Severe respiratory syncytial virus (RSV) infection in infants with neuromuscular diseases and immune deficiency syndromes

Paediatric Respiratory Reviews 10 (2009) 148–153

Contents lists available at ScienceDirect

Paediatric Respiratory Reviews

Review

Severe respiratory syncytial virus (RSV) infection in infants with neuromuscular diseases and immune deficiency syndromes Bernhard Resch 1,*, Paolo Manzoni 2, Marcello Lanari 3 1

Research Unit for Neonatal Infectious Diseases and Epidemiology, Division of Neonatology, Paediatric Department, Medical University of Graz, Austria Division of Neonatology and NICU, S. Anna Hospital. ASO O.I.R.M-S.Anna. Torino, Italy 3 Paediatrics and Neonatology Unit, Hospital of Imola, Italy 2

A R T I C L E I N F O

S U M M A R Y

Keywords: respiratory syncytial virus neuromuscular diseases immune deficiency syndromes lower respiratory tract infection palivizumab

Respiratory syncytial virus (RSV) is an important cause of lower respiratory tract infection (LRTI) in infants and children. There is growing evidence of severe RSV disease in infants with neuromuscular diseases and immune deficiency syndromes. Factors predisposing to a more severe course of RSV disease in neuromuscular diseases include the impaired ability to clear secretions from the airways due to ineffective cough, respiratory muscle weakness, high prevalence of gastro-oesophageal reflux and swallowing dysfunction which leads to aspiration. Similarly, pulmonary disease is a common presenting feature and complication of T-cell immunodeficiency. Infants with severe congenital and acquired immune deficiency syndromes may demonstrate prolonged viral shedding in RSV LRTI and are reported to have increased morbidity and mortality associated with RSV infection. Although not indicated in most guideline statements, palivizumab prophylaxis for these uncommon underlying conditions is under consideration by clinicians. Prospective studies are needed to determine the burden of RSV disease in these children. ß 2009 Elsevier Ltd. All rights reserved.

INTRODUCTION Respiratory syncytial virus (RSV) is an important cause of lower respiratory tract infection (LRTI) in infants and children. Fifty to 90 percent of hospitalizations for bronchiolitis, 5 to 40 percent of those for pneumonia, and 10 to 30 percent of those for tracheobronchitis are caused by RSV.1 The burden of disease is understandable, since virtually all children become infected with RSV within two years after birth, and one percent requires hospitalization.2 RSV is known to cause severe LRTI in preterm infants, children with bronchopulmonary dysplasia (BPD), and children with congenital heart disease. Palivizumab, a humanized monoclonal antibody against the F-protein of RSV given monthly over the RSV season for prophylaxis of severe RSV infections, has been shown to significantly reduce RSV-related hospitalizations and morbidity in these high-risk infants.3–5 Hence, palivizumab is recommended by the American Academy of Pediatrics (AAP) for such populations,6,7 and guidelines of many countries including Austria and Italy adopted these indications.8,9 Certain risk factors have been implicated in more severe disease that include low

* Corresponding author. Division of Neonatology, Paediatric Department, Medical University of Graz, Auenbruggerplatz 30, A-8036 Graz, Austria. Tel.: +43 316 385 81134; Fax: +43 316 385 2678. E-mail address: [email protected] (B. Resch). 1526-0542/$ – see front matter ß 2009 Elsevier Ltd. All rights reserved. doi:10.1016/j.prrv.2009.06.003

socioeconomic status, crowded living conditions, indoor smoke pollution, a family history of asthma or atopy, and perhaps infection with the A subgroup of RSV.10 Mortality rates associated with RSV infection are generally low in previously healthy infants (< 1% of those hospitalized), but increase significantly in high-risk infants11–15. Another phenomenon following early RSV LRTI comprises recurrent episodes of wheezing mimicking early childhood asthma during childhood. The prevalence of respiratory symptoms appears to diminish over the first years of life,16 but recent studies observed either reactive airway disease17 or lung function abnormalities18 even until adolescence. Additionally, there is growing evidence of severe RSV disease in infants with neuromuscular diseases19–21 and immune deficiency syndromes.22–27 This review aims to summarize current epidemiologic knowledge of the association of RSV LRTI with neuromuscular diseases and immune deficiency syndromes, to describe mechanisms behind this interaction, and to discuss strategies including palivizumab for prophylaxis of severe RSV disease in these particular groups of infants. RESPIRATORY PROBLEMS AND MORBIDITY IN INFANTS WITH NEUROMUSCULAR DISEASES Children with neuromuscular diseases that result in an impaired ability to clear secretions from the airways are at

