Low Levels of Immunoglobulins and Mannose-Binding Lectin Are Not Associated With Etiology, Severity, or Outcome in Community-Acquired Pneumonia

Low Levels of Immunoglobulins and Mannose-Binding Lectin Are Not Associated With Etiology,... Open Forum Infectious Diseases MAJOR ARTICLE Low Levels of Immunoglobulins and Mannose-Binding Lectin Are Not Associated With Etiology, Severity, or Outcome in Community-Acquired Pneumonia 1,2,3 1,2,3,a 2,3 1,3 2,3,4 5 6 7 William W. Siljan, Jan C. Holter, Ståle H. Nymo, Einar Husebye, Thor Ueland, Lillemor Skattum, Vidar Bosnes, Peter Garred, 2,3,8 4,9,10,11 2,3,8,10 1,3 Stig S. Frøland, Tom E. Mollnes, Pål Aukrust, and Lars Heggelund 1 2 Department of Internal Medicine, Drammen Hospital, Vestre Viken Hospital Trust, Drammen, Norway; Research Institute of Internal Medicine, Oslo University Hospital Rikshospitalet, Oslo, 3 4 Norway; Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway; Research Laboratory, Nordland Hospital, Bodø, and Faculty of Health Sciences, K.G. Jebsen TREC, University of Tromsø, Tromsø, Norway; Department of Laboratory Medicine, Section of Microbiology, Immunology and Glycobiology, Lund University and Clinical Immunology and Transfusion 6 7 Medicine, Region Skåne, Lund, Sweden; Department of Immunology, Section of Medical Immunology, Oslo University Hospital Ullevaal, Oslo, Norway; Laboratory of Molecular Medicine, Department of Clinical Immunology, Rigshospitalet and Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark; Section of Clinical Immunology and Infectious 9 10 Diseases, Oslo University Hospital Rikshospitalet, Oslo, Norway; Department of Immunology, Faculty of Medicine, University of Oslo, Oslo, Norway; K.G. Jebsen Inflammatory Research Center, University of Oslo, Oslo, Norway; Centre of Molecular Inflammation Research, Norwegian University of Science and Technology, Trondheim, Norway. Background. Disease severity and outcome in community-acquired pneumonia (CAP) depend on the host and on the challenge of the causal microorganism(s). We measured levels of immunoglobulins (Igs) and complement in 257 hospitalized adults with CAP and examined the association of low levels of Igs or complement to microbial etiology, disease severity, and short-term and long-term outcome. Methods. Serum Igs were analyzed in blood samples obtained at admission and at 6 weeks postdischarge if admission levels were low. Serum complement deficiencies were screened with a total complement activity enzyme-linked immunosorbent assay (ELISA), with further analyzes performed if justified. Disease severity was assessed by the CURB-65 severity score. Short-term outcome was defined as a composite end point of intensive care unit (ICU) admission and 30-day mortality, and long-term outcome as 5-year all-cause mortality. Results. At admission, 87 (34%) patients had low levels of at least 1 Ig, with low IgG2 as the most prevalent finding (55/21%). IgG levels were lower in bacterial than viral CAP (8.48 vs 9.97 g/L, P = .023), but low Igs were not associated with microbial etiology. Fifty-five (21%) patients had low lectin pathway activity, of which 33 (13%) were mannose-binding lectin (MBL) deficient. Low ad- mission levels of any Ig or MBL were not associated with disease severity, short-term outcome, or long-term outcome. Excluding patients defined as immunocompromised from analysis did not substantially ae ff ct these results. Conclusion. In hospitalized adults with CAP, low admission levels of Igs or complement were in general not associated with microbial etiology, disease severity, short-term outcome, or long-term outcome. Keywords. complement; etiology; immunoglobulin; mannose-binding lectin; mannose-binding protein-associated serine pro- teases; mortality; pneumonia. Community acquired-pneumonia (CAP) still has high mor- Immunoglobulins (Igs) are fundamental mediators of bidity and mortality worldwide despite