant severe itching with the need for daily intake of antihistamines. During the first two weeks after birth, histamine crises spontaneously occurred 1-2 times a day, which looked like sudden redness of the skin, short-term appearance of blisters, an increase in itching, screaming and extreme excitement, turning into a fainting state. The duration of the crisis varied from several minutes to an hour. With a strong attack, wheezing on inspiration was noted, once the attack was accompanied by a stop of breathing for 10-15 seconds.

Since early childhood, the child complained of episodic abdominal pain of a pulling-stabbing nature. The attack lasts 30-60 minutes, there is no convincing effects of drotaverine and nonsteroidal anti-inflammatory drug administration. There were unmotivated weekly episodes of vomiting, with no stool сhanges. Evident causes of pain and vomiting were not revealed, endoscopic studies were not performed.

At the age of three months, the child was re-examined. We present the results of the survey. Histological analysis of the skin revealed changes typical of mastocytosis. A widespread proliferate was found, consisting mainly of cells with partially elongated fragmented nuclei expressing tryptase and CD117. No expression of Langerin, CD1a and S100 was detected. A mutation of the KIT D816V gene was detected in DNA from skin biopsy using PCR technique. The concentration of tryptase in the blood was 17.3 (normally, 11.4) µg/l. The dermatological diagnosis of urticaria pigmentosa has been confirmed. Additional analyses were performed to determine the aggressiveness and the degree of organ involvement. The concentration of hemoglobin, reticulocytes, the number of platelets, leukocytes with a leukocyte formula, the rate of erythrocyte sedimentation within the age norm. The blood clotting INR, prothrombin and thromboplastin time, concentration of potassium, sodium, urea, creatinine, uric acid, bilirubin, C-reactive protein, albumin, β-2 microglobulin, immunoglobulin E, fibrinogen, activity of alanine and asparate aminotransferase, lactate dehydrogenase and antithrombin III were within normal ranges. Histological and cytological analysis of the bone marrow revealed normal pattern, with only reactive changes. Ultrasound examination showed normal condition of abdominal organs. There were no signs of aggressive mastocytosis such as cytopenia, liver and bone impairment.

From birth, the child received cetirizine in maximum doses. In severe crises, dimethinden, betamethasone were added, and prednisone was administered once.

The parents reported that the main provoking factors were temperature changes, hot water, emotions, eating hot food, rubbing clothes, as well as acute infectious diseases. From four months of life, the frequency and severity of the crises decreased, from 6 months the vesicular rash disappeared, and from 12 months these crises ceased. However, skin itching with a marked decrease in the quality of life and the need for daily intake of antihistamines, as well as occasional intake of betamethasone, persisted for several years. The itching decreased after sunlight exposure during the summer time. At the age of two, the concentration of blood tryptase returned to normal. Since the age of three, hypersensitivity to changing air and water temperature has decreased.

At 2 years and 8 months, pain and impaired movement evolved in the left shoulder joint. А neoplasm was detected in the left humerus. According to histological and immunohistochemical analysis, osteoblastoma was diagnosed. After the month radical excision of the tumor within healthy tissues was performed. The operation proceeded without complications.

During the following years, abdominal complaints persisted but the rash decreased, with residual moderate skin itching requiring occasional administration of antihistamines. Focal pale hyperpigmentation of the skin is noted (see Fig. 3). Currently, the boy attends primary school.

Discussion

Mastocytosis is a poorly understood clonal disorder with a generally favorable prognosis. As in the presented case, mastocytosis most often appears in the first two years of life. The results of the analysis of a large group of children showed that in 23% of cases, the disease manifests immediately after birth [14]. Recent studies show that the childhood and adult mastocytosis is a clonal neoplasm by its origin. The C-KIT D816V mutation detected in the presented child is one of the most frequent. In the study of Bodemer C. it was found in 42% of children with mastocytosis [3]. The detection of the mutation in the presented child confirmed the diagnosis, since there was no need for chemotherapy.

The vast majority of children, despite the mast cell clonality, develop a complete or partial regression of the symptoms within the first years of life [2, 14]. In our experience, upon observation of 163 children with mastocytosis, the median time of clinical resolution was 34 (2-226) months [5]. The probability of regression increases with the onset of the disease in early childhood and does not depend on the severity of mastocytosis manifestations [5, 14, 15].

Due to high probability of spontaneous regression, parents and the attending physician should provide symptomatic treatment so that the child could tolerate the disease until its resolution. According to various studies, 29.5-64% of children with mastocytosis require pharmacological treatment [2, 16-18]. Most often, long-term use of H1 and H2 histamine blockers, as well as cromoline sodium, a stabilizer of mast cell membranes, is recommended to relieve the symptoms. Treatment with short courses of glucocorticosteroids is acceptable when the effect is not complete, [13, 19]. The therapy has been satisfactorily tolerated for many years, being quite safe, as shown by the present case and other observations [20]. A follow-up of 111 children with mastocytosis showed that the number of patients with severe course is less than 5%, while, in most cases, the disease either does not require regular treatment or is easily controlled by antihistamines [16]. In our clinical case, the antihistamine therapy proved to be insufficient, thus requiring usage of glucocorticosteroids. However, this severe course seems to be uncommon in mastocytosis.

