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Association between Severe Pandemic 2009 Influenza A (H1N1) Virus Infection and Immunoglobulin G2 Subclass Deficiency

  1. C.L. Gordon1,
  2. P.D.R. Johnson1,10,
  3. M. Permezel5,
  4. N.E. Holmes1,
  5. G. Gutteridge2,
  6. C.F. McDonald3,
  7. D.P. Eisen6,10,
  8. A.J. Stewardson6,
  9. J. Edington7,
  10. P.G.P. Charles1,
  11. N. Crinis4,
  12. M.J. Black8,
  13. J. Torresi1,10, and
  14. M.L. Grayson
  1. 1Infectious Diseases Department, Austin Health, Melbourne
  2. 2Intensive Care Department, Austin Health, Melbourne
  3. 3Respiratory Department, Austin Health, Melbourne
  4. 4Pathology Department, Austin Health, Melbourne
  5. 5Department of Obstetrics and Gynaecology, Mercy Hospital for Women, Melbourne
  6. 6Victorian Infectious Diseases Service, Royal Melbourne Hospital, University of Melbourne, Melbourne
  7. 7Intensive Care Unit, Bendigo Health, Melbourne, Australia
  8. 8Pathology Department, Alfred Health, Melbourne, Australia
  9. 9Department of Epidemiology and Preventive Medicine, Monash University, Melbourne, Australia
  10. 10Department of Medicine, University of Melbourne, Melbourne, Australia
  1. Reprints or correspondence: Prof M. Lindsay Grayson, Infectious Diseases Dept, Austin Hospital, Austin Health, PO Box 5555, Studley Rd, Heidelberg, VIC, Australia 3084 (Lindsay.Grayson{at}austin.org.au).

  1. Presented in part: 49th Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC), San Francisco, CA, 12–15 September 2009 (abstract V–1269b).

 
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Abstract

Severe H1N1 infection appears to be associated with immunoglobulin G2 subclass deficiency in both nonpregnant and pregnant patients. Healthy pregnant women were mildly deficient in immunoglobulin G2, but pregnant women with severe H1N1 infection had lower levels. Immunoglobulin G2 deficiency persisted after recovery in the majority (73%) of cases.

Background. Severe pandemic 2009 influenza A virus (H1N1) infection is associated with risk factors that include pregnancy, obesity, and immunosuppression. After identification of immunoglobulin G2 (IgG2) deficiency in 1 severe case, we assessed IgG subclass levels in a cohort of patients with H1N1 infection.

Methods. Patient features, including levels of serum IgG and IgG subclasses, were assessed in patients with acute severe H1N1 infection (defined as infection requiring respiratory support in an intensive care unit), patients with moderate H1N1 infection (defined as inpatients not hospitalized in an intensive care unit), and a random sample of healthy pregnant women.

Results. Among the 39 patients with H1N1 infection (19 with severe infection, 7 of whom were pregnant; 20 with moderate infection, 2 of whom were pregnant), hypoabuminemia (P<.001), anemia (P<.001), and low levels of total IgG (P=.01), IgG1 (P=.022), and IgG2 (15 of 19 vs 5 of 20; P=.001; mean value ± standard deviation [SD], 1.8±1.7 g/L vs 3.4±1.4 g/L; P=.003) were all statistically significantly associated with severe H1N1 infection, but only hypoalbuminemia (P=.02) and low mean IgG2 levels (P=.043) remained significant after multivariate analysis. Follow-up of 15 (79%) surviving IgG2-deficient patients at a mean (±SD) of 90±23 days (R, 38–126) after the initial acute specimen was obtained found that hypoalbuminemia had resolved in most cases, but 11 (73%) of 15 patients remained IgG2 deficient. Among 17 healthy pregnant control subjects, mildly low IgG1 and/or IgG2 levels were noted in 10, but pregnant patients with H1N1 infection had significantly lower levels of IgG2 (P=.001).

Conclusions. Severe H1N1 infection is associated with IgG2 deficiency, which appears to persist in a majority of patients. Pregnancy-related reductions in IgG2 level may explain the increased severity of H1N1 infection in some but not all pregnant patients. The role of IgG2 deficiency in the pathogenesis of H1N1 infection requires further investigation, because it may have therapeutic implications.