advances in its man- humoral immunity by neutralization, opsonization, and agement [1], resulting in an increasing number of hospital phagocytosis of pathogens and by contributing to comple- and intensive care unit (ICU) admissions [2, 3]. Patients with ment activation [5]. Deficiencies in this antibody-mediated primary or secondary immunodeficiencies are more suscepti- immune system implicate a significant risk of recurrent infec- ble to pulmonary infections, and the occurrence of secondary tions, in particular those caused by encapsulated bacteria in immunodeficiencies is rising, caused by wider use of immuno- the respiratory tract [6, 7]. In the acute phase of infectious suppressive medications [4]. diseases such as sepsis and severe influenza, low levels of Igs have been associated with an unfavorable outcome [8–10]. Correspondingly, an association between subnormal levels of Received 27 September 2017; editorial decision 21 December 2017; accepted 3 January 2018. Present affiliation: Department of Microbiology, Oslo University Hospital Ullevaal, Oslo, Norway Igs, predominantly total IgG and IgG1/2 subclasses, and dis- Correspondence: W.  W. Siljan, MD,  Department of Internal Medicine, Drammen Hospital, ease severity has been reported in CAP and influenza A H1N1 Vestre Viken Hospital Trust, NO-3004 Drammen, Norway (williasi@ulrik.uio.no). cohorts [11–13]. However, the relevance of Ig levels in relation Open Forum Infectious Diseases © The Author(s) 2018. Published by Oxford University Press on behalf of Infectious Diseases to microbial etiology in CAP is less clear, although it is well Society of America. This is an Open Access article distributed under the terms of the Creative known that IgG and in particular IgG2 are of major impor- Commons Attribution-NonCommercial-NoDerivs licence (http://creativecommons.org/licenses/ by-nc-nd/4.0/), which permits non-commercial reproduction and distribution of the work, in any tance for the pulmonary defense against encapsulated bacteria medium, provided the original work is not altered or transformed in any way, and that the work [14, 15]. Furthermore, whereas an association has been estab- is properly cited. For commercial re-use, please contact journals.permissions@oup.com DOI: 10.1093/ofid/ofy002 lished in primary hypogammaglobulinemia, the significance of Low Immunoglobulin and Complement in CAP • OFID • 1 Downloaded from https://academic.oup.com/ofid/article-abstract/5/2/ofy002/4791230 by Ed 'DeepDyve' Gillespie user on 16 March 2018 a transient decrease in IgG/IgG2 levels during infections like In the current study, patients with missing Ig and comple- CAP is more uncertain. ment analyses at hospital admission (n  =  10) were excluded, e co Th mplement system is a key part of immune defense, leaving a sample of 257 (ie, analysis cohort). (The inclusion constituting a functional bridge between innate and humoral process is summarized in Supplementary Appendix.) Patients immunity [16]. Complement may be activated through 3 major were invited to an outpatient follow-up approximately 6 weeks pathways; the classical, lectin, and alternative, with consider- aer h ft ospital discharge (convalescent phase, n  =  220). When able crosstalk between the pathways and with other branches of analyzing associations with long-term outcome, patients who the immune system. Complement deficiencies have been asso- died were considered responders at their death dates, and those ciated with increased susceptibility to bacterial infections [17]. who survived aer t ft he closing date were considered censored; e m Th ost prevalent deficiencies of the complement system are patients who died within 30  days aer h ft ospital admission mannose-binding lectin (MBL) and complement component 2 (n = 10) were excluded. Patients lost to follow-up were censored (C2), and it has been shown that individuals with C2 deficiency at the time of