Despite the severity of the complaints, there were no signs of aggressive mastocytosis in the child. Signs of aggressiveness include pronounced organomegaly, anemia, osteolytic syndrome and intestinal damage with weight loss. There were no indications for bone marrow analysis, however, both puncture and trephine biopsy were made and did not reveal specific infiltration [13]. In everyday practice, the severity of symptoms encourages doctors to conduct an in-depth examination of the patient, sometimes being excessive [5].

Osteoblastoma refers to rare bone tumor diseases with a favorable prognosis. According to the analysis of 99 patients, approximately half of them have a lesion of the vertebrae or humerus. Surgical treatment leads to recovery [21]. Localization of osteoblastoma, course, therapy and stable response to treatment of the humerus in the presented child, corresponded to the published data. According to the SEER register analysis (Surveillance, Epidemiology and End Results), where the results of observation in 421 patients with mastocytosis, including children, were analyzed, there was no increase in the number of secondary malignant diseases compared to the average population [22].

Conclusion

The presented clinical observation again confirms that, even in severe skin form of mastocytosis, the prognosis is favorable. The main efforts of attending doctor should be focused on improving the quality of life and emotional comfort of the child and his parents.

Conflict of interest

None declared.

References

Brockow K. Epidemiology, prognosis, and risk factors in mastocytosis. Immunol Allergy Clin North Am. 2014; 34(2): 283-295.
doi: 10.1016/j.iac.2014.01.003
Azaña JM, Torrelo A, Mediero IG, et al. Urticaria pigmentosa: a review of 67 pediatric cases. Pediatr Dermatol. 1994; 11(2): 102-106.
doi: 10.1111/j.1525-1470.1994.tb00560.x
Bodemer C, Hermine O, Palmérini F, et al. Pediatric mastocytosis is a clonal disease associated with D816V and other activating c-KIT mutations. J Invest Dermatol. 2010;130(3):804-815. doi: 10.1038/jid.2009.281
Kimura Y, Jones N, Klüppel M, et al. Targeted mutations of the juxtamembrane tyrosines in the Kit receptor tyrosine kinase selectively affect multiple cell lineages. Proc Natl Acad Sci USA. 2004; 101: 6015-6020.
Potapenko VG, Baikov VV, Boychenko EG, et al. Mastocytosis in children. A prospective study of 163 patients with remote parental surveys. Russian Journal of Pediatric Hematology and Oncology (RZhDGiO). 2021; 8(2): 13-25. doi: 10.21682/2311-1267-2021-8-2-13-25
(In Russian).
Morren MA, Hoppé A, Renard M, et al. Imatinib mesylate in the treatment of diffuse cutaneous mastocytosis. J Pediatr. 2013; 162(1): 205-207. doi: 10.1016/j.jpeds.2012.08.035
Agarwala MK, George R, Mathews V, et al. Role of imatinib in the treatment of pediatric onset indolent systemic mastocytosis: a case report. J Dermatol Treat. 2013; 24(6): 481-483. doi: 10.3109/09546634.2013.802274
Lim KH, Tefferi A, Lasho TL, et al. Systemic mastocytosis in 342 consecutive adults: survival studies and prognostic factors. Blood. 2009; 113(23): 5727-5736. doi: 10.1182/blood-2009-02-205237
Gotlib J, Kluin-Nelemans HC, George TI, et al. Efficacy and Safety of Midostaurin in Advanced Systemic Mastocytosis. Reiter A N Engl J Med. 2016; 374(26): 2530-2541. doi: 10.1056/NEJMoa1513098
DeAngelo DJ, Quiery AT, Radia D, et al. Clinical activity in a phase 1 study of Blu-285, a potent, highly-selective inhibitor of KIT D816V in advanced systemic mastocytosis (AdvSM). Blood. 2017; 130(Suppl 1): 2. doi: 10.1182/blood.V130.Suppl_1.2.2
Srinivasan A, Ilonze CC, Travis SR, et al. Hemophagocytic lymphohistiocytosis in systemic mastocytosis treated with allogeneic bone marrow transplant: A case report. Pediatr Blood Cancer. 2020; 67(1): e28017. doi: 10.1002/pbc.28017
Carter MC, Metcalfe DD. Paediatric mastocytosis. Arch Dis Child. 2002; 86(5): 315-319. doi: 10.1136/adc.86.5.315
Heide R, Beishuizen A, De Groot H, et al. Mastocytosis in children: a protocol for management. Pediatr Dermatol. 2008; 25(4): 493‐500. doi: 10.1111/j.1525-1470.2008.00738.x
Méni C, Bruneau J, Georgin-Lavialle S. et al. Paediatric mastocytosis: a systematic review of 1747 cases. Br J Dermatol. 2015; 172(3): 642-651. doi: 10.1111/bjd.13567
Caplan RM. The natural course of urticaria pigmentosa. Analysis and follow-up of 112 cases. Arch Dermatol. 1963; 87: 146-157.
Potapenko VG, Skoryukova EV, Lisukova EG, et al. Mastocytosis in children. Clinical and laboratory characteristics of a group of 111 patients. Pediatrics. 2018; 97(4): 135-140. doi: 10.24110/0031-403X-2018-97-4-135-140 (In Russian).
Kiszewski AE, Durán-Mckinster C, Orozco-Covarrubias L, et al. Cutaneous mastocytosis in children: a clinical analysis of 71 cases.
J Eur Acad Dermatol Venereol. 2004; 18(3): 285‐290. doi: 10.1111/j.1468-3083.2004.00830.x
Akoglu G, Erkin G, Cakir B, et al. Cutaneous mastocytosis: demographic aspects and clinical features of 55 patients. J Eur Acad Dermatol Venereol. 2006; 20(8): 969‐973. doi: 10.1111/j.1468-3083.2006.01696.x
Minutello K, Gupta V. Cromolyn Sodium. In: StatPearls. Treasure Island (FL): StatPearls Publishing; 2020.
Cardet JC, Akin C, Lee MJ. Mastocytosis: update on pharmacotherapy and future directions. Expert Opin Pharmacother. 2013; 14(15): 2033-2045. doi: 10.1517/14656566.2013.824424
Berry M, Mankin H, Gebhardt M, et al. Osteoblastoma: a 30-year study of 99 cases. J Surg Oncol. 2008; 98(3): 179-183.
doi: 10.1002/jso.21105
Shivarov V, Gueorguieva R, Ivanova M, et al. Incidence of second solid cancers in mastocytosis patients: a SEER database analysis. Leuk Lymphoma. 2018; 59(6): 1474-1477. doi: 10.1080/10428194.2017.1382694