Since the onset of the current novel influenza A (H1N1) virus pandemic, it has been recognized that certain risk factors, such as pregnancy, obesity, and immunosuppression, are associated with severe disease [1, 2]. In Victoria, Australia, which was one of the key regions for the H1N1 pandemic in the Southern Hemisphere [3, 4], such risk factors have been frequently observed in our sickest patients, but the explanation for this association has remained elusive [5].

We identified immunoglobulin G2 (IgG2) subclass deficiency in 1 young pregnant patient who had an unusual presentation with severe H1N1 infection that required intensive care unit (ICU) admission. Because of this observation, we systematically assessed total IgG and IgG subclasses in all patients with H1N1 infection requiring ICU care (many of whom were pregnant) and compared these results with those obtained from all inpatients with less severe H1N1 infection (ie, those patients who did not require ICU admission), as well as a random sample of healthy pregnant women who presented for routine antenatal care.

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Methods

The study was initially undertaken at Austin Health (AH), a tertiary university teaching hospital in Melbourne, Australia. After the observation of IgG2 deficiency in a patient with H1N1 infection, all patients with polymerase chain reaction (PCR)–proven H1N1 infection who were sufficiently unwell to require admission to AH underwent routine hematological and biochemical assessment, had their serum immunoglobulin levels and subclasses determined, and were reviewed for their clinical features, demographic characteristics, and treatment outcome. Acute-phase serum samples were either assessed prospectively or were retrieved from storage for analysis; patients for whom there were no appropriate stored serum samples were noted but not included in the study. Because of the potential therapeutic implications of our initial findings, and after discussions with the Department of Human Health Victoria, we subsequently broadened recruitment to 2 other hospitals in Victoria (Royal Melbourne Hospital [RMH] and Bendigo Health [BH]), which were actively managing patients with severe H1N1 infection and had ICU admission criteria that were similar to those at AH, to obtain similar acute-phase serum specimens and clinical details.

The following definitions were used for the study: patients with severe H1N1 infection were defined as those with confirmed H1N1 infection who required admission to the ICU for respiratory (invasive or noninvasive mechanical ventilation) and/or vasopressor support, whereas patients with moderate H1N1 infection were defined as those who required hospital inpatient (but not ICU) care. Community-acquired pneumonia was defined according to the Infectious Diseases Society of America guidelines [6].

The clinical and laboratory features of patients with severe H1N1 infection at the 3 recruitment sites (AH, RMH, and BH) were compared with those of patients with moderate H1N1 infection (AH). All patients who were found to be IgG subclass deficient during their acute illness were followed up to obtain convalescent immunoglobulin and IgG subclass levels to assess whether the identified deficiency was transitory or persistent.

Because a large number of our patients with severe H1N1 infection were pregnant, we investigated the immunological status of a random sample of healthy pregnant women to compare these results with those observed among pregnant women with moderate and severe H1N1 infection. Thus, we obtained serum samples from 15–20 healthy pregnant women who had antenatal outpatient visits at the Mercy Hospital for Women (Melbourne, Australia) on 19 or 20 July 2009.

All data were summarized and analyzed according to H1N1 infection severity (severe vs moderate), presence of pregnancy, and, if the patient was pregnant, presence of H1N1 illness (patients with H1N1 infection vs healthy control subjects). Ethics committee approval was obtained at all 4 participating centers that undertook the study.

Laboratory assays. The presence of H1N1 infection was confirmed by strain-specific PCR at the Victorian Infectious Diseases Reference Laboratory and World Health Organization Influenza Reference Laboratory (Melbourne, Australia) using standard H1N1 assays.

Serum immunoglobulins (IgG, IgM, and IgA) were assessed using both a Beckman IMMAGE 800 analyzer (Beckman Coulter) and an Abbott Architect ci8200 analyzer (Abbott Laboratories, Abbott Park) in accordance with the manufacturers' instructions. Similarly, immunoglobulin subclasses (IgG1, IgG2, IgG3, and IgG4) were measured using Binding Site Human IgG Subclass kits on a Beckman IMMAGE 800 analyzer in accordance with the manufacturer's instructions. The reference ranges for normal adults according to the manufacturer were as follows: total IgG, 7.0–16.5 g/L; IgG1, 3.8–9.3 g/L; IgG2, 2.4–7.0 g/L; IgG3, 0.22–1.76 g/L; IgG4, 0.04–0.86 g/L. Routine hematological and biochemical analyses were performed in the Pathology Departments at contributing hospitals.

