key: cord-272143-6ej3eibd
authors: Benavides‐Nieto, Marta; Méndez‐Echevarría, Ana; del Rosal, Teresa; García‐García, María Luz; Casas, Inmaculada; Pozo, Francisco; de la Serna, Olga; Lopez‐Granados, Eduardo; Rodriguez‐Pena, Rebeca; Calvo, Cristina
title: The role of respiratory viruses in children with humoral immunodeficiency on immunoglobulin replacement therapy
date: 2018-12-21
journal: Pediatr Pulmonol
DOI: 10.1002/ppul.24214
sha: 
doc_id: 272143
cord_uid: 6ej3eibd

BACKGROUND: The role of viruses in children with respiratory tract infections and humoral immunodeficiencies has hardly been studied. We have evaluated these infections in children with humoral immunodeficiencies who required immunoglobulin replacement therapy, considering their relationship with symptoms, lung function, bacterial co‐infection, and outcomes. METHODS: We conducted a prospective case‐control study during a 1‐year period, including children with humoral immunodeficiencies receiving immunoglobulin replacement therapy. For each patient, at least one healthy family member was included. Respiratory samples for viral detection were taken every 1‐3 months, and in case of respiratory tract infections. Symptoms questionnaires were filled biweekly. Spirometry and sputum culture were performed in every episode. RESULTS: Sixty‐six episodes were analyzed in 14 patients (median age 12 years; IQR 7‐17), identifying 18 respiratory viruses (27.3%), being rhinovirus the most frequently isolated one (12/18; 66%). Positive viral episodes were associated with clinical symptoms (89% vs 43%), more frequent antibiotic treatment (44% vs 15%) or hospital admission (22% vs 0%) than negative ones. Patients with positive viral detection showed impaired lung function, with lower FEV1 and FVC values. CONCLUSIONS: In our experience, viral respiratory tract infections can cause significant respiratory symptoms and impaired lung function, in children with HID, despite immunoglobulin replacement therapy. These patients could benefit from the monitoring of viral infections, as these may be a gateway for ongoing lung damage.

Children with severe T-cell immunodeficiencies present impaired clearance of respiratory viruses, and pulmonary complications of viral infections are leading causes of morbidity and mortality in this group of patients. 1 However, the role of respiratory viruses in children with other types of primary immunodeficiency (PID), mainly those with humoral immunodeficiencies (HID) or diseases of immune dysregulation, has hardly been studied.

Children with HID usually suffer from recurrent bacterial respiratory infections, resulting in progressive bronchiectasis and chronic lung disease. [2] [3] [4] [5] Immunoglobulin replacement therapy (IRT) reduces the frequency of these infections. However, despite adequate IRT, recurrent respiratory infections are still one of the leading causes of morbidity and mortality in these patients. [2] [3] [4] Little data are currently available regarding the susceptibility to respiratory viruses of hypogammaglobulinemic patients receiving IRT. 4, 6, 7 However, some other viruses have been described which play significant roles in these patients. [8] [9] [10] [11] Human herpesvirus 8 (HHV-8) has been associated with granulomatous/lymphocytic interstitial lung disease (GLILD) in patients with common variable immunodeficiency (CVID), 8 and enterovirus is a known cause of fatal meningoencephalitis in patients with X-linked agammaglobulinemia (XLA). 9, 10 In addition, there are several recent reports showing an increased susceptibility to viral respiratory infections in adults with CVID receiving IRT, 4-7 that can contribute to chronic and persistent pulmonary inflammation. 2, 7 We report, to the best of our knowledge, the first study that analyses respiratory viruses in pediatric patients with predominantly antibody deficiency who required IRT, considering their relationship with clinical symptoms and pulmonary function, bacterial co-infection, treatment and outcomes.

We conducted a prospective case-control single-center study during 1 year (November 2016 to October 2017) in a National Reference Unit for PID in Madrid, Spain.

We included patients less than 18 years of age diagnosed with HID who required IRT. Patients with combined immunodeficiency and/or reduced proliferative responses to mitogens (PHA, PWM, ConA) were excluded. Patients with HID who did not require IRT and/or patients receiving immunosuppressive treatments other than rituximab were excluded.

Committee. Informed consents were obtained from patients and parents.

For each patient, a healthy control was included, usually one of their parents. Respiratory samples (nasopharyngeal aspirate [NPA] for patients and nasopharyngeal swab for controls) were obtained every one to three months, coinciding with intravenous immunoglobulin administration or outpatient clinic evaluations, both in the patient and in the control group. Other investigations performed during the same visit in the patient group included: spirometry (in patients older than 5 years), spontaneous sputum culture (in patients older than 10 years), IgG levels, full blood count (FBC), C-reactive protein, and erythrocyte sedimentation rate (ESR).

