Referral
Subject: Referral for Evaluation of Recurrent Infections and Neutropenia in a Pediatric Patient
Dear Colleague,
I am writing to refer a 2-year-old male patient for further evaluation and management concerning his recurrent history of infections and associated haematological findings. The child has been experiencing frequent infections, nearly monthly, primarily manifesting as upper respiratory tract infections occasionally accompanied by gastrointestinal symptoms. These episodes are generally mild but have necessitated hospital admissions lasting 2 to 3 days.
Clinical History: Recurrent infections, predominantly upper respiratory, with some instances of gastrointestinal involvement.
Current Presentation: The patient’s infections, though typically mild, have been recurrent and sufficiently severe to require short hospital stays. The frequent nature of these infections raises concerns about an underlying immunological or haematological disorder.
Laboratory Findings:
- Complete Blood Count (CBC): Reveals neutropenia with the most recent absolute neutrophil count recorded at 300/microL. This finding is particularly concerning as it may be contributing to the frequency and nature of his infections.
Given the pattern of recurrent infections coupled with significant neutropenia, a detailed evaluation by a pediatric haematologist or immunologist is warranted to investigate potential underlying causes, such as congenital neutropenia, immune deficiencies, or other hematologic disorders.
The family is very concerned about the recurrent nature of his illnesses and the impact on his health and development. They are keen on understanding the underlying causes and receiving guidance on long-term management strategies.
Thank you for your attention to this referral.
Reply
Dear Colleague,
Thank you for your referral of the 2-year-old male patient for further evaluation of his recurrent infections and neutropenia. We have completed an initial assessment and subsequent investigations to elucidate the underlying cause of his haematological findings.
Clinical and Family History: The patient has experienced multiple episodes of mild infections, primarily upper respiratory, which have been managed with antibiotics and supportive care. There is no history of severe infections, recurrent abscesses, candida infections, or chronic diarrhoea. Additionally, there is no significant family or social history of similar conditions or other haematological disorders.
Physical Examination: Upon examination, the child appeared well, active, and thriving. He showed no dysmorphic features or skeletal anomalies. Notable findings include a congested throat and small cervical lymph nodes measuring 0.5×0.5 cm, but no organomegaly or other lymphadenopathy was observed. The chest was clear, and the abdomen was soft and lax.
Recommended Management Plan:
- Ongoing Monitoring: CBC three times weekly for the next 6 weeks and regular reticulocyte counts to closely monitor his haematological status, in addition to virology screening, peripheral blood film, serum immunoglobulins, ANA, anti ds-DNA antibodies.
- Supportive Care: Continue with supportive care during episodes of neutropenia to prevent infections and manage symptoms.
Initial Impression:
Neutropenia for work up.
Investigation Results and Follow-up
- Neutropenia: Persistent, with counts as low as 300/microL.
- Anaemia: Mild, microcytic hypochromic anaemia was noted.
- Other Tests: Virology screening for common pathogens (HIV, Hepatitis A, B, C, Parvovirus B19, Varicella, CMV, EBV) returned negative. Anti-neutrophil antibody, Anti-nuclear antibody (ANA), and complement levels (C3, C4) were also negative. A blood film confirmed neutropenia without any abnormal cells. Serum immunoglobulins were within normal limits.
Given the pattern of neutropenia, which intensifies approximately every four weeks, and moderate neutrophil counts observed intermittently, further genetic testing was performed. This testing revealed a mutation in the ELA2 gene, confirming the diagnosis of cyclic neutropenia.
Recommendations:
Genetic Counselling: Due to the genetic nature of the diagnosis, referral to genetic counselling is recommended for the family to discuss the implications and management of cyclic neutropenia.
Follow-Up: The child will require ongoing monitoring and management of his condition, including potential interventions during periods of severe neutropenia to prevent infection and manage symptoms effectively.
Discussion
Neutropenia, characterized by a reduction in circulating neutrophils in the non-marginal pool which comprises about 4-5% of total body neutrophil stores, is a significant haematological condition with potential severe clinical implications. Most neutrophils are sequestered in the bone marrow either as mitotically active cells or as mature post-mitotic cells. While granulocytopenia encompasses a broader spectrum, including reductions in neutrophils, eosinophils, and basophils, it is often synonymous with neutropenia, focusing predominantly on the neutrophil lineage.
Clinical Presentation and Diagnosis: Neutropenia is typically identified in patients presenting with fever or recurrent bacterial infections and can also be discovered during routine laboratory evaluations or during assessments for other medical conditions. Confirmatory diagnosis requires repeat testing including a complete blood count (CBC), differential count, and a detailed manual review of a peripheral blood smear.
Here are some of the main types of neutropenia:
- Congenital Neutropenia:
- Severe Congenital Neutropenia (Kostmann Syndrome): A genetic disorder characterized by extremely low levels of neutrophils and a high susceptibility to infections from birth.
- Cyclic Neutropenia: A condition where neutrophil levels cyclically drop significantly every few weeks, leading to periodic increased risk of infections.
- Congenital Dysgranulopoietic Neutropenia: A group of disorders where neutropenia is due to ineffective granulopoiesis in the bone marrow.
- Acquired Neutropenia:
- Autoimmune Neutropenia: The immune system develops antibodies that destroy neutrophils. This type can occur in adults and children.
- Drug-induced Neutropenia: Certain medications, including chemotherapy drugs, antibiotics, and antipsychotics, can cause neutropenia as a side effect.
- Infection-induced Neutropenia: Various bacterial and viral infections can temporarily reduce neutrophil count.
- Idiopathic Neutropenia:
- Chronic Idiopathic Neutropenia: A diagnosis of exclusion when no specific cause of long-lasting neutropenia is found, and where the bone marrow typically shows maturation arrest of granulocytes.