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increased risk for more severe illness in case of respiratory viral disease. Physiologically the diaphragm is the most important inspiratory muscle, responsible for approximately 70% of ventilation at rest. Accessory muscles of inspiration include the external intercostal, scalene and sternocleidomastoid muscles. Muscles of expiration include the internal intercostal and abdominal wall muscles; these are not required during breathing at rest, due to the passive recoil properties of the thoracic cage, but are important for the generation of an adequate cough. Assuming normal function of the brain and lungs, respiratory failure will not usually occur until respiratory muscle strength has fallen to around 25 to 30% of normal. The accessory muscles can provide adequate ventilation in patients even with diaphragmatic paralysis from bilateral phrenic nerve palsy, and around half the patients with unilateral phrenic nerve palsy are entirely asymptomatic.28 In addition to reduction of airflow, respiratory muscle weakness results in a decline of the functional residual capacity of the lungs. This increases the work of breathing, because at lower volumes the lungs are less distensible. Furthermore, the reduction of lung volume alters the ventilation/ perfusion relationship, resulting in less efficient gas exchange. In patients with respiratory muscle weakness the adequacy of central respiratory drive is particularly important. The transient reduction of the respiratory drive observed during rapid eye movement (REM) sleep leads to hypopnoea, oxygen desaturation and hypercarbia in these patients with hypotonia of the accessory respiratory muscles. Once the respiratory reserve is compromised, any increase in the respiratory load can lead to diaphragmatic fatigue and respiratory failure. Factors increasing the respiratory load include increased respiratory rate (as it occurs in LRTIs or even in case of fever), increased stiffness of the lung (e.g., lung consolidation or atelectasis), and abdominal distension, for example induced by constipation.29 Children with severe neurological impairment and chronic lung disease are a disparate patient group with many causes for their respiratory problems. These patients represent a population who frequently presents to hospital and in whom there is an increasingly high expectation of intervention. Poor cough and hence difficulty in clearing secretions, recurrent LRTIs and colonisation with commensal bacteria are the main mechanisms responsible for respiratory disease in these children. They often suffer from chronic aspiration of secretions and subsequent lower airway inflammation that if unrecognised may cause bronchiectasis and lung parenchymal damage.30 The consequences of LRTI in a child with severe neurological impairment and chronic lung disease are severe. Prolonged hospital stay in this population impacts significantly on the child´s quality of life and places them at risk of acquiring further nosocomial infections.31 In summary, causes of respiratory complications in children with neuromuscular diseases include 1) low functional residual capacity due to less thoracic muscular support and normal lung recoil, 2) ineffective cough due to inspiratory muscle weakness, compromised ability to close the glottis and expiratory muscle weakness, 3) scoliosis due to decreased muscle support, 4) decreased spontaneous movement, which reduces the normal redistribution of ventilation, and 5) high prevalence of gastro-oesophageal reflux and swallowing dysfunction which leads to aspiration.32