If patients developed respiratory symptoms between visits, additional sputum culture and nasopharyngeal aspirates were performed in the first 3 days after symptom onset, as well as an additional spirometry. In children older than 10 years of age who needed antibiotic for treating respiratory infections, the sputum samples were obtained before starting the therapy. Every moment in which a respiratory sample was obtained from a patient was defined as an episode.

Symptoms questionnaires elaborated ad hoc were filled out systematically biweekly by patients and controls, recording fever, increased respiratory secretions, cough, respiratory distress, sputum Three independent RT-PCR assays were performed to detect sixteen respiratory viruses as previously published by our group. [12] [13] [14] Influenza A, B, and C viruses were detected by using previously described primer sets only to amplify influenza viruses in a multiplex PCR assay. 12 A second multiplex PCR was used to detect parainfluenza viruses 1-4, human coronaviruses 229E and OC43, enteroviruses, and rhinoviruses (RV). 13 Presence of respiratory syncityal virus (RSV) A and B types, human metapneumovirus, human bocavirus, and adenoviruses were investigated by a third multiplex RT-nested PCR-BRQ method. 14 Spontaneous sputum samples were collected using sterile specimen containers and immediately processed or stored at 4°C until BENAVIDES-NIETO ET AL. | 195 processing was feasible. Samples were cultured on standard media, and potential respiratory tract pathogens were identified and tested for antimicrobial susceptibility.

Pulmonary function tests were performed on all patients at study entry and repeated with every sample collection. Spirometry was performed according to established guidelines 15 16 

During the study period, 14 patients with predominantly antibody deficiency were included (5 girls and 9 boys). Their main immunological diagnoses are reported in Table 1 .

The median age of patients was 12 years (IQR 7-17), and only two of them were younger than 5 years. Eleven patients were receiving intravenous IRT and three patients, subcutaneous IRT. Immunological status at inclusion is described in Table 2 .

Eighteen healthy adult family members (mother and/or father) of the patients were included as healthy control subjects (at least one control per case included). On the other hand, other authors have hypothesized that persistent and recurrent viral respiratory infections could adversely affect the microbiome, leading to an increased bacterial density in children's nasopharyngeal tract, predisposing to sinopulmonary bacterial infections. 17, 18 As other authors, 4 we recommend screening for viral infection in children with HID and acute respiratory symptoms to avoid unnecessary antibiotic treatment. However, viral testing is routinely performed only in children with severe combined immunodeficiency (SCID). 1, 4 Regarding HID, protocols present a great deal of variation across Europe in the management of lung complications. 19 There is an urgent need for consensus guidelines on how to monitor lung complications and how to treat respiratory infections in HID patients. 19 Not all our patients were typical HID such as XLA or CVID. Three of our cases were SCID patients who had received a hematopoietic cell transplant, but presented persistent B-cell lymphopenia and hypogammaglobulinemia. Although most children with SCID recover cellular immunity 1 year after transplantation, many patients are likely to be on IRT for a considerable period until full reconstitution of B-cell immunity has been achieved. 20,21 B-cell immune reconstitution and its consequences regarding viral respiratory infections have not been deeply investigated in these patients. Our data support that these patients are also prone to viral respiratory infections, which impact lung function and lead to antibiotic consumption. Another patient was an AD-HIES. Regarding humoral immunity, many patients with AD-HIES require immunoglobulin infusions due to memory B-cell lymphopenia and decline in specific antibody titers. 22 Recurrent respiratory tract infections have been described in these children, and more than 90% of them develop pneumonia. 22 Although bacteria are detected in 44% of respiratory exacerbations, viral pneumonia has also been reported. 22 Lung sequelae in these patients are frequent, mainly as bronchiectasis. 22 Thus, monitoring viral infections in these children may be important.

One patient in our series suffered from APDS2. While the disease is heterogeneous, respiratory infections and their complications are frequent and often severe. 23 The spectrum of pathogens is highly reminiscent of other primary antibody deficiency syndromes such as CVID. 23 Coulter et al 24 seem to play a role in children with HID, as has also been described in adults. 7, 17 Further studies are needed to improve our knowledge about the impact of respiratory viral infections, their prevention and management in children with IRT, with the aim of avoiding short-and longterm consequences. 

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The role of respiratory viruses in children with humoral immunodeficiency on immunoglobulin replacement therapy

To Claire Marsden for the revision of the English language. This study has been partially supported by FIS (Fondo de Investigaciones Sanitarias-Spanish Health Research Fund) Grant No. PI15CIII/00028.

The authors declare no conflict of interest.