Secondary Logo

Journal Logo

Supplement Article

Viral Respiratory Infections in Children with Technology Dependence and Neuromuscular Disorders

Panitch, Howard B. MD

Author Information
The Pediatric Infectious Disease Journal: November 2004 - Volume 23 - Issue 11 - p S222-S227
doi: 10.1097/01.inf.0000144670.78558.c7
  • Free

Abstract

Viral acute respiratory infections represent a significant cause of morbidity and mortality across all ages.1–3 Among infants younger than 1 year of age, respiratory syncytial virus (RSV) infection is the leading cause of hospitalization4 and is also a major cause of infant mortality.1,3 In contrast, influenza virus causes greater morbidity and mortality in older children and the elderly.1,5 Furthermore the morbidity and mortality related to viral respiratory infections is greater among patients with chronic underlying conditions.5–7

In recognition of the risk for serious lower respiratory tract disease resulting from RSV infection, the American Academy of Pediatrics identified certain groups that might benefit from immunoprophylaxis against RSV.8 These include infants younger than 24 months of age with a history of chronic lung disease of infancy (bronchopulmonary dysplasia), who have required therapy for their lung disease within 6 months of the onset of the RSV season; infants with hemodynamically significant congenital heart disease; and some premature infants. A prospective survey of physician practices regarding RSV immunoprophylaxis, however, demonstrated that there are children outside of these guidelines who have chronic underlying conditions and are also considered at risk for serious RSV lower respiratory tract infection (LRTI).9

Another recent survey of 45 pediatric specialists who cared for a total of 3714 children with chronic underlying conditions resulting in technology dependence supported the notion that practitioners should consider such children as being at increased risk for severe viral respiratory infections.10 Here children were considered technology-dependent if they required long term supplemental oxygen, had a chronic tracheostomy or required mechanical ventilation or continuous positive airway pressure for part or all of the day. Of the survey respondents, 98% recommended that this population of children receive influenza vaccination, 89% recommended RSV immunoprophylaxis for selected technology-dependent children and 51% recommended prophylaxis for children older than 2 years of age. The factors perceived most often to contribute to increased severity of influenza or RSV infection in this group included young age, prior history of difficulty handling a viral respiratory illness, small weight or size, decreased motor tone and restrictive lung disease.

The risks of viral infection to those children with chronic underlying conditions requiring technology dependence or to those children with neuromuscular disorders have not been well-studied, although they are anecdotally recognized. For instance, although this population of patients is commonly believed to be at increased risk for severe RSV disease in the first year or two of life, little is known about that risk as they age.

RSV ILLNESS IN OLDER CHILDREN WITH BRONCHOPULMONARY DYSPLASIA

In a retrospective 4-year study of all children younger than 3 years of age enrolled in the Tennessee Medicaid program, Boyce et al11 demonstrated that infants with bronchopulmonary dysplasia (BPD) are at increased risk for hospitalization from RSV through the first 2 years of life. In the third year, however, the number of RSV hospitalizations per 100 children with BPD was still 10 times greater than the number per 100 children born at term without underlying lung disease (Table 1). No attempt was made to describe the characteristics of those children with BPD who were older than 2 years of age who required hospitalization.

T1-7
TABLE 1:
RSV Hospitalizations per 100 Children

Passerotti et al12 examined the cost associated with RSV hospitalization in the population of children with BPD who were older than 24 months of age. They reviewed hospital admissions for all children between 2 and 5 years of age who were followed in their health care system during a 36-month period. They found 8 children with a history of BPD who required hospitalization because of an RSV illness. This cohort of children spent a total of 73 days in the hospital, with an average length of stay of 9.1 ± 8.3 days (range, 3-26 days). In addition, 5 of the 8 required intensive care unit (ICU) care, lasting 10.4 ± 7.4 days. Among the children in this age group, RSV infection was responsible for 35% of all BPD admissions. Again the characteristics that might predispose those children to more severe illness with an RSV infection were not explored.

BRONCHOPULMONARY DYSPLASIA AND TECHNOLOGY DEPENDENCE

Several studies have noted a relationship between increased severity of RSV illness among those infants with BPD who required supplemental oxygen at the time of hospitalization or shortly before. One retrospective study conducted over 3 years found that 10 of 64 (15.6%) former preterm infants who developed BPD required hospitalization for an RSV illness before the age of 2 years.13 When the subset of infants with BPD who remained dependent on supplemental oxygen was analyzed, however, 8 of 25 (32%) infants had an RSV-related hospitalization. The authors also found that for all preterm infants, a supplemental oxygen requirement at the time of nursery discharge constituted a significant risk for subsequent RSV hospitalization.