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RESPIRATORY PROBLEMS AND MORBIDITY IN INFANTS WITH IMMUNE DEFICIENCY SYNDROMES Pulmonary disease is a common presenting feature and complication of T-cell immunodeficiency. Defective phagocyte function may either be due to hereditary defects in hydrogen peroxidase generation or to neutropenia. Neutropenia can be caused by a myelodysplastic disease itself like in Kostmann syndrome or more often be induced by myelosuppressive therapy with anti-neoplastic agents. T-cells control phagocytic function as well as antibody production, being also able to kill infected cells. Thus, T-cell defects implicate a wide variety of immune abnormalities including opportunistic infections, autoimmune disease, and increased incidence of neoplasia. In prospectively studied HIV patients, acute viral bronchitis was found to be the most frequent respiratory problem followed by bacterial pneumonia42 and regular supplementation of immune globulins was demonstrated to significantly reduce the occurrence of bacterial infections.33 The most frequent opportunistic pathogen is Pneumocystis jirovecii, but bronchoalveolar lavage fluid should also be tested for viruses including cytomegalovirus, RSV, herpes simplex virus, parainfluenza, influenza and adenovirus.34 In a retrospective review including 15 children with severe combined immune deficiency (SCID) and 19 with DiGeorge syndrome at the time of their first presentation during a 15-year period from 1981 to 1995 pulmonary disease was a common presenting feature.35 Thirteen of 15 children with SCID (87%) developed pulmonary disease during the time of observation, nine children died and pulmonary disease was the primary cause of death in five of them. Six children presented with chronic cough from persistent respiratory tract infection and four with respiratory distress from acute pneumonia. Three children developed respiratory distress during the investigation for their immunodeficiency. The median age for the development of pulmonary manifestations was four months (range 3–9 months). After the initial diagnosis, pulmonary disease remained a common cause of morbidity and mortality in those children whose immunodeficiency was not corrected by bone marrow transplantation. Although pulmonary disease was not a major presenting feature in children with DiGeorge syndrome, pulmonary complications were common. These included recurrent bacterial and viral infections and bronchomalacia, which complicated management and predisposed to morbidity and mortality, even in those without a T-cell defect (Table 1).35 RSV INFECTION IN INFANTS WITH NEUROMUSCULAR DISEASES The Pediatric Investigators Collaborative Network on Infections in Canada (PICNIC) conducted a chart review of patients admitted with RSV infection to 12 tertiary care paediatric hospitals from 1988 to 1991.12 The hospital course of children with BPD was compared with that of children with other underlying pulmonary disorders. Children with pulmonary and tracheobronchial malformations, parenchymal lung diseases and neurogenic disorders had significantly higher rates of intensive care unit (ICU) admission and mechanical ventilation when compared with the BPD group. A review of the PICNIC RSV database by Arnold et al.19 compared the hospital experiences of infants with BPD with those of children

Table 1 Pulmonary disease in children with DiGeorge syndrome35

DiGeorge + DiGeorge

Bronchomalacia

Recurrent infections

Lung fibrosis

Viral infections

Bacterial infections

25% 22%

50% 22%

50% -

50% 11%

25% 11%

DiGeorge +/ ; DiGeorge syndrome with/without T-cell defect.

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who had other preexisting pulmonary conditions. One hundred and fifty-nine out of 1516 patients hospitalized for RSV disease had preexisting lung disorders including six children with neurogenic disorders and impaired airway clearance and 17 children with recurrent aspirations. Interestingly, those children with underlying neurologic disorders were significantly older with a mean age of 3 years compared with any other group. All patients had durations of hospitalization comparable to that of patients with BPD and a similar proportion in each group required ICU admission. A history of home supplemental oxygen therapy at the time of hospitalization was significantly associated with the need for mechanical ventilation. Out of a prospective RSV data base including data from 14 paediatric hospitals in Germany from 1999 to 2005, covering six consecutive RSV seasons, 73 of 1541 (4.7%) patients with neuromuscular impairment were identified.21 Forty-one of these children (56%) had at least one additional risk factor for a severe course of RSV infection including prematurity in 30, congenital heart disease in 19, chronic lung disease in 6 and immunodeficiency in 8 patients (multiple risk factors in some patients). Median age at diagnosis of RSV infection (14 compared to 5 months), overall risk for seizures (15.1% vs. 1.6%) and rate of mechanical ventilation (9.6% vs. 1.9%) were all higher in the infants with neuromuscular impairment. Multivariate regression analysis revealed neuromuscular impairment as an independent risk factor for ICU admission (OR 4.94; 2.69–8.94) and mechanical ventilation (OR 3.85; 1.28–10.22). A cohort study including all children with severe RSV infection using ICU admission as a marker of severity revealed a considerable proportion of children having serious underlying conditions/ co-morbidities.36 Of 406 patients included over an 8-year time period 98.5% required mechanical ventilation and 8.6% died, half of them directly RSV-related (4.4%). All of the RSV deaths had preexisting medical conditions – chromosomal abnormalities in 29%, cardiac lesions in 27%, neuromuscular disease in 15%, chronic lung disease in 12%, large airway abnormality in 9%, and immunodeficiency in 9%. Additionally, there was an interaction effect between pre-existing disease, nosocomial RSV infection and mortality. The ICU stay was longer and children were older in these cases. Summarizing these results, morbidity - expressed as duration of hospitalization, ICU admission and mechanical ventilation rates and mortality associated with RSV infection are increased in infants with neuromuscular diseases and generally, these children are older compared to other groups when hospitalized for RSV disease. RSV INFECTION IN INFANTS WITH IMMUNE DEFICIENCY SYNDROMES Patients with SCID and those with AIDS appear to be highly susceptible to severe, persistent infections due to a variety of microorganisms, of which viruses likely are the most common.37 In 1984 a 6-month-old male infant was reported with SCID being hospitalized for progressive respiratory distress.38 Examination during hospitalization disclosed widespread pulmonary infiltrates that did not respond to intensive therapy. The patient died eight days after admission. Autopsy revealed P. jirovecii pneumonia and widespread giant cell pneumonia. RSV was cultivated from lung specimens obtained at autopsy. Specific immunofluorescent staining of the cytoplasm of alveolar lining cells with RSV antiserum was demonstrated and the electron microscopic appearance of giant cells was compatible with RSV infection. The authors concluded that RSV should be added to the list of viruses causing giant cell pneumonia. In 1985 two additional cases of fatal RSV infection in infants with assumed SCID were reported.39 Open lung biopsy revealed