Statistical analysis. Univariate analysis was undertaken using Fisher's exact test, Student's t test, or the Wilcoxon rank-sum test (as appropriate) with Stata software, version 8.2 (Stata Corporation), to identify features associated with H1N1 infection severity. Variables that were potentially associated (P<.2) on univariate analysis were included in a multivariate analysis to identify features statistically associated with severe H1N1 infection. Similarly, a univariate analysis of the clinical and laboratory features of healthy vs H1N1-infected pregnant participants was undertaken to assess for any associations with the presence of H1N1 infection. A P value of ⩽.05 was considered to be statistically significant.

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Results

Severe versus moderate H1N1 infection. A total of 47 patients with acute H1N1 infection (19 with severe infection and 28 with moderate infection) were assessed from 30 May through 16 August 2009. Appropriate serum specimens were available for 39 patients (19 with severe infection and 20 with moderate infection), and results are shown in Table 1. Among the 8 patients for whom no serum samples were available, no special features were noted to explain the lack of stored serum samples.

Patient demographic data and comorbidities for the 39 participants were similar between the severe and moderate H1N1 infection groups, except that pregnancy was more common among patients in the severe H1N1 infection group (7 of 19 vs 2 of 20); however, this difference did not achieve statistical significance (P=.065; Table 1).

Hypoalbuminemia and anemia were more common among patients with severe H1N1 infection (P<.001 for both; Table 1). Similarly, the presence of severe H1N1 infection was significantly associated with low levels of total IgG (12 of 19 vs 4 of 20 patients; P=.01), IgG1 (11 of 19 vs 4 of 20 patients; P=.022) and IgG2 (15 of 19 vs 5 of 20 patients; P=.001; Table 1 and figure 1), compared with patients with moderate H1N1 infection. Furthermore, 1 patient with severe H1N1 infection (patient A) was a pregnant woman at 21 weeks gestation (age, 16 years and 11 months) who had an IgG2 level of 1.1 g/L, which was reported as normal on the basis of the IgG2 reference ranges used for children (age ⩽16 years: 0.6–5.0 g/L) but would have been considered to be deficient if the adult reference ranges (age ⩾17 years: 2.4–7.0 g/L) had been applied.

Figure 1
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Figure 1

Serum immunoglobulin G (IgG) (total), IgG1, and IgG2 levels for patients with acute H1N1 infection stratified according to disease severity (severe vs moderate) and compared with healthy pregnant (Preg) patients. Data are shown for pregnant patients with H1N1 infection (•), nonpregnant patients with H1N1 infection (□), and healthy pregnant control patients (∘). Dashed line, mean value of each grouping; dotted line, lower limit of normal adult range for the relevant immunoglobulin.

Assessment of the mean (± standard deviation [SD]) concentrations of total IgG and IgG subclasses demonstrated that patients with severe H1N1 infection had significantly lower levels of IgG2 (and therefore lower levels of total IgG) than did patients with moderate H1N1 infection (Table 1). However, the mean (±SD) levels of IgG1 (4.2±3.9 vs 5.2±1.9 g/L; P=.31), IgG3 (0.50±0.28 vs 0.77±0.55 g/L; P=.07) and IgG4 (0.28±0.43 vs 0.24±0.24; P=.68) were not significantly different between patients with severe and patients with moderate H1N1 infection (Figure 1).

Figure 2
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Figure 2

Comparison of serum immunoglobulin G subclass 2 (IgG2) levels among patients with IgG2 deficiency during severe H1N1 infection and with recovery (nonpregnant and pregnant women). Data are shown for pregnant patients with H1N1 infection (•) and nonpregnant patients with H1N1 infection (□). Dashed line, pregnant patient at time of initial IgG2 sample; dotted line, lower limit of normal adult range for IgG2.

Table 1
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Table 1

Comparison of Results for Immunoglobulin (Ig) Levels for Patients with Severe versus Moderate H1N1 Infection

The association between pregnancy, hypoalbuminemia, anemia, and low levels of IgG2 with severe H1N1 infection were assessed in a multivariate model. The results are shown in Table 2. Abnormal liver function test results were not included in this analysis, because they were correlated with hypoalbuminemia (P=.024). After this analysis, only low mean serum concentrations of IgG2 and albumin remained statistically significantly associated with severe H1N1 infection, compared with moderate H1N1 infection (P=.043 and P=.02, respectively; Table 2).