Groothuis et al14 prospectively followed 30 infants with BPD who were being monitored in a home oxygen program for a single RSV season. During the observation period, 27 infants had at least 1 acute respiratory illness, of which 16 (59%) were attributable to RSV. Of those 16 illnesses, 11 resulted in hospitalization; and in 7 instances, the stay was prolonged (>7 days). Two other children did not need hospitalization, but they did require reinstitution of supplemental oxygen therapy. Unlike healthy children in whom the risk for an RSV-related hospitalization is greatest before 6 months of age, 5 of the BPD infants in the study were older than 1 year of age. In addition, 4 had a previous history of a documented RSV infection.

These findings led the investigators to conclude that RSV infection was the major cause of rehospitalization during the winter months. In addition, previous known infection was not protective for subsequent severe infection in this group of patients. The single most important risk factor for severe infection was current use of supplemental oxygen or oxygen use within 3 months of the time of RSV infection.

OTHER UNDERLYING CONDITIONS AND RSV DISEASE

Arnold et al15 compared the hospital experiences of infants with BPD with those of children who had other preexisting pulmonary conditions. In a 2-year, prospective, multicenter study, researchers identified 159 of 1516 patients who were hospitalized for an RSV illness and had a preexisting lung disorder, including: cystic fibrosis (8); BPD (91); tracheoesophageal fistula (9); pulmonary malformation (20); neurogenic disorders associated with impaired airway clearance (6); recurrent aspiration (17); or another pulmonary condition (8). Those children hospitalized with cystic fibrosis were younger than any other group (mean age, 33.4 weeks), whereas those with underlying neurologic disorders were significantly older (mean age, 161.6 weeks). Once hospitalized, all patients with preexisting lung disorders had a duration of hospitalization similar to that of patients with BPD (median, 5–13 days), and a similar proportion in each group required care in an intensive care unit (ICU). The proportion of children who required admission to an ICU and who required mechanical ventilation was significantly greater among children who were receiving home supplemental oxygen at the time of hospitalization compared with those who never required home oxygen therapy.

As these studies illustrate, the need for supplemental oxygen at the time of or shortly before an RSV lower respiratory illness is associated with a more severe course in patients with underlying respiratory disease. The role that supplemental oxygen plays in modifying the course of an RSV illness, however, is unknown. One theory is that the use of supplemental oxygen in patients with compromised respiratory systems alters the inflammatory response to RSV. Another possibility is that the need for supplemental oxygen might reflect other factors that could contribute to the severity of an RSV illness.

LUNG MECHANICS AND SUPPLEMENTAL OXYGEN REQUIREMENT

Factors that could contribute to the severity of an RSV illness could relate to either airway or parenchymal function, or both. Talmaciu et al16 measured the lung mechanics of infants older than 2 years of age with BPD who still required supplemental oxygen and compared them with the mechanics of infants with BPD who had been weaned from supplemental oxygen by 2 years of age. The 2 groups were matched for gestational age as well as for weight and length at the time of study. Although no differences between the 2 groups were found in any measurement of tidal mechanics, including respiratory rate, tidal volume, lung compliance or expiratory conductance, forced expiratory flow per centimeter of body length tended to be lower among the infants who were still dependent on supplemental oxygen. Furthermore when forced flows were normalized to lung volume, there was a significant difference between the 2 groups: volume-corrected flow in the group of oxygen-dependent infants was 0.34 ± 0.21 s−1 compared with 0.81 ± 0.40 s−1 in those who had weaned (P < 0.003).

The authors speculated that the reduced flows and persistence of oxygen dependence could both be explained if those infants who continued to require supplemental oxygen also had a more simplified arrangement of alveoli, with larger and fewer alveoli present. Such alveolar simplification would result in diminished surface area for gas exchange and a reduction in elastic recoil. Elastic recoil is the force exerted by the lung through alveolar wall attachments to airway walls that tethers the small airways and prevents them from collapsing. Thus a reduced alveolar number would also favor small airway collapse during forced exhalation.