- Isoimmune Neutropenia:
- Neonatal Isoimmune Neutropenia: Occurs when maternal antibodies against foetal neutrophil antigens cross the placenta and destroy foetal neutrophils.
- Secondary Neutropenia:
- Often a result of underlying disorders such as aplastic anaemia, large spleen (splenomegaly), or certain cancers that interfere with bone marrow function.
- Nutritional Neutropenia:
- Deficiencies in vital nutrients like vitamin B12, folate, or copper can lead to reduced neutrophil production.
Congenital Forms of Neutropenia:
- Severe Congenital Neutropenia (SCN): Often suspected in infants due to early onset of severe bacterial infections within the first year of life, with an absolute neutrophil count (ANC) consistently below 200/microliter. Clinical manifestations might include omphalitis post-birth, recurrent otitis media, pneumonitis, and skin or liver abscesses. Patients with SCN frequently suffer from aphthous stomatitis and gingival hyperplasia, which may lead to early loss of permanent teeth.
- Cyclic Neutropenia: This condition features a regular cycle of neutropenia approximately every 21 days. During periods of neutrophil nadir, patients may exhibit symptoms such as malaise, fever, mucosal ulcers, cervical adenopathy, and localized abscesses. Diagnosis is typically confirmed through documentation of ANC below 200/microliter over several cycles, measured at least twice weekly for six to eight weeks. Genetic testing for mutations in the ELANE gene, which are found in 90-100% of cases, can confirm the diagnosis.
Management Strategies: The American Society of Clinical Oncology (ASCO) provides guidelines for managing patients with profound neutropenia, particularly those at risk of infections. For outpatients with profound neutropenia (ANC below 100/µL for more than seven days) without fever, prophylactic measures including antibacterial and antifungal prophylaxis are recommended. Preferred agents include oral fluoroquinolones for bacterial infections and oral triazoles for fungal infections. These guidelines also emphasize the need for careful assessment of patients with febrile neutropenia to determine the necessity of full hospitalization, utilizing tools such as the MASCC scoring system or Talcott’s rules to evaluate complication risks.
Advanced Care Considerations: For patients with cyclic or severe congenital neutropenia, the focus extends beyond managing acute infections to include monitoring for potential complications like organ damage and transformation to more severe bone marrow disorders. Regular follow-ups and comprehensive care are critical to manage the cyclic patterns of neutropenia effectively and to prevent severe infections and other complications.
In conclusion, neutropenia, particularly when congenital, requires meticulous clinical attention and management to mitigate the risks associated with severe infections and to improve overall patient outcomes. The establishment of a precise diagnosis through thorough clinical and laboratory evaluation, followed by targeted treatment and preventive strategies, is essential in the care of patients with this condition.
Read More Articles About Neutropenia
Diagnosis and therapeutic decision- making for the neutropenic patient
How to approach neutropenia
The European Guidelines on Diagnosis and Management of Neutropenia in Adults and Children: A Consensus Between the European Hematology Association and the EuNet-INNOCHRON COST Action
Check the correct answers.
Question-1:
Correct Answer: B) Cyclic neutropenia
Explanation: Cyclic neutropenia is a disorder characterized by regular and predictable episodes of severe neutropenia that occur approximately every three weeks (21 days). This condition is most commonly associated with mutations in the ELANE gene, which encodes a neutrophil elastase. This periodic drop in neutrophil counts often leads to increased susceptibility to infections during the nadir of the cycle. Kostmann syndrome, also associated with mutations in the ELANE gene, presents as severe congenital neutropenia but does not have the cyclic pattern observed in cyclic neutropenia. Shwachman-Diamond syndrome and Chediak-Higashi syndrome involve neutropenia but are distinguished by additional systemic manifestations and different genetic mutations.
Question-2:
Correct Answer: B) Immediate initiation of broad-spectrum antibiotics
Explanation: In pediatric patients presenting with severe chronic neutropenia and signs of acute infection, such as fever and oral ulcers, the immediate initiation of broad-spectrum antibiotics is critical to manage potential bacterial infections, which can rapidly become life-threatening due to the impaired immune response associated with low ANC levels. This approach is essential to cover a wide range of potential bacterial pathogens until specific causative agents can be identified and targeted treatments can be adjusted accordingly. While the administration of granulocyte colony-stimulating factor (G-CSF) is crucial for long-term management to increase neutrophil counts and reduce the frequency and severity of infections, it does not address the immediate risk of infection. IVIG and corticosteroids are not primary treatments for acute bacterial infections in the context of severe neutropenia.
References
- Beutler E, Lichtman MA, Coller BS, Kipps TJ, eds. Williams Hematology. 5th Ed. New York, NY: McGraw-Hill; 1995. 815-24, 844-58.
- Lee GR, Foerster J, Lukens J, et al, eds. Wintrobe’s Clinical Hematology. 10th ed. Philadelphia, Pa: Lippincott Williams & Wilkins; 1999. Vol 2: 1862-82.
- Palmer SE, Stephens K, Dale DC. Genetics, phenotype, and natural history of autosomal dominant cyclic hematopoiesis. Am J Med Genet 1996; 66:413
- Mulcahy N. New ASCO Guideline on Neutropenia and Fever. Medscape Medical News. Jan 16 2013. Available at http://www.medscape.com/viewarticle/777736. Accessed: January 22, 2013.
- Flowers CR, Seidenfeld J, Bow EJ, et al. Antimicrobial Prophylaxis and Outpatient Management of Fever and Neutropenia in Adults Treated for Malignancy: American Society of Clinical Oncology Clinical Practice Guideline. J Clin Oncol. 2013 Jan 14.
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