last contact. are more prone to infections and severe outcome in pneumo- Of the 257 patients in this study, 45 were considered im- nia [17]. MBL is a soluble pattern recognition molecule, mainly munocompromised. An immunocompromised host included exerting its effects through opsonization of pathogens and the occurrence of (i) primary or secondary immunodeficiency, subsequent activation of the lectin complement pathway [18]. defined as antibody deficiency, human immunodeficiency virus Genetically determined MBL deficiency is very prevalent, as (HIV), organ transplant, and/or receiving chemotherapy and/ complete deficiency ae ff cts 5% to 10% and low levels are seen in or radiation therapy within the past 3 months; (ii) active malig- up to 30% of the Caucasian population [19]. With the exception nancy, defined as any cancer except basal—or squamous—cell of patients with cystic fibrosis [20] and, potentially, common cancer of the skin that was active at the time of presentation variable immunodeficiency (CVID) [21], the significance of or diagnosed within 1  year of presentation; or (iii) immuno- MBL deficiency in relation to CAP remains unclear. suppressive drug use, defined as any use of systemic steroids, We have previously reported that by using extended diagnos- Azathioprine, TNF inhibitor, Cyclosporine, Cyclophosphamide, tics, a high microbial yield was achieved in a well-defined co- or Methotrexate within the past 3 months. hort of patients with CAP [22]. The objective of this study was All patients provided written informed consent. The study to assess the presence of low Ig levels and decreased activation was approved by the Regional Committee for Medical and of the 3 major complement activation pathways at hospital ad- Health Research Ethics in South-Eastern Norway (ref. number mission and, if present, examine their association to microbial S-06266a), and a waiver of consent was obtained from the com- etiology, disease severity, and short-term and long-term out- mittee to link patient data to death certificates (2012/467 A). come. We hypothesized that low Ig levels, especially low IgG2, Data Collection and Definitions and decreased complement activation at admission would be Baseline data collection and definitions have been described associated with bacterial etiology and unfavorable outcome elsewhere [22, 23]. In brief, demographic, clinical, and labora- in CAP. tory data were collected within 48 hours of admission. The mean time from hospital admission to study inclusion was MATERIALS AND METHODS 0.6  ±  0.5  days, and 250 of 257 (97%) patients were included Study Population and Design within 24 hours. The microbial etiology of CAP was established The study was performed in an acute care 270-bed general by use of comprehensive microbiological testing (ie, bacterial hospital in Drammen, Vestre Viken Hospital Trust, in South- cultures, serology, urinary antigen tests, and polymerase chain Eastern Norway between January 1, 2008, and January 31, 2011; reaction [PCR]). 267 patients aged ≥18  years admitted with suspected pneu- Blood Sampling monia to the Department of Internal Medicine were consecu- Blood samples were obtained at hospital admission and at the tively included. Patients were screened for eligibility within the scheduled 6-week follow-up, with serum and plasma samples first 48 hours of hospital admission by determining presence drawn into pyrogen-free vacutainer tubes. Tubes for plasma of CAP criteria, defined by (i) a new pulmonary infiltrate on samples contained ethylenediaminetetraacetic acid (EDTA) chest radiograph, (ii) rectal temperature >38.0°C, and (iii) at as anticoagulant. Serum or plasma was separated from whole least 1 of the following symptoms or signs: cough (productive blood within 60 minutes by refrigerated centrifugation at 2000 g or nonproductive), dyspnea, respiratory chest pain, crackles, for 12 minutes and stored in