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Introduction

Case report

Figure 1. Newborn baby with severe course of urticaria pigmentosa, a clinical feature of skin mastocytosis

Figure 3. The patient is 10 years old. Residual manifestations of mastocytosis on the skin

From birth, the child received cetirizine in maximum doses. In severe crises, dimethinden, betamethasone were added, and prednisone was administered once.

Discussion

Conclusion

Conflict of interest

None declared.

References

Brockow K. Epidemiology, prognosis, and risk factors in mastocytosis. Immunol Allergy Clin North Am. 2014; 34(2): 283-295.
doi: 10.1016/j.iac.2014.01.003
Azaña JM, Torrelo A, Mediero IG, et al. Urticaria pigmentosa: a review of 67 pediatric cases. Pediatr Dermatol. 1994; 11(2): 102-106.
doi: 10.1111/j.1525-1470.1994.tb00560.x
Bodemer C, Hermine O, Palmérini F, et al. Pediatric mastocytosis is a clonal disease associated with D816V and other activating c-KIT mutations. J Invest Dermatol. 2010;130(3):804-815. doi: 10.1038/jid.2009.281
Kimura Y, Jones N, Klüppel M, et al. Targeted mutations of the juxtamembrane tyrosines in the Kit receptor tyrosine kinase selectively affect multiple cell lineages. Proc Natl Acad Sci USA. 2004; 101: 6015-6020.
Potapenko VG, Baikov VV, Boychenko EG, et al. Mastocytosis in children. A prospective study of 163 patients with remote parental surveys. Russian Journal of Pediatric Hematology and Oncology (RZhDGiO). 2021; 8(2): 13-25. doi: 10.21682/2311-1267-2021-8-2-13-25
(In Russian).
Morren MA, Hoppé A, Renard M, et al. Imatinib mesylate in the treatment of diffuse cutaneous mastocytosis. J Pediatr. 2013; 162(1): 205-207. doi: 10.1016/j.jpeds.2012.08.035
Agarwala MK, George R, Mathews V, et al. Role of imatinib in the treatment of pediatric onset indolent systemic mastocytosis: a case report. J Dermatol Treat. 2013; 24(6): 481-483. doi: 10.3109/09546634.2013.802274
Lim KH, Tefferi A, Lasho TL, et al. Systemic mastocytosis in 342 consecutive adults: survival studies and prognostic factors. Blood. 2009; 113(23): 5727-5736. doi: 10.1182/blood-2009-02-205237
Gotlib J, Kluin-Nelemans HC, George TI, et al. Efficacy and Safety of Midostaurin in Advanced Systemic Mastocytosis. Reiter A N Engl J Med. 2016; 374(26): 2530-2541. doi: 10.1056/NEJMoa1513098
DeAngelo DJ, Quiery AT, Radia D, et al. Clinical activity in a phase 1 study of Blu-285, a potent, highly-selective inhibitor of KIT D816V in advanced systemic mastocytosis (AdvSM). Blood. 2017; 130(Suppl 1): 2. doi: 10.1182/blood.V130.Suppl_1.2.2
Srinivasan A, Ilonze CC, Travis SR, et al. Hemophagocytic lymphohistiocytosis in systemic mastocytosis treated with allogeneic bone marrow transplant: A case report. Pediatr Blood Cancer. 2020; 67(1): e28017. doi: 10.1002/pbc.28017
Carter MC, Metcalfe DD. Paediatric mastocytosis. Arch Dis Child. 2002; 86(5): 315-319. doi: 10.1136/adc.86.5.315
Heide R, Beishuizen A, De Groot H, et al. Mastocytosis in children: a protocol for management. Pediatr Dermatol. 2008; 25(4): 493‐500. doi: 10.1111/j.1525-1470.2008.00738.x
Méni C, Bruneau J, Georgin-Lavialle S. et al. Paediatric mastocytosis: a systematic review of 1747 cases. Br J Dermatol. 2015; 172(3): 642-651. doi: 10.1111/bjd.13567
Caplan RM. The natural course of urticaria pigmentosa. Analysis and follow-up of 112 cases. Arch Dermatol. 1963; 87: 146-157.
Potapenko VG, Skoryukova EV, Lisukova EG, et al. Mastocytosis in children. Clinical and laboratory characteristics of a group of 111 patients. Pediatrics. 2018; 97(4): 135-140. doi: 10.24110/0031-403X-2018-97-4-135-140 (In Russian).
Kiszewski AE, Durán-Mckinster C, Orozco-Covarrubias L, et al. Cutaneous mastocytosis in children: a clinical analysis of 71 cases.
J Eur Acad Dermatol Venereol. 2004; 18(3): 285‐290. doi: 10.1111/j.1468-3083.2004.00830.x
Akoglu G, Erkin G, Cakir B, et al. Cutaneous mastocytosis: demographic aspects and clinical features of 55 patients. J Eur Acad Dermatol Venereol. 2006; 20(8): 969‐973. doi: 10.1111/j.1468-3083.2006.01696.x
Minutello K, Gupta V. Cromolyn Sodium. In: StatPearls. Treasure Island (FL): StatPearls Publishing; 2020.
Cardet JC, Akin C, Lee MJ. Mastocytosis: update on pharmacotherapy and future directions. Expert Opin Pharmacother. 2013; 14(15): 2033-2045. doi: 10.1517/14656566.2013.824424
Berry M, Mankin H, Gebhardt M, et al. Osteoblastoma: a 30-year study of 99 cases. J Surg Oncol. 2008; 98(3): 179-183.
doi: 10.1002/jso.21105
Shivarov V, Gueorguieva R, Ivanova M, et al. Incidence of second solid cancers in mastocytosis patients: a SEER database analysis. Leuk Lymphoma. 2018; 59(6): 1474-1477. doi: 10.1080/10428194.2017.1382694