BASELINE LUNG FUNCTION AND VIRAL-INDUCED WHEEZING

Reduced lung function at baseline has been implicated as a risk factor for significant airway obstruction during acute respiratory illnesses. Several epidemiologic studies have demonstrated that compared with infants with normal lung function, infants whose lung function is already reduced before any respiratory illness occurs are at increased risk for recurrent episodes of wheezing.17–19 By similar reasoning, it is possible that infants with BPD and lower baseline lung function would be more likely to be hospitalized with an RSV illness compared with those infants with BPD whose lung function is closer to normal.

To test this hypothesis, we reviewed the lung mechanics from 134 infants who were diagnosed with BPD and who had undergone pulmonary function testing from October 1989 through August 1998.20 Both inpatient and outpatient charts were then reviewed to determine which infants were hospitalized with an RSV infection. Sixty-three (63) infants were excluded from analysis because they: (1) had received immunoprophylaxis or were part of a study in which they may have received immunoprophylaxis (N = 30); (2) had the pulmonary function study performed only after an RSV hospitalization (N = 27); or (3) had pulmonary function measurements obtained >1 year before the RSV illness (N = 6). Of the remaining infants, pulmonary function studies were obtained from 50 infants who were never hospitalized with an RSV LRTI and from 21 infants hospitalized with an RSV LRTI. The 2 groups had similar birth weights, gestational ages and duration of neonatal ventilation. Their study age, weight and length were similar as well. The age at RSV hospitalization for the 21 infants was 23.4 ± 2.5 months (range, 4–44 months), and 10 of the infants were older than 2 years of age at the time of their RSV hospitalization.

There was no difference between the 2 groups in any of the tidal mechanics measured. The median value of forced expiratory flow (V′max FRC or maximal flow at the functional residual capacity point), however, was significantly lower in the 21 infants who subsequently were hospitalized with an RSV illness (P < 0.0001). When V′max FRC was plotted as a percentage of published predicted values,21 a value <60% of predicted was significantly associated with RSV hospitalization (P = 0.001) (Fig. 1). The odds ratio of requiring hospitalization for an RSV LRTI if V′max FRC were <60% of predicted was 16.8 (confidence interval, 2.1, 135.6). When analyzing demographic data, only family history of asthma was significantly different between the groups. Applying a forward stepwise logistic regression, a Z score for V′max FRC below −2 was the strongest single factor associated with hospitalization (P = 0.01). The addition of a family history of asthma was the only variable that strengthened the association of the model (P = 0.003).

F1-7
FIGURE 1.:
Maximal forced expiratory flow from partial expiratory flow-volume maneuvers in 50 infants with BPD who had never been hospitalized and in 21 infants with BPD who were subsequently hospitalized with an RSV illness. Values are presented as a function of percent predicted from published values in normal children21 and as a function of age. Only one of the children subsequently hospitalized with RSV infection had a preexisting value of V ′max FRC that was >60% of predicted values.

SURFACTANT DEFICIENCY OR DYSFUNCTION

Severity of RSV illness and a preexisting need for supplemental oxygen, especially in infants with chronic lung disease, could also reflect dysfunction or deficiency of surfactant.22–24 Several lines of investigation suggest that surfactant dysfunction plays some role in the ongoing pathophysiology of established BPD.24 The concentration of phosphatidylcholine in bronchoalveolar lavage fluid from BPD infants at the end of the first year of life was significantly reduced compared with fluid from infants who experienced neonatal respiratory distress but who then recovered.22 Elsewhere exogenous surfactant replacement was associated with a transient improvement in oxygenation in a small group of infants with early BPD.25 Furthermore animal models of BPD suggest that although adequate or even excessive amounts of surfactant proteins A and D are made, their secretion into the alveolar space is severely impaired, and their concentrations in lavage fluid are reduced.26 Both surfactant proteins A and D are also important first line host defenses against RSV and other viruses.27 Polymorphisms in their genes have been associated with severe RSV disease.28,29 Thus in some children with BPD, the need for supplemental oxygen could be a marker for surfactant dysfunction or deficiency, which could also predispose those children to more severe viral illnesses.