RSV as the sole pathogen in a 9-year-old child with immunodeficiency having developed severe bronchiolitis necessitating mechanical ventilation.40 A first study on immunocompromised infants with RSV infection was published by Hall et al in 1986.23 Over ten consecutive winters, 608 children five years old or younger who were hospitalized with RSV infection had been prospectively studied to evaluate the relation between their immune status and the severity of their infection.23 Among them, forty-seven (7.7%) had been immunocompromised by chemotherapy, steroid therapy, or a primary immunodeficiency disorder. Among the immunocompromised children, those receiving chemotherapy for cancer and those with immunodeficiency disease had more severe RSV disease, with pneumonia occurring at all ages, and a higher mortality rate. Children receiving long-term steroid therapy did not appear to have more severe clinical manifestations than normal children. Viral shedding, however, was significantly greater and more prolonged in the children receiving steroid therapy, and particularly in those receiving chemotherapy or with an immunodeficiency disease. Giant-cell pneumonia was documented in one child with leukaemia. Over half of the immunocompromised children acquired the RSV infection nosocomially. These pilot findings indicated that children receiving chemotherapy for cancer and those with immunodeficiency disease are at risk for complicated or fatal infections from RSV. RSV and parainfluenza virus infection carry a poor prognosis in SCID, particularly if the viral load is high. Following bone marrow transplantation patients with high viral load develop severe pneumonitis at engraftment which may possibly be modulated by immunotherapy.41 Viral pneumonitis is among the known pulmonary complications of human immunodeficiency virus (HIV) infection. Pneumonitis due to herpes simplex virus, varicella-zoster, and RSV has occasionally been reported in AIDS patients, and this is of practical importance because of the availability of effective treatment.42 During the winter of 1986 to 1987 ten HIV-infected children24 experienced RSV infection, in most cases presenting as RSV pneumonia, and only one case was identified as having bronchiolitis. Two courses of disease were fatal in children aged below one year and having a severely reduced percentage of helper T lymphocytes. Both patients had concomitant infection with P. aeruginosa and P. jirovecii. Viral shedding was reported to be prolonged up to 90 days, compared to 18 days in non HIV-infected controls. Similar results have been reported in a larger prospective cohort study with viral shedding up to 199 days.25 No differences were noted between HIV- and non-HIV-infected children regarding duration of illness, temperature, respiratory rate or oxygen saturation. The RSV epidemic in HIV-infected children in South Africa was reported to be significantly more perennial compared to HIV negative children during a one-year study. Interestingly, there was a significantly higher case fatality rate of 7.5% (including RSV, influenza, parainfluenza, and adenovirus) compared to 0% in HIV negative children.27 A prospective study over two RSV seasons identified 39 of 268 HIV positive children (14.6%) with RSV associated LRTI who had a four-fold increased relative risk for death.43 Findings in HIV-infected children with RSV disease are summarized in Table 2. Thirty-five out of 1584 patients hospitalized due to RSV infection were diagnosed having compromised immune function by a retrospective chart review study.12 In comparison with other groups these infants showed the longest durations of hospital stay with a median of 39 days. A similar observation was again presented by an author from the PICNIC study group reporting on a prospective cohort study with enrolment of 689 patients.44 Underlying morbidities including congenital heart disease, chronic