Table 2
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Table 2

Multivariate Analysis of Features Potentially Associated with Severe versus Moderate H1N1 Infection

Among the 21 patients identified as IgG2 deficient during the acute stage of H1N1 infection (16 with severe infection, including patient A; 5 with moderate infection), convalescent serum samples was obtained from 15 patients (71%; 11 with severe infection, 6 of whom were pregnant; 4 with moderate infection, 1 of whom was pregnant) a mean (±SD) of 90±23 days (range, 38–126 days) after the initial acute-phase specimen was obtained. Convalescent-phase serum samples were not available for 6 patients, because 2 had died, 3 were not contactable, and 1 refused testing. Serum IgG2 results are shown in Figure 2. Among the 11 patients with previous severe H1N1 infection, serum IgG2 levels remained in the deficient range for 8 (73%; 3 postpartum, one pregnant, and 4 nonpregnant; Figure 2). Two of the 3 patients with severe H1N1 infection with normal convalescent serum IgG2 levels were postpartum women; 1 of these 2 women had received intravenous pooled immunoglobulin as a component of her therapy for severe H1N1 infection, but this was 77 days before testing of convalescent-phase serum samples. Notably, the only patient with severe H1N1 infection with normal convalescent-phase IgG2 levels who was nonpregnant was only mildly deficient during the acute phase of illness (acute-phase IgG2 level, 2.1 g/L; convalescent-phase IgG2 level, 2.6 g/L; normal range, ⩾2.4 g/L). Of the 4 patients with moderate H1N1 infection who were assessed at follow-up, 3 remained IgG2 deficient, including 1 woman who was still pregnant at this time (Figure 2).

Persistence of immunoglobulin deficiency was less prominent for non-IgG2 subclasses. Among the 8 patients with severe H1N1 infection who were initially deficient in IgG1, 6 had normal IgG1 levels on testing of convalescent-phase serum samples (data not shown). Similarly, hypoalbuminemia had resolved in most patients (9 of 14 assessable patients); however, of the other 5 patients, 2 remained pregnant at the time of follow-up.

Immunoglobulin levels and pregnancy. A total of 9 patients with H1N1 infection were pregnant (23%; table 1). Serum immunoglobulin levels for these patients were compared with levels for 17 healthy pregnant control subjects, and results are shown in Figure 1 and Table 3. The healthy pregnant women were slightly older than those with H1N1 infection, but both groups were similar with regard to mean gestation period (Table 3). Among the 17 healthy patients, 10 had mildly low IgG1 and/or IgG2 levels, compared with the standard reference range for nonpregnant women (IgG1 alone, 4 patients; IgG2 alone, 4 patients; IgG1 and IgG2, 2 patients). However, pregnant women with H1N1 infection had significantly lower mean levels of total IgG (P<.001), IgG1 (P=.005), and IgG2 (P=.001) than did the 17 control subjects (Table 3 and Figure 1).

Table 3
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Table 3

Comparison of Results for Pregnant Women with H1N1 Infection versus Healthy Control Subjects

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Discussion

Although a number of authors have described the clinical features of H1N1 infection [7–9], including those of pregnancy as a risk factor for severe H1N1 infection [10], this is, to our knowledge, the first report to identify a potential association between H1N1 disease severity and the presence of immunoglobulin subclass deficiency. Patients with severe H1N1 infection were significantly more likely to be deficient in IgG2 than were patients with moderate H1N1 infection (P=.001); IgG2 deficiency was not necessarily noticeable if only total IgG levels were assessed. Furthermore, our findings suggest that, for the majority of such patients (11 of 15 patients; 73%), IgG2 deficiency persists after recovery from H1N1 infection, regardless of whether the illness was associated with possible risk factors, such as pregnancy. Low IgG2 levels are therefore less likely to be simply related to a severe inflammatory response, as is sometimes noted for acute-phase reactants, such as albumin, creatine kinase, and lactate dehydrogenase [8, 11].

IgG subclass deficiency is usually asymptomatic, and low levels of 1 or more IgG subclasses can be found in 2%–20% of healthy individuals [12, 13]. If symptomatic, patients with IgG subclass deficiency tend to have recurrent sinopulmonary bacterial infections [13]. However, to our knowledge, IgG subclass deficiency has not been studied in detail in humans with influenza infection, although in mouse models, anti-influenza antibody (and specifically IgG) has a key role in virus control in the lower respiratory tract, compared with the upper respiratory tract [14, 15]. In humans, Logtenberg et al [16] described a single patient with severe transitory hypogammaglobulinemia associated with acute influenza A virus infection. However, in this case, all immunoglobulin classes (IgG, IgM, and IgA) were affected. Other than this report, we can find no other association between influenza and immunoglobulin deficiency.