VIRAL ILLNESSES IN CHILDREN WITH NEUROMUSCULAR DISEASE

Children with neuromuscular diseases that result in an impaired ability to clear secretions from the airways are also at risk for more severe illness after viral infections. Acute upper respiratory infections can lead to atelectasis or pneumonia by several mechanisms. The infection itself often is accompanied by an increase in the quantity of nasal and oral secretions. Nasopharyngeal secretions cannot only increase in amount but they can also become thicker, especially if they become purulent. This combination can overwhelm an already compromised swallowing mechanism and therefore can lead to an increased risk for aspiration of infected upper airway secretions into the lower respiratory tract. Weakened respiratory muscles result in an impaired cough mechanism; thus those secretions are more difficult to clear from the lower airways. Airway obstruction from retained secretions can then result in areas of atelectasis or pneumonia. Acute viral upper respiratory infections have also been shown to cause an acute deterioration in respiratory muscle strength among healthy adults.30 Thus a patient with marginal respiratory muscle strength could develop weakness that is severe enough to hamper effective airway clearance during an acute viral illness.

The role of immunization against influenza virus or of immunoprophylaxis against RSV has not been studied in a population of children with neuromuscular weakness. Nevertheless such patients have been identified as being at increased risk for more severe disease in the event of infection,5,7,15 and severe neuromuscular weakness was recently cited as a risk factor for more severe RSV disease in preterm infants born between 32 and 35 weeks gestation.8,31

CLINICAL EXPERIENCE IN CHILDREN WITH NEUROMUSCULAR DISEASE AND VIRAL ILLNESS

Even before the American Academy of Pediatrics (AAP) recognized neuromuscular disease as a modifier of disease severity in its revised guidelines for RSV immunoprophylaxis,8 practitioners already viewed that group of children as being at increased risk for severe infection. With the use of the Palivizumab Outcomes Registry, a multicenter prospective data collection of children receiving RSV immunoprophylaxis, Speer et al32 identified those infants with neuromuscular disorders and congenital airway abnormalities who received RSV immunoprophylaxis in the 2002–2003 season. Those children were given immunoprophylaxis before the revised AAP guidelines listed such conditions as severity risk factors. Of the 6291 children enrolled in the Registry, 569 (9%) were identified as having either an airway abnormality or central nervous system/neuromuscular disorder. Those in the latter category included children with hydrocephalus, cerebral palsy or genetic defects/chromosomal abnormalities (n = 202), peripheral nerve defects (n = 2) and neuromuscular disorders (n = 17). Of those with central nervous system/neuromuscular disorders, 4 (1.8%) required hospitalization for an RSV illness, compared with 57 (1%) of the 5722 children with neither airway nor neuromuscular disorders. The authors concluded that these patients are at high risk for RSV hospitalization. Their data also suggest that pediatricians view such patients similarly.

SUMMARY

The factors associated with technology dependence and neuromuscular weakness that increase the severity of viral respiratory illnesses remain to be elucidated. The need for supplemental oxygen could reflect not only parenchymal abnormalities but also small airway dysfunction. The presence of a tracheostomy allows the normal barriers of the upper airway to be bypassed and facilitates aspiration of infected particles into the lower airways. The need for chronic mechanical ventilation could reflect abnormalities of lung compliance or resistance, or possible prolonged surfactant dysfunction. Alternately the reasons that a child requires chronic mechanical ventilation could also be associated with impaired airway clearance. Children with neuromuscular weakness could have preexisting swallowing dysfunction that is exacerbated by acute respiratory illnesses and that then leads to aspiration of infected secretions. The risk for atelectasis or pneumonia will be increased in those children with either expiratory or inspiratory muscle weakness. In addition, the acquired weakness associated with acute viral infections could exacerbate respiratory muscle fatigue and predispose children with neuromuscular weakness to respiratory failure.

Although the number of children who are technology-dependent or who have severe neuromuscular weakness is small, their risk of severe disease after viral respiratory infection may be similar to that of premature infants or other high risk groups. A better understanding of the factors responsible for severe disease in these children would help to create better strategies for treatment and prevention.

DISCUSSION

Comment: When I was doing transplant medicine, we had a very high incidence of EBV [Epstein-Barr virus]-mediated lymphoma in a transplant population that was getting lung transplants. It turned out that even though many of these children, on average, were 12, 13 and 14 years old, relative to their peer cohort, their EBV exposure was enormously low, and it was probably because they led a very sequestered life. Their parents and their doctors have basically been telling them to avoid people who are sick at school and probably curtailed a lot of after school activities.