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Потапенко1, Сергей Р. Талыпов2" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(103) "

Всеволод Г. Потапенко¹, Сергей Р. Талыпов²

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¹ Городская клиническая больница №31, Санкт-Петербург, Россия
² Национальный медицинский исследовательский центр детской гематологии, онкологии и иммунологии им. Д. Рогачева, Москва, Россия

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Мастоцитоз – заболевание системы крови с накоплением кланальных тучных клеток в одном или нескольких органах. У детей чаще всего поражается кожа. У большей части болезнь регрессирует самостоятельно, независимо от тяжести клинических проявлений.

Описание случая

Заболевание дебютировало сразу после рождения в виде тяжелой типичной уртикарной и везикулярной сыпи, ежедневных приливов и зуда. Проводилось симптоматическое лечение антигистаминными препаратами и короткими курсами глюкокортикостероидов. С 4 месяцев началась положительная динамика: разрешились приливы, прошли боли в животе, уменьшились сыпь, зуд, снизилась потребность в фармакотерапии. В 2 года и 9 месяцев ребенок был радикально прооперирован по поводу остеобластомы. В настоящее время сохраняется умеренный кожный зуд, ребенок растет и развивается по возрасту, антигистаминные препараты принимает лишь эпизодически.

Заключение

Клиническое наблюдение демонстрирует самостоятельный регресс заболевания даже при тяжелом течении.

Ключевые слова

Мастоцитоз, клиническое наблюдение, пигментная крапивница, триптаза, антигистаминные средства, C-KIT, тучные клетки.

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Vsevolod G. Potapenko¹, Sergey R. Talypov²

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¹ Municipal Clinical Hospital No. 31, St. Petersburg, Russia
² D. Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology, Moscow, Russia

Correspondence:
Dr. Vsevolod G. Potapenko, PhD, Hematologist, Hematology Department, Municipal Clinical Hospital № 31, Pr. Dinamo, 3, 197110, St. Petersburg, Russia
Phone: +7 (905) 284-51-38
E-mail: potapenko.vsevolod@mail.ru

Citation: Potapenko VG, Talypov SR. Severe course of cutaneous mastocytosis in a child. Case report. Cell Ther Transplant 2022; 11(2): 58-62.

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Mastocytosis is a disease of the blood system with the accumulation of clonal mast cells in one or more organs. In children, the skin is most often affected. In most cases, the disease regresses spontaneously, regardless of severe clinical manifestations.

Case description

The disease was diagnosed after birth. Mastocytosis manifested with severe typical urticular and vesicular rash, daily hot flashes and itching. Skin infiltration with mast cells was confirmed by immunohistological examination of the skin. Symptomatic treatment was carried out with antihistamine drugs and short courses of glucocorticosteroids. The disease started to resolve since 4 months of age, with reduction of: hot flashes, abdominal pain, rash, and itching, thus decreasing the needs for drug therapy. At the age of 2 years 9 months, the child underwent radical surgery for osteoblastoma. Currently, moderate skin itching persists, the child develops according to his age, takes antihistamines only occasionally. Hence, this clinical observation demonstrates benign course of mastocytosis, even in severe cases.

Keywords

Мastocytosis, сase report, pigmented urticaria, tryptase, C-KIT, mast cells.

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Vsevolod G. Potapenko¹, Sergey R. Talypov²

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Case description

Keywords

Мastocytosis, сase report, pigmented urticaria, tryptase, C-KIT, mast cells.

Case description

Keywords

Мastocytosis, сase report, pigmented urticaria, tryptase, C-KIT, mast cells.