several aliquots at –80ºC. Samples or reduced respiratory sounds. If the chest radiographic exam- were thawed only once. ination uncovered noninfectious causes such as pulmonary infarction, tumor, or bronchiectasis, or if the patient had been Ig and Complement Analyses hospitalized within the past 2 weeks, the patient was excluded Serum levels of IgM, IgA, IgG, and IgG subclasses (IgG1, from the study. IgG2, IgG3, IgG4) at hospital admission were quantified by 2 • OFID • Siljan et al Downloaded from https://academic.oup.com/ofid/article-abstract/5/2/ofy002/4791230 by Ed 'DeepDyve' Gillespie user on 16 March 2018 immunonephelometr y (BN ProSpec nephelometer, Siemens AG, logistic regressions were used to assess the association be- Germany, and Cobas 8000 analyzer, Roche AG, Switzerland). tween Ig or complement parameters and short-term outcome. The reference values are given in Supplementary Appendix. In Adjusted Cox regression analysis was used to assess the asso- patients with levels of IgG or IgG2 below reference range at ciation between Ig or complement parameters and long-term hospital admission, samples from the 6-week follow-up were outcome. A  2-sided P value <.05 was considered significant. analyzed. Statistical analyses were performed using STATA, version 14.0, Complement deficiencies were screened in serum with a for Windows (Stata Corp LP, College Station, TX) and SPSS, total complement activity enzyme-linked immunosorbent version 23.0, for Windows (IBM Corp, Armonk, NY). assay (ELISA; Complement system Screen, Wieslab, Euro RESULTS Diagnostica, Malmö, Sweden). The method includes classical pathway (CP), lectin pathway (LP), and alternative pathway Ig Levels Below Reference Range (AP) activity with a common readout for terminal pathway ac- At hospital admission, 87 (34%) patients had levels below the tivity and has been described in detail previously [24]. The val- reference range of at least 1 Ig (IgM, IgA, IgG, IgG1, IgG2, IgG3, ues are given in percentage related to a standard serum defined or IgG4), with low IgG2 levels as the most prevalent finding (55 to contain 100% activity. e Th reference ranges are given in the patients/21%) (Figure  1). At the 6-week follow-up, IgG levels Figure 2 legend. Patients with indications of complement defi- remained low in more than one-third of patients with sub- ciency from the screening were further analyzed for the com- normal levels at admission (12 patients, 40%). In particular, plement proteins described below. 39 out of the 50 (78%) patients with low IgG2 at admission (2 MBL was quantified using an ELISA described in detail pre- deceased, 3 missing samples) had levels below the reference viously [19]; low levels were defined as <50  ng/mL. C1q and range at the 6-week follow-up (Figure 1). We found no increase C2 were quantified at Region Skåne, Lund, Sweden, and C3 and in comorbidities (cardiovascular disease [CVD], chronic ob- C4 at Oslo University Hospital, Oslo, Norway, using standard structive pulmonary disease [COPD], autoimmune disease, immunochemical techniques. diabetes mellitus, renal disease, neurological disease) among In brief, mannose-binding lectin–associated serine protease patients with low IgM, IgA, IgG, or IgG2 levels compared with 1 and 2 (MASP-1 and MASP-2, respectively) deficiencies were the rest of the study population. identified by genotyping for MASP1 G426E (rs28945068) and Ig Levels in Relation to Microbial Etiology MASP2 D120G (rs72550870), while analysis of MASP-2 bind- Low levels of any Ig at hospital admission were not related to ing to MBL or ficolins was performed in serum with an assay a specific group of microbial etiology. However, serum levels from Hycult Biotech (HM2190-IA, Uden, the Netherlands) [25, of IgG differed significantly between the groups of etiology 26]. Plasma levels of MASP-2 were quantified by an ELISA kit (P  =  .027), with lower levels seen in