Thus, it is uncertain whether we have simply identified a cohort of patients with H1N1 infection with underlying unrecognized IgG2 deficiency, or whether there is an interaction between the H1N1 virus and the host that leads to such deficiency. Given that the half-life of IgG2 is ∼3 weeks [17], a potent and specific interaction between H1N1 virus and host B cells would need to occur to lead to such a precipitous decrease in serum IgG2. Bone marrow apoptosis of B cells by influenza virus has been demonstrated in mice [18], but how this relates to disease in humans remains unclear. However, the fact that the IgG2 deficiency that we identified appears to persist in most cases long after disease resolution (convalescent serum samples were collected a mean (±SD) of 90±23 days after the acute phase of illness) suggests the possibility of potential long-term implications for these patients and that follow-up of moderate and severe cases of H1N1 infection may be warranted.

Because of our findings, we hypothesize that IgG2 deficiency may be associated with an inability to mount an early effective immune response to influenza and may therefore be linked to severe disease. Furthermore, if the IgG2 deficiency that we observed is long-lasting or permanent, will this affect the patients' likely response to influenza vaccination? Response to influenza vaccination is measured by specific neutralization assays, rather than by total immunoglobulin concentrations, and it is not known whether response to influenza vaccination by individuals who are IgG2 subclass deficient is diminished.

Pregnancy is a known risk factor for increased severity of both seasonal and pandemic influenza infections [19–23], which is thought to be attributable to pregnancy-related physiologic and immunologic changes, such as decreased lung capacity and increased cardiovascular demand, as well as a shift away from cell-mediated immunity to humoral immunity [24]. Our finding that a substantial number (10 of 17) of our healthy pregnant cohort had mildly low IgG1 and/or IgG2 levels is consistent with the known decrease in immunoglobulin levels that occurs during normal pregnancy and resolves after delivery [25, 26]. Low IgG2 levels in pregnant women could therefore potentially explain why pregnancy appears to be a risk factor for severe H1N1 infection [2–4]. However, this alone does not appear to explain the significantly lower levels of IgG2 observed among pregnant patients with H1N1 infection, compared with levels among our healthy pregnant control subjects (P=.001), nor the fact that IgG2 deficiency persisted postpartum in some women with severe H1N1 infection.

Although IgG2 deficiency appears to be associated with H1N1 infection severity, it remains uncertain whether administration of immunoglobulin to patients who are IgG2 deficient is likely to be therapeutically beneficial. We administered pooled immunoglobulin to some of our patients with severe H1N1 infection who had IgG2 deficiency, but our observations were uncontrolled. Nevertheless, convalescent blood products were administered during the Spanish influenza pandemic with a reduction in mortality [27], and more recently, convalescent-phase plasma samples obtained from a patient who recovered from H5N1 influenza infection was used successfully [28]. Further investigation of the use of convalescent-phase blood products in severe pandemic H1N1 infection is needed.

Our study has a number of important limitations, including being of relatively limited size and lacking suitable specimens to analyze patient cellular immunity or to assess influenza virus neutralization, and we have not compared our findings with those that might be expected among healthy nonpregnant control subjects. Furthermore, with the number of cases of H1N1 infection now decreasing in Australia, our findings need to be confirmed in other geographical locations (although the H1N1 strain circulating in Victoria appears to be the same as that isolated in the Northern Hemisphere) [4].

Nevertheless, we considered our finding of a statistically significant association between IgG2 deficiency and H1N1 infection severity to be sufficiently notable and hypothesis-generating in terms of potential clinical therapeutic importance that prompt notification of these data to clinicians managing cases of H1N1 infection was warranted.

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Acknowledgments

We are grateful to the medical and pathology staff at all participating centers, but particularly Geoff Raines, for his assistance in rapidly collating the clinical and laboratory data described. We are also grateful to the Ethics Committee members at all sites for the expedited review of our project submission.

Financial support. National Health and Medical Research Council of Australia Strategic Award.

Potential conflicts of interest. All authors: no conflicts.

  • Received August 21, 2009.
  • Accepted November 23, 2009.
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  1. Clin Infect Dis. (2010) 50 (5): 672-678. doi: 10.1086/650462
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