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¹ Municipal Clinical Hospital No. 31, St. Petersburg, Russia
² D. Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology, Moscow, Russia

Citation: Potapenko VG, Talypov SR. Severe course of cutaneous mastocytosis in a child. Case report. Cell Ther Transplant 2022; 11(2): 58-62.

¹ Municipal Clinical Hospital No. 31, St. Petersburg, Russia
² D. Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology, Moscow, Russia

Citation: Potapenko VG, Talypov SR. Severe course of cutaneous mastocytosis in a child. Case report. Cell Ther Transplant 2022; 11(2): 58-62.

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Всеволод Г. Потапенко¹, Сергей Р. Талыпов²

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Описание случая

Заключение

Клиническое наблюдение демонстрирует самостоятельный регресс заболевания даже при тяжелом течении.

Ключевые слова

Описание случая

Заключение

Клиническое наблюдение демонстрирует самостоятельный регресс заболевания даже при тяжелом течении.

Ключевые слова

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Introduction

According to the World Health Organization, the Russian Federation is among 30 countries with high tuberculosis burden. BCG vaccine has a proven protective effect against tuberculous meningitis and disseminated tuberculosis in children [1]. The Bacillus Calmette-Guérin (BCG) vaccine is produced from a live and attenuated strain of Mycobacterium bovis. In Russian Federation the primary BCG vaccination is mandatory for all newborns is at 3-7 days of life. Although vaccination with BCG is considered to be safe, it may cause regional (BCG-itis) and disseminated (BCG-osis) complications in immunocompromised host. As it is given early in life, some patients may receive the vaccine before some specific contraindications are revealed.

There is currently no systematic published data on complicated BCG vaccination in infants with acute leukemia. The term "infant leukemia" generally refers to acute lymphoblastic leukemia (ALL) diagnosed in patients younger than 1 or acute myeloid leukemia (AML) registered in children younger than 2 years [2].

We report 2 cases of children with infant acute leukemia developing BCG vaccination complications and demonstrate a possible therapeutic approach to this condition.

Case descriptions

Figure 1. BCG-itis in Patient No.1

Figure 2. Chest X-ray pattern of Patient No.1

Figure 3. Chest СT scan of Patient No.1

Figure 4. BCG-itis resolution after treatment in Patient No.1

Clinical case 1

A 1-month-old girl was admitted to R.M. Gorbacheva Children Research Institute in February 2020. She was a term neonate (birth weight 3.130 kg) born by normal vaginal delivery. The mother underwent regular prenatal check-ups revealing vaginal candidiasis and anemia of pregnancy. The patient received BCG-M vaccine on the 3^rd day of life. In February 2020, routine CBC performed in a 9-day-old neonate have shown a high WBC counts of 265×10⁹/l with 43% of blast cells in peripheral blood. The diagnosis of infant AML, FAB M4, ХХ t(2;11) with KMT2A rearrangement was established. At the time of the diagnosis the patient had no clinical signs of any disease. Patient received 1^st AM42E chemotherapy course according to AML-MRD 2018 protocol with a dose reduction due to young age and was then referred to R. M. Gorbacheva Children Research Institute for further treatment. Upon admission to the clinic on February 19^th 2020, the pancytopenia (Hb 69 g/l, Plt 2×10⁹/l, WBC 1.5×10⁹/l) and high serum C-reactive protein level (156 mg/l) were found, thus leading to diagnosis of febrile neutropenia. The examination on admission revealed skin hyperemia at the BCG-M vaccination site and elbow area of the arm (Fig. 1). Empirical therapy regimen consisting of meropenem, linezolid, and anidulafungin was administered.

The chest X-ray (Fig. 2) and computed tomography (Fig. 3) have been performed in order to find possible sings of generalized BCG infection did not yield any abnormal findings.

According to pediatric phthisiologist’s recommendation, isoniazid was administrated in order to control BCGitis symptoms and prevent the spread of BCG infection possible due to AML therapy-associated immunosuppression. Along with systemic therapy the local treatment consisting of dimexide lotion and hypertonic solution were used.

The signs of local BCGitis resolved after one month after treatment initiation.

In April 2020, the patient achieved complete remission with minimal residual disease persistence registered by flow cytometry. The child then received hAM chemotherapy regimen instead of FLAida, which should have been given according AML-MRD 2018 protocol, due to the risk of life-threatening generalized BCG-infection. By the end of May 2020, the patient was found to be COVID-19 infection PCR test-positive without clinical or CT signs of infection. In July 2020 he received 3 anti-Covid-19 convalescent plasma transfusions (10 ml/kg) due to prolonged SARS-CoV-2 persistence. The SARS-CoV-2 negative status was achieved after the second transfusion. Haploidentical allogeneic stem cell transplantation was performed on 24^th of July in complete remission. Conditioning regimen consisted of intraveneous busulfan (12 mg/kg) and fludarabin. Graft-versus-host disease prophylaxis included post-transplant cyclophosphamide, tacrolimus and everolimus. Engraftment was achieved on day +20. By June 2022 the patient has full donor chimerism, there are no signs of AML and no symptoms of BCG infection.