bacterial than viral CAP (Hycult Biotech), with a reference range of 170–1196 ng/mL. (P = .023). For IgA, IgM, or any of the IgG subclasses, no rela- Outcome Measures tion to microbial etiology was seen (Table  1). Additionally, in Based on the etiology, patients were categorized into 4 groups: patients with low levels of any Ig, CAP caused by encapsulated (i) bacterial, (ii) viral, (iii) viral-bacterial, and (iv) unknown. bacteria (S. pneumoniae and H. Influenzae) did not occur more In addition, patients with Streptococcus pneumoniae or frequently (P = .734). Haemophilus influenzae were studied separately. Disease sever- Ig Levels in Relation to Disease Severity, Short-term Outcome, and Long- ity was evaluated by the validated CURB-65 scoring system term Outcome [27]; patients with a CURB-65 score of <3 were classified into a Patients with low IgG or IgG2 at both time points did not pres- low-risk group and ≥3 into a high-risk group. Short-term out- ent with a higher CURB-65 severity score (P = .594) than other come was defined as a composite end point of ICU admission CAP patients. Moreover, there were no differences in Ig levels and 30-day mortality [28]. Long-term outcome was defined as between patients with high (≥3) vs low (< 3) CURB-65 severity 5-year all-cause mortality. score (Table 2). Statistical Analysis In all, 39 (15%) patients were survivors requiring ICU admis- Categorical variables were expressed as counts (percentages), sion, while 10 (4%) patients died within 30  days of hospital and continuous variables were presented as mean (standard admission. In univariate logistic regression analysis, Igs were deviation) for normally distributed data or median (25th–75th not associated with an adverse short-term outcome when percentiles) for visually skewed data. Continuous variables were assessed as continuous variables (Table 3). Similarly, Igs below analyzed using a t test, and comparison of categorical variables the reference range were not associated with an adverse short- were compared using the χ test or 1-way ANOVA, where ap- term outcome (Table 3). propriate, whereas Tukey’s test was performed for post hoc test Excluding patients who died within 30  days of hospital of differences between pair of groups. Univariate and adjusted admission, 5-year mortality was 26% (65/246 patients, 1 lost Low Immunoglobulin and Complement in CAP • OFID • 3 Downloaded from https://academic.oup.com/ofid/article-abstract/5/2/ofy002/4791230 by Ed 'DeepDyve' Gillespie user on 16 March 2018 Ig levels below reference range Admission 6 weeks 7 7 IgM IgA IgG IgG1 IgG2 IgG3 IgG4 Figure  1. Patients with serum immunoglobulin levels below reference range at hospital admission and 6-week follow-up in 257 hospitalized patients with communi- ty-acquired pneumonia. Data are presented as numbers. Only patients with low IgG or IgG2 at hospital admission were analyzed at 6-week follow-up. Abbreviation: Ig, immunoglobulin. Complement Deficiencies to follow-up). In age- and gender-adjusted Cox regression ana- Screening of serum samples documented 55 (21%) patients lysis, low levels of Igs were not associated with increased 5-year with low or undetectable lectin pathway activity, of which 3 also mortality (Supplementary Table  2). Adjustment for clinically had a defective classical pathway activity (Figure 2). One of the significant comorbidities (CVD, COPD, active malignancy, and 3 patients had an MBL deficiency, was quantified for C1q, and renal disease) did not ae ff ct results for disease severity, short- had only a slightly reduced level. The other 2 had normal MBL term outcome, or long-term outcome. and were quantified for C2 and C4, both with normal levels. Ig Results Excluding Immunocompromised Patients Abnormalities in functional activity of the alternative pathway Forty-five patients were defined as immunocompromised at were not observed in our patient cohort (Figure 