Skip to main content

A term infant with severe hypereosinophilia secondary to CMV infection and the STAT1 gene mutation: a case report

List of authors


Hypereosinophilia is a rare presentation in all age groups, particularly when it is severe, persistent, and progressive. We describe the clinical characteristics and course of severe hypereosinophilia in a full-term Saudi female neonate. A febrile respiratory illness evolved with a progressive increase in peripheral blood leukocyte and eosinophil counts, reaching 44.9% of leukocytes and an absolute value of 57,000 cells/µl. Different etiological examinations (for viral, bacterial, immunodeficiency, hyper IgE syndrome, gene mutations) revealed extremely high CMV antigenemia and a homozygous mutation in the STAT1 gene. Anhelation was relieved by oxygen and anti-viral treatment. Steroids brought a dramatic response in peripheral blood counts within 24 h. After a 6-week course of antiviral and steroid treatment at home, she had an excellent general condition. Conclusion: Although a rare pathology, it is important to consider genetic disorders when there is an atypical immune response to viral infections.

Peer Review reports


Although, mild to moderate hypereosinophilia (HE) is reported in 14-76% of preterm neonates, severe HE in neonates is rare, which favors diagnostic and therapeutic concerns. HE is defined as an absolute eosinophil count (Ec) in neonatal peripheral blood > 500 cells/µl [1]. The condition is classified as mild, moderate, or severe; (mild, Ec – 500–1500 cells/µl; moderate, 1500–5000 cells µl; severe, > 5000 cells/µl). Germline mutations in signal transducer and activator of transcription1 (STAT1) gene lead to primary immunodeficiency, they are classified as defects in intrinsic and innate immunity. Homozygous and heterozygous, gain-of-function (GOF) and loss-of-function (LOF) mutations in the STAT1 gene are described. Here we report an infant with LOF STAT1 gene mutation and moderate HE that progressed to severe form over 2 months and review the relevant literature.

Case report

Clinical data and results

A full-term female of a 2-week of age was incubated for a febrile illness and poor general condition at the Maternity and Children Hospital, Makkah, Saudi Arabia. An uneventful pregnancy and delivery except for a febrile illness in mid-pregnancy was reported, birth weight was 2800 g. She is the firstborn baby in a consanguineous marriage, with no reported family history of immunodeficiency, autoimmunity, mycobacterial infection, prenatal abnormalities, or abortions.

Clinical findings & diagnostic assessment

At the incubator, a diagnosis of aseptic meningitis was adopted having cerebrospinal fluid (CSF) analysis showing an increased white blood cell count (WBC) – 62/µl; mononuclear – 96.3% and polymorphonuclear – 3.7%, high protein content – 125 mg/dl, and low glucose – 2 mmol/l. CSF cultures didn’t grow organisms. Complete blood count (CBC) showed 21,800 cells/µl leukocytes, 11,800 cells /µl absolute neutrophil count (ANC), 5400 cells/µl Lymphocytes, 1600 cells/µl eosinophils, 13 gm/dl hemoglobin (Hb), and 630,000 cells/µl platelets, erythrocyte sedimentation rate (ESR) was 7 mm/h. Antibiotics in the form of ampicillin and gentamicin and supportive treatment were introduced. She was discharged 19 days later with a satisfactory evolution and a WBC – 22,000 cells/µl, and Ec – 5200 cells/µl. Two weeks later, the infant exhibited frequent high-grade fever and spasmodic cough for which she was admitted to the general pediatric ward. No history of antibiotics or nonsteroidal anti-inflammatory drug use or other premedication was registered. Signs were as follows: blood pressure 95/59 mmHg, heart rate 145/min, respiratory rate 32/min, temperature 39.8 °C, oxygen saturation in room air – 97%, capillary refill time of 2 s, and body weight – 3.5 kg. Occasional desaturation to 80s% was documented with bottle-feeding or coughing. The physical examination was unremarkable except for hepatomegaly of 3–4 cm below the costal margin. No heart murmur or abnormal breath sounds were observed. Initially, the patient was treated for sepsis after sending blood and CSF samples for culture/sensitivity with antibiotics in the form of meropenem and vancomycin. No bacterial growth was revealed. A chest x-ray was performed, which revealed ground glass opacity bilaterally. A differential diagnosis (DD) of a congenital infection versus acquired chlamydia infection was adopted. The striking issue was the steady increase in WBC/Ec reaching 127/ 57,000 cells/µl (44.9%) associated with progressive normocytic anemia (Hb 7.4 gm/dl). The peripheral blood smear showed leukocytosis with striking eosinophilia with no blasts. To reach a specific diagnosis, further tests were performed with the following results: immunoglobulins [IgA, 71 mg/dl (reference range (rr) 70–400 mg/dl); IgG, 850 mg/dl (rr 700–1600 mg/dl); IgE, 204 mg/dl (rr 0-100 mg/dl); IgM, 130 mg/dl (rr 40–230 mg/dl)]. Both renal and liver functions were normal, as well as serum electrolytes, lactate dehydrogenase (LDH) was 755 IU/L. A computed tomography (CT) scan of the chest showed bilateral lower lobe consolidation (Fig. 1). A virology study showed no reactivity to human immunodeficiency virus (HIV) or hepatitis viruses, however, both IgG and IgM to cytomegalovirus (CMV) were high, and CMV polymerase chain reaction (PCR) was sent. Bone marrow aspiration/biopsy was not done. The maternal CMV antibody status was sought however, samples were lost. The possibility of genetically related disease was considered, and whole exome sequencing (WES) was performed.