Clinical case 2

A 1-month-old girl was admitted to R.M. Gorbacheva Children Research Institute in August 2019. The child was born from the second pregnancy (second birth) by caesarean section. She received BCG-M vaccine on the 3^rd day of life. Then, as the child was one month old, the routine check-up revealed hepatosplenomegaly. The CBC have shown a high WBC count of 112×10⁹/l with 90% of blasts. Also 76.2% of lymphoblasts with CD45dim/SSClow/CD19+/CD38+/CD123+/CD10-/CD20-/CD22-/CD7-/CD117-/CD33-/CD13-/CD64-/CD15-/sIgM-/cytIgM-/MPO-/cytCD3-/cytCD79а+ immunophenotype were found in bone marrow, which corresponded to B-I ALL (EGIL). The blasts cytogenetics was characterized by chromosome rearrangements 46,XX,t(11;19)(q23;p13)[4]/46,XX[16]. The girl was enrolled in Interfant 2006 protocol with 2/3 dose reduction during remission induction due to young age at diagnosis. The hematological remission and MRD-negative status by flow cytometry and molecular biology test were achieved on day 36. She then proceeded to consolidation therapy (Protocol IB) starting on 17^th of September 2019. On day 5 of consolidation regimen the 9-mm upper left shoulder (BCGm vaccination site) infiltrate with central pustule appeared, although the child had not yet developed post-chemotherapy cytopenia. The regional lymph nodes were not enlarged. According to pediatric phthisiologist’s recommendation isoniazid was added to antimicrobial therapy regimen (already containing meropenem, linezolid and anidulofungin). The chemotherapy was suspended till BCGitis regression (de-evolution of pustules and crusts formation). After BCGitis resolved isoniazid treatment stopped due to hematological toxicity (agranulocytosis) development. An allogeneic hemopoietic stem cell transplantat from matched related donor was performed on 12^th of November 2019 with conditioning regimen consisting of intravenous busulfan (12 mg/kg) and fludarabin. The graft-versus-host disease prophylaxis was post-transplant cyclophosphamide-based. On day +27 post HSCT the MRD-negative remission with partial (40%) donor chimerism were registered. The patient received donor lymphocyte infusion in order to boost donor chimerism. Then, 1^st isolated bone marrow relapse was diagnosed on day +63. The patient received FLAG chemotherapy in January 2020. However in February 2020 ALL progression (75% of CD22-positive blasts in bone marrow) was confirmed. The 3 weekly inotuzumab ozogamicin infusions (0.8 mg/m², 0.5 mg/m², and 0.5 mg/m²) were administered leading to MRD-negative remission achievement on 5^th of March 2020. Then, on 16^th March 2020 the patient received a second allogeneic stem cell transplantation from haploidentical donor (father). Conditioning regimen consisted of treosulfan (36 g/m²) and fludarabin, the graft-versus-host disease prophylaxis included post-transplant cyclophosphamide and sirolimus. Engraftment was registered on day +17. The patient developed a Grade2 skin acute graft-versus-host disease successfully treated by glucocorticoids administration. By June 2022 she is alive, in remission, and retains full donor chimerism. The growth and development are normal.

Discussion

Adverse reactions to BCG vaccination are likely to be substantially underreported with only 1-10% of them being registered [3, 4]. These complications may be mild as well as severe. For the mild complications, e.g., cutaneous lesions (hyperemia, swelling, soreness, abscess formation, keloid and blister formation), the rate is estimated to be less than 1/1,000. Local ulceration at the vaccination site, suppurative lymphadenitis, osteitis, osteomyelitis, and disseminated BCG infection are severe complications, which occur in approximately two cases per 1 million of vaccinations [5].

Although BCG vaccination is contraindicated in patients with cancer, the majority of children are immunized at birth before the diagnosis is established. We describe two different cases of BCG vaccination complications, which may have very different pathogenesis. The first case demonstrates opportunistic BCG infection development in patient with profound cytopenia and immune deficiency. The second BCGitis case developed past CBC counts recovery and may be explained by immune reconstitution inflammatory syndrome. Immune reconstitution syndrome is usually presented in patients with HIV receiving highly active antiretroviral therapy (HAART) and is defined as paradoxical worsening of an opportunistic infection correlating with immune recovery [6]. This phenomenon is not unique to HAART recipients and has also been described in context of high-dose systemic steroids and chemotherapy withdrawal [7, 8].

There are currently no guidelines for anti-mycobacterial therapy and prophylaxis in infants with history of BCG vaccination at birth developing secondary immune deficiency due to hematological malignancy and chemotherapy. Also, different approaches are used to manage immune reconstitution syndrome-associated BCGitis, including surgical debridement, needle aspiration, steroids and anti-mycobacterial treatment. In some cases spontaneous resolution without intervention or antibiotics has occurred [9]. In our patients the BCGitis was successfully treated by chemotherapy suspension and combination of local and systemic antimycobacterial treatment.

Conflict of interests

None declared.

