Title of Case(s)

Treatable and underdiagnosed case of Systemic Inflammatory Response Syndrome(SIRS)

Background

Hemophagocytic lymphohistiocytosis (HLH) is a rare but aggressive and potentially fatal condition characterized by excessive immune activation which has variable clinical presentation and lack specific symptoms and signs but prompt initiation of treatment is essential for the survival of affected patients. It can occur by familial and acquired form. Infections can play a role as triggers in the secondary form of HPLS. A case of HLH associated with scrub typhus is being reported here which is very rare.

Case Presentation Summary

Child was admitted with complaints of fever, cough and vomiting for 4 days and was suspected to have Scrub typhus in view of generalised lymphadenopathy and hepatomegaly. Baseline investigations showed low hemoglobin with leucopenia and thrombocytopenia. In view of fever with hepatomegaly, child was started on Inj.ceftriaxone ,T.Doxycycline after sending blood culture. Scrub IgM was reactive. Blood and urine culture showed no growth after 48 hours of incubation period. So IV antibiotic was stopped and T.doxycycline continued for 7 days. In view of persistent continuous fever spikes more than 5 days, hepatomegaly and bicytopenia, HLH work up was done which showed high ferritin(544 ng/ml), hypertriglyceridimia, hypofibrinogenemia.She was suspected to have Secondary HLH following scrub typhus. Bone marrow aspiration was done which showed neutophilic precursor within macrophage (Hemophagocytic activity) which was strongly diagnostic of HLH. Hence, she was given 1 dose of Intravenous Immunoglobulin. Blood counts were monitored serially which showed platelets counts were in increasing trend. Repeat CRP was negative and LDH was found to be in decreasing trend. The child improved symptomatically and was discharged.

Key Learning Points

Rapid defervescence was noted in patient with HLH associated with scrub typhus, although much remains unknown. We recommend that clinicians should be aware of the local epidemiology of scrub typhus and the potential for patients to develop HLH as a complication and treat patients promptly.

Title of Case(s)

Two brothers with recurrent abscesses

Background

Chronic granulomatous disease (CGD) is a rare primary immunodeficiency. It predisposes to abscess formation with coagulase positive microorganisms, fungal infections and granuloma formation in the bowel wall, mimicking Crohns disease (CD). Mortality is high, but decreases on treatment.

Case Presentation Summary

A 10 year old boy diagnosed with CD presented to the pediatric emergency with fever and abdominal pain. The patient was currently on treatment with Azathioprin, 5-ASA and Prednisolone. At arrival CRP was 120 and abdominal CT showed a liver abscess. He was admitted and started on Piperacillin/Tazobactam. The abscess was surgically drained and Staphylococcus aureus grew on culture. Treatment was switched to Clindamycin and he gradually improved.

On further questioning it was revealed that the boy, starting at age 3, had recurrent skin infections with Staphylococcus aureus in the nasal and rectal region. The recurrent infections in the rectal area had prompted a colonoscopy revealing granulomas, leading to diagnosis of CD.

The patient’s 16 year old brother was also previously diagnosed with CD. Since the age of 1 he had been treated for abscesses in the liver, mediastinum and lung.

Evaluation of oxidative burst activity was performed on both brothers, confirming the diagnosis of CGD. They are currently on Trimethoprim-Sulfamethoxazole and Itraconazole prophylaxis awaiting bone marrow transplantation.

Key Learning Points

Even though rare, CGD should be suspected in patients with severe infections with coagulase positive microorganisms, especially in conjunction with CD. Around 20 % of CGD is X-linked. Recognition and diagnosis is of uttermost importance since TNF-alfa-inhibitors, common in the treatment of CD, could cause fatal infections in patients with CGD.

Title of Case(s)

Keep Your Ears Open

Background

Although adenosine deaminase (ADA) deficiency is extremely rare (approximately 1:375,000 -1:660,000 live births), it is the most common cause of severe combined immunodeficiency (SCID). Early diagnosis and treatment are crucial for this otherwise fatal disease.