Therapeutic interventions

Waiting for the results, treatment was started with intravenous immunoglobulins (IVIG) – 2 gm/kg with no measurable effect. Then, intravenous (IV) prednisone 1 mg/kg per dose every 12 h was initiated. The next day, WBC/Ec came as 62/39,000 cells/µl (29.5%). Fevers finally subsided with the improved general condition. CMV viral load was shown to be – 18,700,000 IU/ml confirming the diagnosis of CMV infection. A CT brain scan, hearing, and ophthalmological assessment were unremarkable. Anti-viral treatment in the form of IV ganciclovir was started at the hospital for 21 days in addition to steroids.

Follow-up & outcomes

The infant responded favorably to treatment and was discharged later with clear lungs and full oral feeding. CBC before discharge showed WBC/Ec – 17,000/646 cells/µl. Steroid and anti-viral treatment continued at home orally, until clinical and laboratory remission. The result of WES came later with the finding of – a homozygous LOF variant in the STAT1 gene; c.1760_1761del (p.Glu587fs).

Fig. 1
figure 1

Chest computed tomography. Diffuse bilateral air space consolidation with air bronchogram seen more at the basal segment of both lower lung lobes


Hypereosinophilia is classified into a primary form; hypereosinophilic syndrome (HES); related to bone marrow proliferative diseases, and a secondary form most commonly related to infections and allergic reactions. HES is defined by a persistent Ec ≥ 1500 cells/µl, absence of a secondary cause, and evidence of eosinophil-associated pathology. While primary HE in children is rare, the secondary (reactive) form is most frequent in this age group [2, 3]. Secondary HE is reported in a wide range of conditions including allergic drug reactions, primary immunodeficiency disorders, connective tissue disorders, respiratory eosinophils (e.g. Churg-Strauss syndrome), aspergillosis, gastrointestinal tract eosinophilia and, paraneoplastic syndromes [1, 4,5,6]. Hernández-Benítez R et al. reported an infant with severe atopic dermatitis and WBC/Ec – 43,900/30,200 cells/µl [7].

Eosinophils have a vital share in the immune defense mechanisms, besides tissue regeneration and remodeling processes [3]. Through degranulation and the production of a network – the so-called eosinophil extracellular traps (EET), they are believed to have an important share in the pathogen immune response [8, 9]. Being stimulated, eosinophils release inflammatory mediators and procoagulants, which may be associated with thrombotic events and tissue fibrosis [1, 2, 5]. The subsequent organ damage depends on the site of eosinophilic infiltration, which most often affects the skin, circulation, respiratory system, gastrointestinal (GI) tract, and nervous system [10]. Despite children commonly presenting with GI symptoms, contrary to adults, the patient in this report exhibited mainly respiratory symptoms. Similar presenting symptoms were reported by Juan He et al. in a term infant with Ec – 27,000 cells/µl that declined over 3 months with non-specific treatment being of an unclear etiology [11]. Krous HF et al. reported one case of neonatal death due to eosinophilic myocarditis [12].