References

Global tuberculosis report, WHO 2020. Access: www.who.int/publications/i/item/9789240013131
Brown P. Treatment of infant leukemias: challenge and promise. Hematology Am Soc Hematol Educ Program. 2013;2013:596-600.
doi: 10.1182/asheducation-2013.1.596
Lotte A, Wasz-Hockert O, Poisson N, Engbaek H, Landmann H, Quast U, et al. Second IUATLD study on complications induced by intradermal BCG-vaccination. Bull Int Union Tuberc Lung Dis. 1988; 63(2):47-59. PMID: 3066422
Lotte A, Wasz-Höckert O, Poisson N, Dumitrescu N, Verron M, Couvet E. BCG complications. Estimates of the risks among vaccinated subjects and statistical analysis of their main characteristics. Adv Tuberc Res. 1984;21:107-193. PMID: 6475644
Tural-Kara T, Ozdemir H, Erat T, Yahsi A, Ciftci E. Local Cutaneous complications after bacille Calmette-Guerin vaccine: Experience of a single center. Int J Clin Pediatr. 2017;6(3-4):37-41. doi: 10.14740/ijcp279w
Alexander A, Rode H. Adverse reactions to the Bacillus Calmette-Guerin vaccine in HIV-positive infants. J Pediatr Surg. 2007;42(3):549-552. doi: 10.1016/j.jpedsurg.2006.10.059
Barretto J, Wirk B. Early recognition of immune reconstitution inflammatory syndrome leads to avoidance of endotracheal intubation. World J Oncol. 2012;3(4):194-198. doi: 10.4021/wjon527w
Miceli MH, Maertens J, Buve K, Grazziutti M, Woods G, Rahman M, Barlogie B, et al. Immune reconstitution inflammatory syndrome in cancer patients with pulmonary aspergillosis recovering from neutropenia: Proof of principle, description, and clinical and research implications. Cancer. 2007;110(1):112-120. doi: 10.1002/cncr.22738
Puthanakit T, Oberdorfer P, Punjaisee S, Wannarit P, Sirisanthana T, Sirisanthana V. Immune reconstitution syndrome due to bacillus Calmette-Guérin after initiation of antiretroviral therapy in children with HIV infection. Clin Infect Dis. 2005;41(7):1049-1052.
doi: 10.1086/433177

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Introduction

We report 2 cases of children with infant acute leukemia developing BCG vaccination complications and demonstrate a possible therapeutic approach to this condition.

Case descriptions

Figure 1. BCG-itis in Patient No.1

Figure 2. Chest X-ray pattern of Patient No.1

Figure 3. Chest СT scan of Patient No.1

Figure 4. BCG-itis resolution after treatment in Patient No.1

Clinical case 1

The chest X-ray (Fig. 2) and computed tomography (Fig. 3) have been performed in order to find possible sings of generalized BCG infection did not yield any abnormal findings.

The signs of local BCGitis resolved after one month after treatment initiation.

Clinical case 2

Discussion

Conflict of interests

None declared.

References

Global tuberculosis report, WHO 2020. Access: www.who.int/publications/i/item/9789240013131
Brown P. Treatment of infant leukemias: challenge and promise. Hematology Am Soc Hematol Educ Program. 2013;2013:596-600.
doi: 10.1182/asheducation-2013.1.596
Lotte A, Wasz-Hockert O, Poisson N, Engbaek H, Landmann H, Quast U, et al. Second IUATLD study on complications induced by intradermal BCG-vaccination. Bull Int Union Tuberc Lung Dis. 1988; 63(2):47-59. PMID: 3066422
Lotte A, Wasz-Höckert O, Poisson N, Dumitrescu N, Verron M, Couvet E. BCG complications. Estimates of the risks among vaccinated subjects and statistical analysis of their main characteristics. Adv Tuberc Res. 1984;21:107-193. PMID: 6475644
Tural-Kara T, Ozdemir H, Erat T, Yahsi A, Ciftci E. Local Cutaneous complications after bacille Calmette-Guerin vaccine: Experience of a single center. Int J Clin Pediatr. 2017;6(3-4):37-41. doi: 10.14740/ijcp279w
Alexander A, Rode H. Adverse reactions to the Bacillus Calmette-Guerin vaccine in HIV-positive infants. J Pediatr Surg. 2007;42(3):549-552. doi: 10.1016/j.jpedsurg.2006.10.059
Barretto J, Wirk B. Early recognition of immune reconstitution inflammatory syndrome leads to avoidance of endotracheal intubation. World J Oncol. 2012;3(4):194-198. doi: 10.4021/wjon527w
Miceli MH, Maertens J, Buve K, Grazziutti M, Woods G, Rahman M, Barlogie B, et al. Immune reconstitution inflammatory syndrome in cancer patients with pulmonary aspergillosis recovering from neutropenia: Proof of principle, description, and clinical and research implications. Cancer. 2007;110(1):112-120. doi: 10.1002/cncr.22738
Puthanakit T, Oberdorfer P, Punjaisee S, Wannarit P, Sirisanthana T, Sirisanthana V. Immune reconstitution syndrome due to bacillus Calmette-Guérin after initiation of antiretroviral therapy in children with HIV infection. Clin Infect Dis. 2005;41(7):1049-1052.
doi: 10.1086/433177

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Рахманова1, Олеся В. Паина1, Олеся С. Юдинцева1, Анна А. Старшинова2, Елена В. Семенова1, Людмила С. Зубаровская1" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(284) "

Жемал З. Рахманова¹, Олеся В. Паина¹, Олеся С. Юдинцева¹, Анна А. Старшинова², Елена В. Семенова¹, Людмила С. Зубаровская¹

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¹ НИИ детской онкологии, гематологии и трансплантологии им. Р. М. Горбачевой, Первый Санкт-Петербургский государственный медицинский университет им. акад. И. П. Павлова, Санкт-Петербург, Россия
² Национальный медицинский исследовательский центр им. В. В. Алмазова, Санкт-Петербург, Россия

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Осложненное течение вакцинации БЦЖ считается редким состоянием, однако иммунокомпрометированные пациенты, в том числе дети раннего возраста с гемобластозами на фоне химиотерапии, имеют высокий риск развития данного нежелательного явления. На сегодняшний день в литературе отсутствует информация о ведении осложненной вакцинации БЦЖ у пациентов с младенческим лейкозом.