I believe the assumption is being made that the technology-dependent population has been exposed over time and as a result, has built up some degree of natural immunity. Also these patients are not truly immunosuppressed. They become functionally immunosuppressed because they cannot clear their airways.

Howard Panitch, MD: I agree with what was just said. We really do not know what the titers are in those children. We had reason to look at EBV titers in the context of transplant. We then went back and realized these children were getting exposed at the time of transplant. I would wager that this population probably has surprisingly low titers against most common respiratory pathogens. But we did not check EBV titers.

Comment: I think it would be easier to sequester yourself from the epidemiology of EBV and RSV. I would also add, however, that the way most mucosal infections occur is not at a specific antibody titer, at which protection occurs and below which it does not. For example, with the polysaccharide antigens, there can be an antibody level above which it is very difficult to show infection. Although there is almost always a general correlation between greater antibody levels and increased protection, it is not necessarily 1 to 1. Thus I would not say that you could simply say that if there is antibody present, there is no need to add more. It is a more complicated relationship.

Howard Panitch, MD: I will also just tell you that in the survey group, 90% or so of the children lived and were cared for at home, and 9% lived in a nursing home situation. About 59% went to school, day care or another group activity. So although they were in a home environment, they were still exposed to other children.

REFERENCES

1. Thompson WW, Shay DK, Weintraub E, et al. Mortality associated with influenza and respiratory syncytial virus in the United States. JAMA. 2003;289:179–186.
2. Souza LS, Ramos EA, Carvalho FM, et al. Viral respiratory infections in young children attending day care in urban Northeast Brazil. Pediatr Pulmonol. 2003;35:184–191.
3. Leader S, Kohlhase K. Recent trends in severe respiratory syncytial virus (RSV) among US infants, 1997 to 2000. J Pediatr. 2003;143:S127–S132.
4. Leader S, Kohlhase K. Respiratory syncytial virus-coded pediatric hospitalizations, 1997 to 1999. Pediatr Infect Dis J. 2002;21:629–632.
5. Izurieta HS, Thompson WW, Kramarz P, et al. Influenza and the rates of hospitalization for respiratory disease among infants and young children. N Engl J Med. 2000;342:232–9.
6. Glezen WP, Greenberg SB, Atmar RL, Piedra PA, Couch RB. Impact of respiratory virus infections on persons with chronic underlying conditions. JAMA. 2000;283:499–505.
7. Navas L, Wang E, de Carvalho V, Robinson J. Improved outcome of respiratory syncytial virus infection in a high-risk hospitalized population of Canadian children. Pediatric Investigators Collaborative Network on Infections in Canada. J Pediatr. 1992;121:348–354.
8. American Academy of Pediatrics—Committee on Infectious Disease. RED BOOK 2003: Policy Statement: revised indications for the use of palivizumab and respiratory syncytial virus immune globulin intravenous for the prevention of respiratory syncytial virus infections. Pediatrics. 2003;112:1442–1446.
9. Parnes C, Guillermin J, Habersang R, et al. Palivizumab prophylaxis of respiratory syncytial virus disease in 2000–2001: results from The Palivizumab Outcomes Registry. Pediatr Pulmonol. 2003;35:484–489.
10. Panitch HB, Cohen A, Boron M, Van Veldhuisen P, Ciesla G. Physician survey on viral pathogens and respiratory disease in technology-dependent children [abstract]. Pediatr Res. 2004;55:603A.
11. Boyce TG, Mellen BG, Mitchel EF Jr, Wright PF, Griffin MR. Rates of hospitalization for respiratory syncytial virus infection among children in Medicaid. J Pediatr. 2000;137:865–870.
12. Passerotti LA, Walters W, Desai V, Otegbeye A. A cost savings projection for respiratory syncytial virus immunization of older children with a history of bronchopulmonary dysplasia [abstract]. Pediatrics. 1999;104(suppl):677.