Often, HE is discovered incidentally. Since the first admission of the present case, eosinophilia was evident in the CBC but most likely passed unnoticed. It wasn’t until the second admission that the severe and progressive increase in WBC/Ec drew attention.

CMV has a broad infectivity range, it is typically associated with immunocompromised patients [13]. There are few documented cases of primary CMV infection associated with eosinophilia [14,15,16,17], although it is not uncommon for viral infections to be associated with eosinophilia, however, their antiviral abilities have been demonstrated mainly in respiratory syncytial virus (RSV) studies [18]. They interact with T-cells and antigen-presenting cells via their granules contributing to adaptive immunity [19, 20]. Kobayashi A reported an infant with severe HE; WBC/Ec – 39.8/21.5 × 103 cells/µl associated with reactivation of CMV and drug hypersensitivity evidenced by lymphocyte transformation test (LTT) [21]. Like the case in this report, they documented a rapid improvement of hypereosinophilia and its associated manifestations with systemic corticosteroid therapy, attributing the therapeutic response and transient clinical course to organ failure with hypereosinophilia.

Further areas of research could aim to discover why a remarkably small percentage of CMV-infected patients have been reported to display eosinophilia. Perhaps it is due to a unique response to viral infection by these individuals’ T-cells and eosinophil proliferation signaling; hypothetically, eosinophilia could be explained by these individuals’ recruitment of CD4 T-cells and subsequent production of interleukin 5(IL 5), an “eosinophil colony-stimulating factor” [22]. If so, perhaps these patients’ unique immune systems may also explain why their course of infection is more severe compared to their typical immunocompetent counterparts. In addition, a genetic basis could be suggested based on the findings in the present case. The STAT1 gene is known to mediate the actions of cytokines involved in innate and adaptive immune defense against viruses and intracellular bacteria [23]. STAT1 mutated patients either in a dominant or a recessive fashion are susceptible to infections with these organisms which reflects the failure of interferon (IFN)-γ- and IFN-α/β-mediated immunity [24,25,26]. According to O’Shea JJ et al. STAT1 mutations probably have a marked impact on the host defense against infections through disturbed T-helper cell responses [27]. STAT1 gain-of-function (GOF) mutations are described in patients with early-onset chronic mucocutaneus candidiasis, bacterial respiratory tract infections, and humoral immunodeficiency, while loss-of-function mutations are to be considered in patients with early-onset mycobacterial disease, osteomyelitis, respiratory tract infections, and Herpesviridae infection. Baris S et al. reported two patients with autosomal dominant mutations in the STAT1 gene; presented with oral candidiasis and recurrent CMV infections, in addition to cavitary mycobacterial lung disease early in life (2–4 months of age) [28].The variant in this report is previously described as a pathogenic LOF mutation, inherited in an autosomal recessive fashion, that leads to a clinical entity called immunodeficiency 31B associated with increased susceptibility to mycobacterial and viral infections. This was described in two unrelated infants who suffered from mycobacterial disease and both died of disseminated viral disease [25]. The clinical course introduced in this report can be explained by the detected gene mutation and its impact on the unique immune response to CMV infection manifesting as severe reactive HE and bilateral pulmonary consolidation. In conclusion, we report an infant case with severe hypereosinophilia and systemic symptoms associated with cytomegalovirus infection and STAT1 gene mutation, and our case might provide novel insight regarding the pathogenesis of reactive HE through a possible link between gene mutation and primary immunodeficiency leading to eosinophil production secondary to imbalance in T-cell stimulation.

Data availability

The datasets used in the current report are available from the corresponding author upon reasonable request.



Degree Celsius




Absolute Neutrophil Count


Complete Blood Count






Cerebrospinal fluid


Computed Tomography


Differential Diagnosis




Eosinophil count


Eosinophil Extracellular Traps














Hypereosinophilic Syndrome


Human Immunodeficiency Virus




Immunoglobulin A


Immunoglobulin E


Immunoglobulin G


Immunoglobulin M

IL 5:

Interleukin 5


International Unit




Intravenous Immunoglobulins








Lactate Dehydrogenase




Lymphocyte Transformation Test








Millimetres of Mercury




Polymerase Chain Reaction


reference range


Respiratory Syncital Virus




Signal Transducer and Activator of Transcription 1


White Blood Cells


Whole Exome Sequencing


  1. Gotlib J. World Health Organization-defined eosinophilic disorders: 2017 update on diagnosis, risk stratification and management. Am J Hematol. 2017;92:1243–59.