Мы сообщаем о 2 случаях успешного лечения пациентов с младенческим лейкозом, у которых на фоне химиотерапии имелось осложненное течение вакцинации БЦЖ, и демонстрируем наш мультидисциплинарный терапевтический подход.

Ключевые слова

Острый миелоидный лейкоз, острый лимфобластный лейкоз, дети младшего возраста, БЦЖ-вакцинация, осложнения, аллогенная трансплантация гемопоэтических клеток.

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Zhemal Z. Rakhmanova¹, Olesya V. Paina¹, Olesya S. Yudinceva¹, Anna A. Starshinova², Elena V. Semenova¹, Ludmila S. Zubarovskaya¹

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¹ RM Gorbacheva Research Institute of Pediatric Oncology, Hematology and Transplantology, Pavlov University, St. Petersburg, Russia
² V.A. Almazov National Medical Research Center, St. Petersburg, Russia

Correspondence:
Dr. Zhemal Z. Rakhmanova, RM Gorbacheva Research Institute of Pediatric Oncology, Hematology and Transplantology, L. Tolstoy St., 6-8, 197022, Pavlov University, St. Petersburg, Russia
Phone: +7 (999) 206-12-76
E-mail: rakhmanovazhemal@gmail.com

Citation: Rakhmanova ZZ, Paina OV, Yudinceva OS, et al. Complicated BCG vaccination during chemotherapy in infant acute leukemia patients. Cell Ther Transplant 2022; 11(2): 54-57.

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BCG vaccination complications, such as BCGitis and BCG-osis are relatively rare complications, which may occur in immunocompromised patients, including infants with hematological malignancies receiving chemotherapy. There is currently very few published data complicated BCG vaccination cases in infants with hematological malignancies. We report 2 children with infant acute leukemia developing BCG vaccination complications demonstrating a multidisciplinary therapeutic approach needed in these cases.

Keywords

Acute myeloid leukemia, acute lymphoblastic leukemia, infants, BCG-itis, BCG-osis, allogeneic stem cell transplantation.

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Rakhmanova1, Olesya V. Paina1, Olesya S. Yudinceva1, Anna A. Starshinova2, Elena V. Semenova1, Ludmila S. Zubarovskaya1" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(203) "

Zhemal Z. Rakhmanova¹, Olesya V. Paina¹, Olesya S. Yudinceva¹, Anna A. Starshinova², Elena V. Semenova¹, Ludmila S. Zubarovskaya¹

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Keywords

Acute myeloid leukemia, acute lymphoblastic leukemia, infants, BCG-itis, BCG-osis, allogeneic stem cell transplantation.

Keywords

Acute myeloid leukemia, acute lymphoblastic leukemia, infants, BCG-itis, BCG-osis, allogeneic stem cell transplantation.

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Citation: Rakhmanova ZZ, Paina OV, Yudinceva OS, et al. Complicated BCG vaccination during chemotherapy in infant acute leukemia patients. Cell Ther Transplant 2022; 11(2): 54-57.

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Ключевые слова

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" } } } }

Clinical case

Severe course of cutaneous mastocytosis in a child. Case report

Vsevolod G. Potapenko¹, Sergey R. Talypov²

Complicated BCG vaccination during chemotherapy in infant acute leukemia patients

Zhemal Z. Rakhmanova¹, Olesya V. Paina¹, Olesya S. Yudinceva¹, Anna A. Starshinova², Elena V. Semenova¹, Ludmila S. Zubarovskaya¹

Clinical case

Severe course of cutaneous mastocytosis in a child. Case report

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Vsevolod G. Potapenko¹, Sergey R. Talypov²

¹ Municipal Clinical Hospital No. 31, St. Petersburg, Russia
² D. Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology, Moscow, Russia

Citation: Potapenko VG, Talypov SR. Severe course of cutaneous mastocytosis in a child. Case report. Cell Ther Transplant 2022; 11(2): 58-62.

Case description

Keywords

Мastocytosis, сase report, pigmented urticaria, tryptase, C-KIT, mast cells.

Clinical case

Complicated BCG vaccination during chemotherapy in infant acute leukemia patients

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Zhemal Z. Rakhmanova¹, Olesya V. Paina¹, Olesya S. Yudinceva¹, Anna A. Starshinova², Elena V. Semenova¹, Ludmila S. Zubarovskaya¹

Citation: Rakhmanova ZZ, Paina OV, Yudinceva OS, et al. Complicated BCG vaccination during chemotherapy in infant acute leukemia patients. Cell Ther Transplant 2022; 11(2): 54-57.

Keywords

Acute myeloid leukemia, acute lymphoblastic leukemia, infants, BCG-itis, BCG-osis, allogeneic stem cell transplantation.