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:

Patients produce systemic and mucosal antibodies after SARS-CoV-2 infection. In the context of ongoing public health measures and vaccination programs, it is crucial to explore practical methods to monitor this humoral immunity. Following our earlier findings of heterogeneity in serum and saliva SARS-CoV-2 antibodies in 2020, we now describe antibody prevalence in serum and saliva of children one year after the beginning of the pandemic and explore associations.

Methods

We assessed SARS-CoV-2 antibody prevalence in serum and saliva of 223 children attending medical services in the Netherlands (irrespective of COVID-19 exposure) from May - October 2021. The cohort included vaccinated and unvaccinated children (< 18 years old) and was compared to 517 unvaccinated children from the April - October 2020 cohort. We measured SARS-CoV-2 spike- and nucleocapsid-specific IgG prevalence in serum and saliva.

Results:

Our cohort contained 75% unvaccinated children, 18% with a PCR-proven history of COVID-19, and a 1:1 male-female ratio. Antibody prevalence increased from 3-4% in both serum and saliva in 2020 to 38% (95% CI 31 - 45) in serum and 31% (95% CI 25 - 38) in saliva in 2021. Paired analysis (figure 1) showed positive titers in both serum and saliva in 53/196 (27%). Prevalence of spike and nucleocapsid-specific IgG was significantly lower in saliva compared to serum (P<0.05). Girls showed a higher prevalence of saliva antibodies as compared to boys (OR 2.26 corrected for age, vaccination status, comorbidity, positive PCR).

Conclusions/Learning Points:

SARS-CoV-2 antibody prevalence in children increased in serum and saliva between 2020 and 2021 in the Netherlands. We observed lower SARS-CoV-2 antibody prevalence in saliva compared to serum, which should be taken into account when evaluating humoral immunity.

Backgrounds:

Infants may develop severe viral respiratory tract infections because their immune system is still undeveloped. Human milk provides passive humoral immunity during the first months of life. During the COVID-19 pandemic, circulation of common respiratory viruses was virtually absent due to the preventative measures resulting in reduced maternal exposure. Therefore, we hypothesized that this might result in lower antibody levels in human milk during the pandemic and, subsequently, decreased protection of infants against viral respiratory tract infections.

Methods

We assessed antibody levels against respiratory syncytial virus (RSV), Influenza virus, and several seasonal coronaviruses in different periods of the COVID-19 pandemic in serum and human milk using a Luminex assay.

Results:

IgG levels against RSV, Influenza, HCoV-OC43, HCoV-HKU1, and HCoVNL63 in human milk were reduced with a factor of 1.7 (p<0.001), 2.2 (p<0.01), 2.6 (p<0.05), 1.4 (p<0.01), and 2.1 (p<0.001), respectively, since the introduction of the COVID-19 restrictions. Furthermore, we observed that human milk of mothers that experienced COVID-19 contained increased levels of IgG and IgA binding to other respiratory viruses.

Conclusions/Learning Points:

Passive immunity via human milk against common respiratory viruses was reduced during the COVID-19 pandemic, which may put breastfed infants at increased risk for respiratory infections.

Backgrounds:

Vaccination of lactating women against COVID-19 may protect not only themselves but also their breast-fed infant through human milk. Therefore, it is important to gain insight into the human milk antibody response after immunization with the various vaccines that are currently widely used. The aim of this study is to determine and compare the antibody response in human milk following vaccination with mRNA- and vector-based vaccines up to over 2 months post-vaccination.

Methods

In this prospective cohort study, human milk samples from women receiving four different SARS-CoV-2 vaccines were collected longitudinally during a period of 70 days. SARS-CoV-2-specific antibodies were measured using an enzyme-linked immunosorbent assay. The area under the curve of the antibody response was determined over 15 and 70 days following vaccination and compared between the different vaccines.

Results:

This study enrolled 134 vaccinated lactating women, who provided a total of 1887 human milk samples. After vaccination with an mRNA-based vaccine, almost all participants (96/97%) showed detectable SARS-CoV-2-specific antibodies in their milk, whereas only 37-50% of the participants who received a vector-based vaccine showed human milk antibodies. The mean area under the curve of SARS-CoV-2-specific antibodies in human milk over 70 days was the highest after vaccination with an mRNA-based vaccine.

Conclusions/Learning Points:

Maternal vaccination during lactation with an mRNA-based vaccine resulted in higher SARS-CoV-2 IgA and IgG responses in human milk compared to vector-based vaccines. Therefore, vaccination with mRNA-based vaccines might not only provide better immunological protection for the mother but also for her breast-fed infant.