B. Resch et al. / Paediatric Respiratory Reviews 10 (2009) 148–153 Table 2 Respiratory syncytial virus infection in HIV-infected children Clinical Parameters

Reported findings

References

Median age in months (range) Mean duration of supplemental oxygen Mean duration of hospitalization Rate of mechanical ventilation Bronchopneumonia/pneumonia Bronchiolitis Case fatality rate Concurrent bacteraemia Maximum viral shedding

7–8.5 (3–48) 4.4 days 6.7 days 7% 92% 15% 1.7–20% 7–20% 90–199 days

24,27,43 43 43 43 43 43 24,43 24,27 24,25

HIV, human immunodeficiency virus.

lung disease (BPD, cystic fibrosis, congenital pulmonary anomaly), immunocompromise (immunodeficiency, immunosuppressant therapy, and use of corticosteroids), other multisystemic disease, gestation less than 37 weeks, and postnatal age younger than 6 weeks were reported in 156 (22,6%) patients. In the 21 infants (3% of the total study population) affected by immunosuppression, prolonged hospitalization compared to other groups was observed (OR 1.7; 1.4–2.2). Admission rates to ICU and rates of mechanical ventilation were not found to be increased. In paediatric patients with underlying malignancies and haematopoietic stem cell transplant recipients followed between 1997 and 2005, the two independent predictors of RSV LRTIs were profound lymphopenia, with absolute lymphocyte counts of < 100 cells per mm3, and age of  2 years. Of all patients with LRTI 31% died as a result of RSV infection.45 In a retrospective observational study and a prospective nationwide birth-cohort study of children with Down syndrome 39 of 395 (9.9%) were hospitalized for RSV LRTI.46 The median duration of hospitalization was 10 days; mechanical ventilation was required for 5 children (12.8%). Interestingly, the odds ratio for RSV LRTI-associated hospitalization was 12.6 among term children with Down syndrome without haemodynamically significant congenital heart disease compared with 10.5 in children with Down syndrome and any congenital heart disease. Thus, Down syndrome, known to constitute an increased risk for infectious diseases, was found to be a novel independent risk factor for severe RSV disease. Pathophysiologic mechanisms possibly underlying the high risk of severe RSV LRTI among children with Down syndrome might include the risk for increased pulmonary vascular resistance, the abnormal upper airway physiology, which makes them prone to apnea, and the altered immune response, with thymus development and function being abnormal. The numbers of B-cells and T-cells are low, especially during the first 2 years of life, and, additionally, the defective T-cell ex vivo proliferative responses to nonspecific and antigenic stimuli, cytokine production, and natural killer cell responses detected in children with Down syndrome are thought to be important to the increased susceptibility to infectious pathogens. Taken together, abnormal innate and adaptive immune responses in these infants could predispose them to more severe RSV disease. IMPLICATIONS FOR PROPHYLAXIS WITH PALIVIZUMAB AND FURTHER PERSPECTIVES Two children below 24 months of age have been reported two and ten months after liver transplantation with prolonged courses of RSV disease and need for mechanical ventilation.47 Extrapolating the experience of bone marrow transplant recipients with combined therapy of ribavirin and palivizumab48 the authors recommended randomized trials in larger paediatric solid organ transplant centres to determine if the use of palivizumab prophylaxis is efficacious in preventing the morbidity associated

