Title of Case(s):

Fever of unknown origin: was it the plane, the parent or the parrot?

Background:

Fever of unknown origin can be a puzzling clinical presentation, especially if signs and symptoms are atypical and if there are multiple potentially relevant exposures.

Case Presentation Summary:

A 10-year-old girl presented with a history of fever for nine days and painful joints. She also reported lower abdominal pain, night sweats and weight loss. A close contact had recently been diagnosed with pulmonary tuberculosis and she had travelled to Suriname prior to presentation. The family history was positive for auto-immune diseases and the patient had a parrot at home.

On physical examination, she was pale and had a temperature of 38.6C, examination was otherwise unremarkable. CRP was 19 mg/L, ESR 35 mm/hr, white cell count 3.5x109/L, haemoglobin 7.0 mmol/L, platelets 201x109/l and ferritin 1209 ug/L. A peripheral blood film showed atypical lymphocytes, no blasts. Abdominal ultrasonography showed enlarged lymph nodes around the aorta and the right iliac artery. Chest X-ray was normal.

Extensive microbiological work-up including testing for tuberculosis did not yield any positive results. A positron emission tomography CT scan showed lymphadenopathy with enhanced fluorine-18-deoxyglucose uptake in both axillae, abdominally and in the left tonsil and mild poly-arthritis in the feet and hands.

A bone marrow biopsy showed normocellular bone marrow with reactive lymphocytosis and hemophagocytosis, but no signs of malignancy. Subsequently, a lymph node from the right axilla was excised for histopathological analysis. This showed a necrotising histiocytic lymphadenitis, typical for Kikuchi disease. She was treated conservatively and recovered swiftly without sequelae.

Key Learning Points:

Kikuchi disease is a rare and generally benign condition of uncertain aetiology that presents with non-specific symptoms including fever and lymphadenopathy. Clinical presentations can vary, and lymph node biopsy is required for definitive diagnosis. When tumour is the rumour, tissue is the issue.

Backgrounds:

The diagnosis of pulmonary tuberculosis (TB) remains difficult in young children. Rapid biomarker-based tests using non-sputum samples are needed. The role of biomarkers in saliva for diagnosing TB in children has not been fully explored.

Methods

We conducted a review of available studies on the use of host-based salivary biomarkers for diagnosing active pulmonary TB in children and adults.

Results:

We found nine studies on salivary host diagnostic biomarkers, one of which involved children. Three studies evaluated the diagnostic performance of antibodies in saliva to antigens of Mycobacterium tuberculosis, with disappointing results. Six studies measured salivary levels of selected cytokines, growth factors, enzymes and other proteins and found that combinations of these markers showed potential in reaching WHO-endorsed performance criteria for a TB triage test. An eight-marker biosignature comprising of salivary granzyme A, growth differentiation factor 15, serum amyloid A, epithelial-neutrophil activating peptide 78, plasminogen activator inhibitor-1, IL-12(p40), IL-13 and IL-21, was most promising and had a sensitivity of 93% and specificity of 100%.¹

(1) Jacobs et al. Diagnostic Potential of Novel Salivary Host Biomarkers as Candidates for the Immunological Diagnosis of Tuberculosis Disease and Monitoring of Tuberculosis Treatment Response. PLoS One. 2016.

Conclusions/Learning Points:

Saliva could be a valuable diagnostic specimen for diagnosing pulmonary TB in children, however little research in this population exists. Based on adult data, combinations of cytokines and other proteins demonstrate promise as new triage tests for TB. Given the differing TB immune response in children, studies in paediatric populations are now needed. The ready availability of saliva and non-invasive nature of collection is especially appealing for young children. Future directions and suggestions for technologies for salivary biomarker discovery and point-of-care test development are discussed.

Backgrounds:

Despite recent advances in diagnostics, childhood tuberculosis (TB) remains underdiagnosed. The novel lateral flow FujiLAM assay detects lipoarabinomannan (LAM) in urine and its sensitivity for the diagnosis of pulmonary TB was found to be higher compared to AlereLAM in adults. However, data on its performance in children is limited.

Methods

We conducted a systematic review assessing the diagnostic performance of FujiLAM for diagnosing paediatric TB, using AlereLAM as a comparator. The last search was conducted in November 2021.

Results:

We identified three studies with data from 698 children for FujiLAM and 619 for AlereLAM. For FujiLAM, pooled sensitivity and specificity using a microbiological reference standard (MRS) were 51% (95%CI 43-59) and 87% (95%CI 84-90), respectively, and 27% (95%CI 23-32) and 87% (95%CI 82-90) using a composite reference standard (CRS). For AlereLAM, sensitivity and specificity were 41% (95%CI 33-50) and 83% (95%CI 79-86) for MRS, and 32% (95%CI 27-37) and 88% (95%CI 84-92) for CRS. Subgroup analyses for FujiLAM suggested an increased sensitivity in children living with HIV, especially when immunocompromised.

Conclusions/Learning Points:

This is the first systematic review of the diagnostic performance of FujiLAM in children, indicating a moderate but potentially superior sensitivity compared to AlereLAM. Our review emphasizes the points to be addressed in forthcoming evaluations, namely the need for prospective assessments from several geographical regions, rigorous application of reference standards, and specific subgroup analyses in children living with HIV and extrapulmonary TB. As an instrument-free point-of-care test that uses an easy to obtain specimen, FujiLAM has the potential to improve TB diagnosis in children, particularly in low-resource settings.

Title of Case(s):

Fever of unknown origin: was it the plane, the parent or the parrot?

Background:

Fever of unknown origin can be a puzzling clinical presentation, especially if signs and symptoms are atypical and if there are multiple potentially relevant exposures.

Case Presentation Summary:

A 10-year-old girl presented with a history of fever for nine days and painful joints. She also reported lower abdominal pain, night sweats and weight loss. A close contact had recently been diagnosed with pulmonary tuberculosis and she had travelled to Suriname prior to presentation. The family history was positive for auto-immune diseases and the patient had a parrot at home.

On physical examination, she was pale and had a temperature of 38.6C, examination was otherwise unremarkable. CRP was 19 mg/L, ESR 35 mm/hr, white cell count 3.5x109/L, haemoglobin 7.0 mmol/L, platelets 201x109/l and ferritin 1209 ug/L. A peripheral blood film showed atypical lymphocytes, no blasts. Abdominal ultrasonography showed enlarged lymph nodes around the aorta and the right iliac artery. Chest X-ray was normal.

Extensive microbiological work-up including testing for tuberculosis did not yield any positive results. A positron emission tomography CT scan showed lymphadenopathy with enhanced fluorine-18-deoxyglucose uptake in both axillae, abdominally and in the left tonsil and mild poly-arthritis in the feet and hands.

A bone marrow biopsy showed normocellular bone marrow with reactive lymphocytosis and hemophagocytosis, but no signs of malignancy. Subsequently, a lymph node from the right axilla was excised for histopathological analysis. This showed a necrotising histiocytic lymphadenitis, typical for Kikuchi disease. She was treated conservatively and recovered swiftly without sequelae.

Key Learning Points:

Kikuchi disease is a rare and generally benign condition of uncertain aetiology that presents with non-specific symptoms including fever and lymphadenopathy. Clinical presentations can vary, and lymph node biopsy is required for definitive diagnosis. When tumour is the rumour, tissue is the issue.