Case Presentation Summary

Baby X was an uncomplicated term birth. His parents were Caucasian and second cousins. He failed his neonatal hearing screening bilaterally and when he returned for review of this at 9 days old, he was noted to be tachypnoeic. CXR showed right sided consolidation with bilateral opacification and he received 48 hours of benzypenicillin and gentamicin, but blood cultures and respiratory virology were negative. Bloods showed a neutropenia and lymphopenia. Differential diagnosis at this point included SCID, HIV and DiGeorge syndrome.

Lymphocyte subsets revealed a total CD3 count 4, total CD4 count 1, total CD8 0, total CD19 1 and total NK 0. Immunoglobulins showed an IgG level of 5.07 gm/l but undetectable IgA and IgM levels. A diagnosis of SCID was made in Baby X, which was later refined to ADA deficiency on finding that the ADA level was 0. He was commenced on subcutaneous immunoglobulin and enzyme replacement therapy with PEG- ADA as well as prophylactic acyclovir and co-trimoxazole.

Baby X underwent bronchoalveolar lavage which was negative for Pneumocystis jirovecii, but from which Aspergillus was isolated in addition to two colonies of Staphylococcus aureus. He was treated with ambisome and flucloxacillin with clinical improvement. Baby X’s brother was found to be a haplotype mismatch. As such, he is currently being considered for gene therapy.

Key Learning Points

ADA-SCID is an immunological emergency, and as such it can be forgotten that it is also a multi-system disease. Bilateral sensori-neural hearing loss is a very common feature and may be due to accumulation of purine substrates. In this patient, bilateral deafness was the first sign of his immunodeficiency.

Title of Case(s)

Worsening lymphadenopathy in a toddler: a sinister diagnosis?

Background

It can be difficult to know when to investigate lymphadenopathy in small children, especially given it is common with frequent coryzal illnesses in that population.

Case Presentation Summary

A two-year-old boy who presented with wheeze was noted to have incidental cervical lymphadenopathy and a two-centimeter palpable spleen. He was otherwise fit and well, born in UK to Vietnamese/Chinese parents: no recent travel, fully immunized, and thriving. He had a normal blood film, raised lymphocytes and CRP/ESR, and other parameters were normal. He responded well to salbutamol, and was discharged home with an urgent outpatient follow-up.

On follow-up he had an ultrasound that confirmed enlarged (9cm) spleen, and several large pathological-looking abdominal nodes, confirmed on CT. He was admitted ?lymphoma for biopsy and work-up. A cervical-node biopsy confirmed reactive marginal zone hyperplasia with no sign of malignancy. Further bloods confirmed ongoing raised CRP/ESR, slight microcytic anaemia.

He was discharged pending further results, which showed:
- Ongoing anaemia (DAT weakly positive)
- Raised B12 (~1600); Normal ferritin; LDH normal
- Reduced vaccine responses to pneumococcal and pertussis
- Raised IgM and IgG
- Raised CD3+ on lymphocyte subsets, otherwise normal
- HIV/Hepatitis/CMV/EBV/Mantoux/IGRA/mycoplasma PCR negative

He had ongoing intermittent fevers and worsening lymphadenopathy, so had further haematology follow-up, including a bone marrow and abdominal-node biopsy. This again showed marginal zone hyperplasia/no oncological cause. He had raised sFasL and CD4/CD8 double-negative T cells (3-5%), with normal lymphocyte apoptosis . He is awaiting primary immunodeficiency genetic results.

Key Learning Points

1) The patient demonstrates immune dysregulation. He fulfils ‘probable’ criteria for Autoimmune lymphoproliferative syndrome (ALPS), a non-malignant disorder of lymphocyte apoptosis.

2) However, ALPS is associated with lymphoma (but rarely presents with it).

3) There is ongoing concern lymphoma may be present (due to ongoing fevers): the lymph node biopsy may represent draining nodes only. He is having a PET-CT for further characterisation.