    Article  CAS  PubMed  Google Scholar 

  2. Wang SA. The Diagnostic Work-Up of Hypereosinophilia. Pathobiol. 2019;86:39–52.

    Article  CAS  Google Scholar 

  3. Schwartz JT, Fulkerson PC. An Approach to the evaluation of Persistent Hypereosinophilia in Pediatric patients. Front Immunol. 2018;9:1944.

    Article  PubMed  PubMed Central  Google Scholar 

  4. Montgomery ND, Dunphy CH, Mooberry M, Laramore A, Foster MC, Park SI, et al. Diagnostic complexities of eosinophilia. Arch Pathol Lab Med. 2013;137(2):259–69.

    Article  PubMed  Google Scholar 

  5. Williams KW, Ware J, Abiodun A, Holland-Thomas NC, Khoury P, Klion AD. Hypereosinophilia in children and adults: a retrospective comparison. J Allergy Clin Immunol Pract. 2016;4(5):941–47.

    Article  PubMed  PubMed Central  Google Scholar 

  6. Akuthota P, Weller PF. Eosinophils and disease pathogenesis. Semin Hematol. 2012;49(2):113–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Hernández-Benítez R, Vicencio-Rivas J, Iglesias-Leboreiro J, Martina-Luna M, Madrazo-Miranda MR, Lases-Rufeil S. Hypereosinophilic syndrome in an infant. Bol Med Hosp Infant Mex. 2019;76(3):134–7.

    PubMed  Google Scholar 

  8. Mukherjee M, Lacy P, Ueki S. Eosinophil Extracellular traps and inflammatory pathologies – untangling the web! Front Immunol. 2018;9:2763.

    Article  PubMed  PubMed Central  Google Scholar 

  9. Matoszka N, Działo J, Tokarz-Deptuła B, Deptuła W. NET and NETosis – new phenomenon in immunology. Postep Hig Med Dosw. 2012;66:437–45.

    Article  Google Scholar 

  10. Bałajewicz-Nowak M, Glanowska I, Hosiawa V, Pityński K, Ludwin I. Eosinophilic ascites: a case report and literature review. Curr Gynecol Oncol. 2018;16:57–63.

    Article  Google Scholar 

  11. Juan He W, Zhou H, Lv L, Tao X-W, Chen P, Wang. A case of severe hypereosinophilia in a term infant. Int J Clin Exp Med. 2018;11(9):10150–55.

    Google Scholar 

  12. Krous HF, Haas E, Chadwick AE, Wagner GN. Sudden death in a neonate with idiopathic eosinophilic endomyocarditis. Pediatr Dev Pathol. 2005;8(5):587–92.

    Article  PubMed  Google Scholar 

  13. Sy AM, Omobomi O, Lenox T, Bergasa NV. Acute cytomegalovirus hepatitis in an immunocompetent host. BMJ Case Rep 2013; 2013:bcr2013201939.

  14. Roberts T, Linenberger M, Chen X. Atypical lymphocytes and eosinophilia in primary cytomegalovirus Mononucleosis. Br J Haematol. 2015;171(4):441.

    Article  PubMed  Google Scholar 

  15. Takeyama J, Abukawa D, Miura K. Eosinophilic gastroenteritis with cytomegalovirus infection in an immunocompetent child. World J Gastroenterol. 2007;13(34):4653–54.

    Article  PubMed  PubMed Central  Google Scholar 

  16. Ramelli GP, Gebbers JO, Tönz O. Chronische, letal verlaufende zytomegalievirus-erkrankung mit hypereosinophilie und multiplem Organbefall Nach Neonataler Infektion [Chronic, fatal, neonatally-acquired cytomegalovirus disease with hypereosinophilia and multiple organ involvement]. Schweiz Med Wochenschr. 1990;120(17):632–40.