13. Deshpande SA, Northern V. The clinical and health economic burden of respiratory syncytial virus disease among children under 2 years of age in a defined geographical area. Arch Dis Child. 2003;88:1065–1069.
14. Groothuis JR, Gutierrez KM, Lauer BA. Respiratory syncytial virus infection in children with bronchopulmonary dysplasia. Pediatrics. 1988;82:199–203.
15. Arnold SR, Wang EE, Law BJ, et al. Variable morbidity of respiratory syncytial virus infection in patients with underlying lung disease: a review of the PICNIC RSV database. Pediatric Investigators Collaborative Network on Infections in Canada. Pediatr Infect Dis J. 1999;18:866–869.
16. Talmaciu I, Ren CL, Kolb SM, Hickey E, Panitch HB. Pulmonary function in technology-dependent children 2 years and older with bronchopulmonary dysplasia. Pediatr Pulmonol. 2002;33:181–188.
17. Martinez FD, Morgan WJ, Wright AL, Holberg CJ, Taussig LM. Diminished lung function as a predisposing factor for wheezing respiratory illness in infants. N Engl J Med. 1988;319:1112–1117.
18. Martinez FD, Morgan WJ, Wright AL, Holberg C, Taussig LM. Initial airway function is a risk factor for recurrent wheezing respiratory illnesses during the first three years of life: Group Health Medical Associates. Am Rev Respir Dis. 1991;143:312–316.
19. Young S, Arnott J, O'Keeffe PT, Le Souef PN, Landau LI. The association between early life lung function and wheezing during the first 2 yrs of life. Eur Respir J. 2000;15:151–157.
20. Panitch HB, Clayton RG, Allen JL. Can lung mechanics identify infants with bronchopulmonary dysplasia (BPD) at risk for hospitalization from respiratory syncytial virus (RSV) infection? [abstract]. Am J Respir Crit Care Med. 1999;159:A154.
21. Tepper RS, Reister T. Forced expiratory flows and lung volumes in normal infants. Pediatr Pulmonol. 1993;15:357–361.
22. Clement A, Masliah J, Housset B, et al. Decreased phosphatidyl choline content in bronchoalveolar lavage fluids of children with bronchopulmonary dysplasia: a preliminary investigation. Pediatr Pulmonol. 1987;3:67–70.
23. Coalson JJ, King RJ, Yang F, et al. SP-A deficiency in primate model of bronchopulmonary dysplasia with infection: in situ mRNA and immunostains. Am J Respir Crit Care Med. 1995;151:854–866.
24. Bancalari E, del Moral T. Bronchopulmonary dysplasia and surfactant. Biol Neonate. 2001;80(suppl 1):7–13.
25. Pandit PB, Dunn MS, Kelly EN, Perlman M. Surfactant replacement in neonates with early chronic lung disease. Pediatrics. 1995;95:851–854.
26. Awasthi S, Coalson JJ, Crouch E, Yang F, King RJ. Surfactant proteins A and D in premature baboons with chronic lung injury (bronchopulmonary dysplasia): evidence for an inhibition of secretion. Am J Respir Crit Care Med. 1999;160:942–949.
27. Griese M. Respiratory syncytial virus and pulmonary surfactant. Viral Immunol. 2002;15:357–363.
28. Lahti M, Lofgren J, Marttila R, et al. Surfactant protein D gene polymorphism associated with severe respiratory syncytial virus infection. Pediatr Res. 2002;51:696–699.
29. Lofgren J, Ramet M, Renko M, Marttila R, Hallman M. Association between surfactant protein A gene locus and severe respiratory syncytial virus infection in infants. J Infect Dis. 2002;185:283–289.
30. Mier-Jedrzejowicz A, Brophy C, Green M. Respiratory muscle weakness during upper respiratory tract infections. Am Rev Respir Dis. 1988;138:5–7.
31. American Academy of Pediatrics—Committee on Infectious Disease. RED BOOK 2003: Technical report: revised indications for the use of palivizumab and respiratory syncytial virus immune globulin intravenous for the prevention of respiratory syncytial virus infections. Pediatrics. 2003;112:1447–1452.
32. Speer M, Cohen A, Boron M, Rankin M, Synagis Outcomes Registry Group. Results from the 2002–03 palivizumab Outcomes Registry: focus on congenital airway abnormalities and neuromuscular disease [abstract]. Pediatr Res. 2004;55:237A–238A.
Keywords:

mechanical ventilation; bronchopulmonary dysplasia; long-term oxygen therapy; respiratory syncytial virus; influenza virus

© 2004 Lippincott Williams & Wilkins, Inc.