Title of Case(s)

Recurrent infections and rash

Background

The case shows how genetics explain clinical presentation.

Case Presentation Summary

A three year old boy was referred to the Children‘s Hospital Iceland due to recurrent upper respiratory tract infections (URTIs) since he was four months old. The boy was thriving normally and never had invasive infections. His younger half-brother was healthy, his mother had an undefined autoimmune disease.

Blood count and thyroid functions were normal. IgG was low but within the reference values, as were values for IgA and IgM (slightly higher). Several diagnoses were considered, including various forms of hypogammaglobulinemia.

The recurrent URTIs continued and eventually treatment with intravenous immunoglobulin (IVIG) was started. The treatment was given for a few years, discontinued during the summer and serum immunoglobulins were re-evaluated every fall. This revealed continuous low Ig´s, not increasing with age as expected.

After three years, his younger brother presented with recurrent infections and low IgM and IgA but no invasive infections.

A year later, the older boy presented with severe skin rash (erythema annulare centrifugum). The tentative diagnosis of common variable immunodeficiency (CVID) was made and whole genome sequencing (WGS) done.

WGS revealed a heterozygous mutation in the TNFRSF13B gene, a known pathogenic mutation causing CVID, IgA deficiency or hypogammaglobulinemia. The presentation is variable, attributed to other modifying genes or environmental factors. The TNFRSF13B (TNF receptor superfamily 13B) gene encodes for a transmembrane activator factor (TACI), that binding to B-cell activator factor (BAFF) or a proliferation-inducing ligand (APRIL) will induce isotype switching and/or production of Ig´s. A mutation in the TNFRSF13B gene therefore leads to malfunctioning TACI receptor and disrupts normal isotype switching and immunoglobulin production.

The brothers and their mother are currently treated with IVIG. The boy is also receiving infliximab for the rash.

Key Learning Points

The case underlines that recurrent infections and/or autoimmune reactions may often be caused by immunodeficiencies.

Title of Case(s)

When Your “Gut feeling” Tells You, It Is Not Just In Your Gut!

Background

Efficient whole-exome sequencing had identified an autosomal recessive variant of TTC7A gene in patients presenting with combined immune deficiency and multiple intestinal atresias (CID-MIA), an extremely rare condition with death occurring before 2 years of age. Here, we report a novel TTC7A mutation discovered in the Republic of Ireland.

Case Presentation Summary

A 35 weeker baby was diagnosed with small and large bowel obstruction antenatally. Exploratory laparotomy revealed multiple atretic bowel sections which required extensive resection and stoma formation. In addition to this, liver wedge biopsy at 2 months of age, confirmed total parenteral nutrition (TPN) associate liver disease. By the age of 3 months, he had undergone three laparotomies with similar histological findings; a complete loss of lumenal continuity and ongoing inflammatory process with mucosal disruption. Persistent lymphopenia associated with multiple episodes of Escherichia Coli sepsis and line-related Staphylococcus epidermidis sepsis triggered a question of possible immune dysfunction. Works of literature which were reviewed bared the correlation between multiple intestinal atresia and immune deficiency. Primary immune deficiency work-up and specific molecular genetic analysis for TTC7A gene were requested. Genetic analysis showed a novel homozygous variant of c.192deIT; p.Phe64Leufs*15, NM_020458.4, rs1476031758 in the TTC7A gene. At present, treatments have been commenced to support his immune system with intravenous immunoglobulin and prophylaxis antibiotics. He is still parenteral nutrition dependent due to the inability to establish enteral autonomy resulting from the intestinal strictures. We liaised his care with Birmingham Children’s Hospital for consideration of multi-visceral transplantation.

Key Learning Points

TTC7A gene should be evaluated in patients with gastrointestinal manifestations and immunodeficiency though we still need to decode about the function of TTC7A gene on intestinal health and how the deficiency results in T-cell and B-cell lymphocytopenia. A research continuum is vital in understanding the pathobiology of TTC7A gene in developing effective therapies for these patients.