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with RSV infection in transplanted patients under the age of 24 months. Recently, experience with palivizumab prophylaxis offered to four term neonates affected by immune disorders including DiGeorge syndrome (one case), congenital HIV infection (two cases) and Wiskott-Aldrich syndrome (one case) and presenting with lymphopenia and neutropenia was reported.49 No side effects had been reported during regular adherence to the monthly injections over the RSV season and no RSV infection occurred during the first two years of age. Speer et al. in 200450 reported on the results from the 20022003 Palivizumab Outcomes Registry, and showed that 9% (569 out of 6291) of the children enrolled in the Registry had been given palivizumab because they had either airways abnormalities or central nervous system/neuromuscular disorders including hydrocephalus, cerebral palsy or inherited chromosomal syndromes/ genetic defects. Fourteen of the 569 infants (2.5%) born with these disorders experienced RSV hospitalization compared to 1% of infants without these disorders. Cohen et al.51 reported on 86 children treated with palivizumab for ‘‘off-label uses’’, enrolling infants with chronic lung disease (BPD) after 24 months of age, trisomy 21, chronic aspiration, severe tracheomalacia, cystic fibrosis and myotonic dystrophy, who had additional risk factors such as sibling(s) at home (71%), day care attendance (15%), tobacco use at home (11%), and history of multiple births (11%). The authors reported on a hospitalization rate for RSV of 3.5% with no ICU admissions, and short hospital stays (mean three days). The mean age at first dose in Cohen’s population was 13.5 months. This data clearly demonstrates that palivizumab should be considered for these high-risk infants. The policy statement of the AAP7 had suggested that the presence of underlying conditions other than prematurity, BPD or congenital heart disease might influence the decision regarding palivizumab prophylaxis. Factors that predispose to respiratory complications included for example neurologic disease in very low birth weight infants, number of young siblings, child care centre attendance, anticipation of cardiac surgery, and distance to and availability of hospital care for severe respiratory illness. It was stated that although specific recommendations for immunocompromised patients cannot be made, children with severe immunodeficiencies (SCID or AIDS) may benefit from prophylaxis. The updated Austrian recommendations for palivizumab prophylaxis52 additionally suggest palivizumab prophylaxis for infants with neuromuscular disease presenting as floppy infant syndrome, with early severe chronic respiratory illness including cystic fibrosis, and with congenital immunodeficiency syndrome or severe immune suppression. In 75 cystic fibrosis patients younger than 18 months, prophylaxis with palivizumab was evaluated retrospectively between the years 1997 and 2005.53 Among palivizumab recipients, 3 out of 35 children were hospitalized for acute respiratory illness compared to 7 out of 40 without prophylaxis. Despite no significant differences the authors concluded that infants with cystic fibrosis – until now not recommended by the AAP for palivizumab prophylaxis – might benefit from RSV immunoprophylaxis. The same was stated for children with Down syndrome.46 Prospective studies on the burden of RSV disease in children with neuromuscular disease and immune deficiency syndromes are still pending. Thus, the authors of this review initiated an Austrian-Italian prospective multicentre cohort study on RSV infections in infants with neuromuscular diseases and immune deficiency syndromes called AIR-NID study over a first RSV season 2008/2009. Until an RSV vaccine will be available results of this prospective observational cohort study might influence recommendations for palivizumab prophylaxis in children with these rare diseases that predispose to a more severe course of RSV disease.

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CONFLICT OF INTEREST STATEMENT The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript including employment, consultancies, stock ownership or options, expert testimony, patents received or pending, or royalties. The authors B.R. and P.M. received honoraria for national and international presentations on the subject of RSV infection and RSV prophylaxis with palivizumab from several Abbott companies. The above mentioned AIR-NID study is funded by a grant from Abbott Company Austria. KEY POINTS  There is growing evidence of severe RSV disease in infants with neuromuscular diseases and immune deficiency syndromes leading to prolonged hospitalizations and higher rates of intensive care unit admissions and in part contributing to a higher mortality rate.  Although not indicated in most guideline statements, palivizumab prophylaxis for these uncommon underlying conditions is under consideration by clinicians.  Prospective studies on the burden of RSV disease in children with neuromuscular disease and immune deficiency syndromes are still pending.

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