    CAS  PubMed  Google Scholar 

  17. Magalhães SM, Duarte FB, Vassallo J, Costa SC, Lorand-Metze I. Multiple lymphoid nodules in bone marrow biopsy in immunocompetent patient with cytomegalovirus infection: an immunohistochemical analysis. Rev Soc Bras Med Trop. 2001;34(4):365–8.

    Article  PubMed  Google Scholar 

  18. Domachowske JB, Dyer KD, Bonville CA, Rosenberg HF. Recombinant human eosinophil-derived neurotoxin/RNase 2 functions as an effective antiviral agent against respiratory syncytial virus. J Infect Dis. 1998;177(6):1458–64.

    Article  CAS  PubMed  Google Scholar 

  19. Rosenberg HF, Domachowske JB. Eosinophils, ribonucleases and host defense: solving the puzzle. Immunol Res. 1999;20(3):261–74.

    Article  CAS  PubMed  Google Scholar 

  20. Ravin KA, Loy M. The eosinophil in infection. Clin Rev Allergy Immunol. 2016;50(2):214–27.

    Article  CAS  PubMed  Google Scholar 

  21. Kobayashi A, Takasawa R, Takasawa K, Nishioka M, Kaneko M, Ono H, et al. An infant case of severe hypereosinophilia and systemic symptoms with multiple drug hypersensitivity and reactivation of cytomegalovirus and BK virus. Allergol Int. 2017;66(3):479–81.

    Article  CAS  PubMed  Google Scholar 

  22. Lopez AF, Begley CG, Williamson DJ, Warren DJ, Vadas MA, Sanderson CJ. Murine eosinophil differentiation factor. An eosinophil-specific colony-stimulating factor with activity for human cells. J Exp Med. 1986;163(5):1085–99.

    Article  CAS  PubMed  Google Scholar 

  23. Casanova JL, Holland SM, Notarangelo LD. Inborn errors of human JAKs and STATs. Immunity. 2012;36(4):515–28.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Dupuis S, Dargemont C, Fieschi C, Thomassin N, Rosenzweig S, Harris J, et al. Impairment of mycobacterial but not viral immunity by a germline human STAT1 mutation. Science. 2001;293(5528):300–3.

    Article  CAS  PubMed  Google Scholar 

  25. Dupuis S, Jouanguy E, Al-Hajjar S, Fieschi C, Al-Mohsen IZ, Al-Jumaah S, et al. Impaired response to interferon-alpha/beta and lethal viral disease in human STAT1 deficiency. Nat Genet. 2003;33(3):388–91.

    Article  CAS  PubMed  Google Scholar 

  26. Boisson-Dupuis S, Kong XF, Okada S, Cypowyj S, Puel A, Abel L, et al. Inborn errors of human STAT1: allelic heterogeneity governs the diversity of immunological and infectious phenotypes. Curr Opin Immunol. 2012;24(4):364–78.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. O’Shea JJ, Holland SM, Staudt LM. JAKs and STATs in immunity, immunodeficiency, and cancer. N Engl J Med. 2013;368(2):161–70.

    Article  PubMed  PubMed Central  Google Scholar 

  28. Baris S, Alroqi F, Kiykim A, Karakoc-Aydiner E, Ogulur I, Ozen A, et al. Severe early-onset combined Immunodeficiency due to heterozygous gain-of-function mutations in STAT1. J Clin Immunol. 2016;36(7):641–48.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references


The authors acknowledge “Tarek Hussein Elsayed Mohamed”, Karary University-College of Medicine, for the valuable sharing in preparing the manuscript.


Not applicable.

Author information

Authors and Affiliations



H.M., S.A., and Sh. S. analyzed and interpreted the patient data regarding the hematological disease. Sh S was a major contributor in writing the manuscript. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Shaimaa Salah.

Ethics declarations

Ethical approval and consent to participate

Not applicable.

Consent to publication

Consent to Publication-Written informed consent was obtained from the parents for publication of the case report and images.

Competing interests

The authors declare no competing interests.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit The Creative Commons Public Domain Dedication waiver ( applies to the data made available in this article, unless otherwise stated in a credit line to the data.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Salah, S., Alshanbari, S.N. & Masmali, H.M. A term infant with severe hypereosinophilia secondary to CMV infection and the STAT1 gene mutation: a case report. BMC Pediatr 24, 408 (2024).

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: