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| CASE REPORT |
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| Year : 2023 | Volume
: 3
| Issue : 2 | Page : 113-116 |
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Recurrent Infections in an Infant: Close Monitoring of Sequential Neutrophil Counts Can Identify Cyclic Neutropenia
Nagamani Agarwal, KA Chaya, P Megha, Anand Subhash
Department of Paediatrics, JJM Medical College, Davangere, Karnataka, India
| Date of Submission | 14-Jul-2022 |
| Date of Decision | 15-Mar-2023 |
| Date of Acceptance | 29-Mar-2023 |
| Date of Web Publication | 24-May-2023 |
Correspondence Address:
Dr. Nagamani Agarwal
Department of Paediatrics, JJM Medical College, Davangere, Karnataka
India
 Source of Support: None, Conflict of Interest: None
DOI: 10.4103/ipcares.ipcares_173_22
Background: Cyclic neutropenia (CyN) is a rare inherited neutrophil disease characterized by a periodic neutropenia with an absolute neutrophil count (ANC) dropping below 0.5 × 109/L every 3–4 weeks, followed by normalization over the next few days. Clinical Description: A 3-year-old boy presented with recurrent episodes of fever, respiratory tract infections, diarrhea, gingivitis, and oral and cutaneous ulcers from 11 months of age, requiring multiple hospitalizations. He was immunized for age, normal development, with an unremarkable family history. An underlying primary immunodeficiency disorder was suspected in view of recurrent multi-site infections since infancy. Management: The hemogram revealed a normal total leukocyte count with severe, neutropenia, lymphocytosis, normal platelet count and severe anemia . Purified protein derivative test and human immunodeficiency virus test were negative. The chest Xray showed right lower lobe consolidation. Blood culture was sterile. Bone marrow study, immunoglobulin profile, and lymphocyte subtyping were within the normal limits. The child was treated symptomatically with parenteral antibiotics and packed red blood cells transfusion. The ANC increased to 2592/mm3 but, again fell by 27 days after admission. Review of previous blood counts showed a fall and rise of ANC every 3–5 weeks. Clinical exome sequencing revealed a heterozygous mutation in the ELANE gene, a pathogenic variant c. 1A>G (p.Met1), confirming the diagnosis of CyN. The child improved with Granulocyte – colony stimulating factor (G-CSF). Conclusion: Diagnosis of CyN can be challenging as it needs a high index of suspicion and meticulous monitoring of blood counts. If suspected, they should be screened for ELANE mutations. Keywords: ELANE mutation, primary immunodeficiency, recurrent oral ulcers
How to cite this article:
Agarwal N, Chaya K A, Megha P, Subhash A. Recurrent Infections in an Infant: Close Monitoring of Sequential Neutrophil Counts Can Identify Cyclic Neutropenia. Indian Pediatr Case Rep 2023;3:113-6 |
How to cite this URL:
Agarwal N, Chaya K A, Megha P, Subhash A. Recurrent Infections in an Infant: Close Monitoring of Sequential Neutrophil Counts Can Identify Cyclic Neutropenia. Indian Pediatr Case Rep [serial online] 2023 [cited 2023 Jun 6];3:113-6. Available from: http://www.ipcares.org/text.asp?2023/3/2/113/377507 |
Cyclic neutropenia (CyN) and severe congenital neutropenia (SCN) are rare inherited granulopoietic disorders characterized by recurrent or persistent severe neutropenia leading to recurrent bacterial infections. In CyN, there is a periodic neutropenia with an absolute neutrophil count (ANC) dropping below 0.5 × 109/L every 3–4 weeks, mirrored by reciprocal cycling of monocytes, neutropenia lasting for 4–5 days per episode. In SCN, neutropenia is persistent.[1] Majority of children with inherited neutropenia present early in infancy, caused by ELANE gene mutation.[2],[3],[4] We report a case of CyN in a toddler who remained asymptomatic until 1 year of age, unlike majority, who present in early infancy.
| Clinical Description | |  |
A 3-year-old boy presented with gradually increasing intensity of fever and cough for 3 weeks and rapid breathing for 5 days. The fever was high grade with rigors and 2–3 spikes in a day. The cough was of insidious onset, gradually increasing in frequency and severity, nonspasmodic, and with no postural or diurnal variation. There was associated decrease in appetite and daily activities, but no history of coryza, sore throat, rash, vomiting, loose motions, urinary complaints, abdominal pain, joint involvement, seizures, or altered sensorium. He also had small, painful ulcers in the oral cavity and whitish patch over the tongue during this period. The child had not been gaining weight over the past one-and-a-half years.
He was apparently healthy till 11 months of age, following which he had recurrent acute respiratory tract infections with fever, every 4–6 weeks, requiring three hospitalizations. Each episode had been associated with similar oral ulcers, whitish patch over the tongue, skin lesions resembling pustules, and multiple swellings in the neck. He also had recurrent episodes of diarrhea and purulent discharge from the left ear. Each illness was managed by oral or parenteral antibiotics and topical antifungal medications. When he was 1½ years old, he had developed a periumbilical abscess that required drainage and medication. [Table 1] shows the timeline of previous events. There was no history of contact with a case of tuberculosis or receiving previous blood transfusion.
He was the second issue of a nonconsanguineous marriage. The antenatal and perinatal period, acquisition of developmental milestones, immunization status, and family history were unremarkable. He weighed 3.1 kg at birth, and cord fell on day 7 of life. His parents and 6-year-old brother were alive and healthy. All of them had a diet adequate in calories and proteins.
Examination revealed a febrile child (101°F) with tachycardia (136/min) in respiratory distress (56 cycles/min, associated with intercostal and subcostal retractions) with SPO2 of 92% at room air and normal blood pressure (86/44 mm of Hg at 50th centile). His weight, height, and head circumference were 8.8 kg (<1st centile), 89 cm (3rd–50th centile), and 49 cm (50th centile), respectively. The mid-upper arm circumference was 10 cm and weight/height was <−3SD, indicating severe acute malnutrition (SAM). There was severe pallor, no cyanosis or pedal edema. Multiple tiny ulcers were seen in the oral cavity [Figure 1] with gingivitis and whitish thick plaque over the dorsum of the tongue. The BCG scar was present. Both the tonsils were congested and showed Grade II enlargement (the Friedman grading scale). Otoscopic examination showed a small central perforation in the left ear. Cervical lymph nodes were enlarged, two on each side, non-tender, and discrete. There was a generalized wasting with flaring of the lower ribs and pectus carinatum. Respiratory system examination showed an increased vocal fremitus and bronchial breathing in various areas over the right lung. There was no hepatosplenomegaly, and other systemic examination was normal.
Based on the clinical phenotype, a provisional diagnosis of SAM with severe pneumonia and severe anemia, and oral candidiasis was made. An underlying primary immunodeficiency disorder (PID) was suspected in view of infantile onset of recurrent infections (bacterial and fungal) involving multiple systems. Secondary immunodeficiency disorders due to human immunodeficiency virus (HIV) infection seemed unlikely since parents were healthy. Other conditions that predispose to recurrent respiratory infections like congenital malformations of the lung or heart and cystic fibrosis were also considered in the differential diagnosis.
| Management and Outcome | | |
The child was treated symptomatically with intravenous injection ceftriaxone and injection amikacin and with topical antifungal medication. The hemogram revealed severe anemia, normal total leukocyte count (8610 cells/mm3) with differential leukocyte count of neutrophils 5%, lymphocytes 88%, and monocytes 5%. There was severe neutropenia (ANC of 430 cells/mm3), lymphocytosis (ALC of 7576 cells/mm3), and normal platelet count (350,000/mm3). Peripheral smear examination revealed microcytic, hypochromic blood picture with neutropenia and lymphocytosis with a few atypical lymphocytes. Creactive protein was raised (245.7 mg/L). The purified protein derivative test and HIV test were negative. The chest Xray showed right lower lobe consolidation [Figure 2]. Swab taken from the whitish lesion over the tongue showed oval budding yeast cells . Blood culture was sterile. Immunoglobulin profile and lymphocyte subtyping done by flow cytometry were within the normal limits [Table 2]. The child was transfused with packed red blood cells . Moderate neutropenia was noted (602 cells/mm3) even on day 8 of treatment. The ANC increased to 2592 cells/mm3 over the next 4 days, falling again to 550 cells/mm3 on day 27. Monocytes and lymphocytes also appeared to oscillate with the same periodicity as neutrophils [Table 3] Review of previous serial blood count (done elsewhere) showed profound neutropenia (ANC of <200/mm3) at admission, which improved following granulocyte colonystimulating factor (GCSF) administration. Severe neutropenia recurred 4 weeks later [Table 4]. Bone marrow aspiration study showed features suggestive of normoblastic bone marrow. | Figure 2: Ulcers over the lower lip, gingivitis, and whitish patch over the tongue
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A diagnosis of CyN was suspected on the basis of clinical features and periodic fall and rise of ANC . Diagnosis was confirmed on Clinical exome sequencing done by Invitae corp. a biotechnology company located at San Francisco, California, U.S.A. , which revealed a heterozygous mutation in the ELANE gene, variant c. 1A>G (p.Met1), classified as a pathogenic variant. Test performed was sequence analysis and deletion/duplication testing of the 407 genes listed in the genes analyzed section (Invitae Primary Immunodeficiency Panel). The final diagnosis was CyN caused by heterozygous mutation in the ELANE gene. Parents were counseled about treatment options including GCSF and bone marrow transplantation. The child has been receiving 0.1 ml (30 μg) of injection filgrastim (recombinant human GCSF) daily by the subcutaneous route for the past 1½ years. Frequency and severity of infections have reduced, . During the last followup, he was 4½ years old, with the weight of 14 kg and height of 96 cm.
| Discussion | | |
Cyclical Neutropenia is a type of primary immunodeficiency disorder (PID), the latter being a heterogeneous group of inherited disorders that affect different components of the immune system. Approximately 80% of mutated genes causing more than 400 known PIDs have been identified.[5] Circumstances in which PIDs should be suspected in an infant or child include unusual, chronic, or recurrent infections, family history of known PID or early infant death, and failure to thrive with or without chronic diarrhea. Additional clues are chronic oral or cutaneous moniliasis, serious infections occurring at unusual sites (liver and brain abscess), and infections with common childhood pathogens, but of unusual severity.[6] Timely diagnosis helps initiate appropriate treatment before irreversible organ damage occurs and also offer genetic counseling.
Our patient, a 3-year-old toddler, born to healthy parents, presented with failure to thrive, and recurrent infections since 11 months of age. erial blood counts of the present and past admission revealed an oscillation of ANC at an interval of 4–5 weeks with reciprocal mirroring of monocytes. suggestive of CyN .
The diagnosis of CyN is made by obtaining blood counts 3 times a week for 6–8 weeks, confirmed by demonstrating a mutation in the ELANE gene located in chromosome 19p13.3 and codes for NE, a serine protease present in the neutrophil granules.[3],[4] Although an autosomal dominant inheritance has been reported, sporadic or de novo mutations in the ELANE gene are also common.[7]
Pathogenesis of CyN is not clear. The most widely accepted hypothesis is that mutant NE leads to accelerated apoptosis of neutrophil precursors.[4] Recurring episodes of severe neutropenia lead to potentially fatal repetitive bacterial and fungal infections.[8] Affected individuals are generally healthy in between neutropenic periods, and symptoms tend to improve with age.[8]
Unlike majority of affected individuals with CyN who present early in life, our patient became symptomatic from 1 year of age. Bellanné Chantelot et al. studied 81 patients with ELANE generelated neutropenia, and the median age of diagnosis in their study was 2.8 months.[9] In a study by Arun et al., 34/52 children with inherited neutropenia had SCN and 18 had CyN. They concluded that clinical phenotype is influenced by other genetic and epigenetic factors apart from the underlying ELANE mutation.[7]
GCSF is the treatment of choice in CyN and has greatly improved the quality of life and survival.[10] GCSF is administered when neutropenia is profound with neutrophil nadir <200 cells/mm3. The dose needed to maintain neutrophil nadir >500 cells/mm3 is usually 2–4 μg/kg/day administered daily or every other day.[6] Hematopoietic stem cell transplantation is the only curative option for whom do not respond to GCSF treatment.[11]
CyN is not associated with an increased risk of malignancy, however, some ELANE mutations may be associated with SCN and increased risk of acute myeloid leukemia.[9] Despite the chronic and intermittent nature of the disease, patients with CyN have a good longterm prognosis.[8]
Declaration of patient consent
The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/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.
| References | | |
| 1. | Horwitz MS, Corey SJ, Grimes HL, et al. ELANE mutations in cyclic and severe congenital neutropenia: Genetics and pathophysiology. Hematol Oncol Clin North Am 2013;27:19-41, vii.  |
| 2. | Dale DC, Makaryan V. ELANE-Related Neutropenia. 2002. In: Adam MP, Mirzaa GM, Pagon RA, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2023. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1533. [Last accessed on 2002 Jun 17, Last updated on 2018 Aug 23]. |
| 3. | Horwitz M, Benson KF, Person RE, et al. Mutations in ELA2, encoding neutrophil elastase, define a 21-day biological clock in cyclic haematopoiesis. Nat Genet 1999;23:433-6. |
| 4. | Köllner I, Sodeik B, Schreek S, et al. Mutations in neutrophil elastase causing congenital neutropenia lead to cytoplasmic protein accumulation and induction of the unfolded protein response. Blood 2006;108:493-500. |
| 5. | Sivasankaran M, Munirathnam D, Balasubramanian S, et al. Diagnostic spectrum and clinical profile of primary immunodeficiency disorders at a tertiary care children hospital in Southern India. Indian Pediatr 2021;58:246-9. |
| 6. | Sullivan KE, Rebecca H. Buckley. Evaluation of suspected immunodeficiency. In: Kliegman RM, St. Geme J, Blum NJ, et al., editors. Nelson Textbook of Pediatrics. 21 st ed., Vol. 3. India: Elsevier; 2020. p. 1097. |
| 7. | Arun AK, Senthamizhselvi A, Hemamalini S, et al. Spectrum of ELANE mutations in congenital neutropenia: A single-Centre study in patients of Indian origin. J Clin Pathol 2018;71:1046-50. |
| 8. | Palmer SE, Stephens K, Dale DC. Genetics, phenotype, and natural history of autosomal dominant cyclic hematopoiesis. Am J Med Genet 1996;66:413-22. |
| 9. | Bellanné-Chantelot C, Clauin S, Leblanc T, et al. Mutations in the ELA2 gene correlate with more severe expression of neutropenia: A study of 81 patients from the French Neutropenia Register. Blood 2004;103:4119-25. |
| 10. | Dale DC, Bolyard A, Marrero T, et al. Long-term effects of G-CSF therapy in cyclic neutropenia. N Engl J Med 2017;377:2290-2. |
| 11. | Choi SW, Levine J. Indications for hematopoietic cell transplantation for children with severe congenital neutropenia. Pediatr Transplant 2010;14:937-9. |
[Figure 1], [Figure 2]
[Table 1], [Table 2], [Table 3], [Table 4]
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