2). study inclusion, leaving 212 patients in the study population MASP-2 Deficiency when excluding these. In this assumed nonimmunocompro- One patient with a lectin pathway deficiency, normal MBL lev- mised group, Ig levels at hospital admission differed signifi- els (1134 ng/mL), and normal classical and alternative pathway cantly between groups of microbial etiology for IgA (P = .048) activity was found to be homozygote MASP-2 deficient. MASP-2 and IgG2 (P  =  .021), with lower levels seen in bacterial than in serum did not form complexes with MBL or ficolins. Protein in viral-bacterial CAP for IgA (mean 2.55  ±  1.13  g/L vs quantification of MASP-2 was in accordance with a defect, being 3.34 ± 2.13 g/L, P = .039) and in bacterial vs viral CAP for IgG2 63 and 29  ng/mL at hospital admission and 6-week follow-up, (mean 2.51 ± 0.99 g/L vs 3.22 ± 1.45 g/L, P = .018). By contrast, respectively, well below the reference range of 170–1196  ng/ low levels of any Ig were not associated with a higher CURB- mL. The patient was a previously healthy female aged 66  years 65 severity score. The number of adverse outcomes in this sub- without tendency to infection. The CURB-65 severity score at group was too low to perform outcome analyses. Table 1. Serum Immunoglobulin Levels (g/L) and Number of Patients With Serum Immunoglobulin Levels Below Reference Range at Hospital Admission in 257 Hospitalized Patients With Community-Acquired Pneumonia, Stratified by Etiology Total Bacterial Viral-Bacterial Viral Unknown (n = 257) (n = 73) (n = 49) (n = 39) (n = 96) P IgM 0.86 ± 0.53 0.91 ± 0.59 0.84 ± 0.51 0.81 ± 0.41 0.95 ± 0.66 .657 IgA 2.83 ± 1.64 2.57 ± 1.09 3.16 ± 2.09 2.91 ± 1.82 2.43 ± 1.25 .139 IgG 9.08 ± 2.87 8.48 ± 2.71 9.26 ± 2.82 9.97 ± 3.04 8.72 ± 2.81 .027 IgG1 6.44 ± 2.53 6.01 ± 2.14 6.51 ± 2.51 7.16 ± 3.06 6.25 ± 2.29 .071 IgG2 2.70 ± 1.23 2.49 ± 1.10 2.81 ± 1.18 2.96 ± 1.46 2.49 ± 1.22 .123 IgG3 0.45 ± 0.31 0.44 ± 0.25 0.48 ± 0.37 0.46 ± 0.33 0.38 ± 0.23 .764 IgG4 0.55 ± 0.55 0.56 ± 0.56 0.51 ± 0.40 0.59 ± 0.68 0.57 ± 0.60 .762 IgG < ref. range 30 (100) 13 (36.7) 3 (10.0) 3 (10.0) 11 (43.3) .099 IgG2 < ref. range 55 (100) 17 (30.9) 6 (10.9) 7 (12.7) 25 (45.5) .313 Data are presented as means and ± standard deviation or No. (%). Group comparison performed with 1-way analysis of variance or χ test as appropriate. Patients with unknown etiology excluded from statistical analysis. Abbreviations: Ig, immunoglobulin. Assessed as dichotomous variables. 4 • OFID • Siljan et al Downloaded from https://academic.oup.com/ofid/article-abstract/5/2/ofy002/4791230 by Ed 'DeepDyve' Gillespie user on 16 March 2018 Patients, No. Table  2. Serum Immunoglobulin Levels (g/L) or Number of Patients DISCUSSION With Low Immunoglobulin Levels at Hospital Admission Stratified by In the present study, admission Ig levels below reference range CURB-65 <3 vs CURB-65 ≥3 in 257 Hospitalized Patients With Community- Acquired Pneumonia were not associated with a specific group of microbial etiology in CAP, but IgG and IgG2 levels were significantly lower in bac- CURB-65 < 3 CURB-65 ≥3 terial than in viral CAP. Second, Ig levels below the reference Immunoglobulin (n = 157) (n = 95) P range at hospital admission were not associated with disease se- IgM 0.91 ± 0.53 0.88 ± 0.66 .737 verity, short-term outcome, or long-term outcome. Third, MBL IgA 2.64 ± 1.67 2.74 ± 1.19 .610 deficiency was not associated with microbial etiology, disease IgG 8.74 ± 2.88 9.17 ± 2.77 .249 IgG1 6.19 ± 2.54 6.56 ± 2.22 .241 severity, or outcome measures. IgG2 2.59 ± 1.23 2.67 ± 1.23 .601 Even though admission Ig levels below the reference range IgG3 0.42 ± 0.24 0.44 ± 0.35 .454 were not associated with a specific microbial etiology in our IgG4 0.53 ± 0.54 0.59 ± 0.59 .409 study, IgG levels were significantly lower in bacterial than in IgG < ref. range 20 (66.7) 10 (33.3) .690 a viral CAP, and when excluding immunocompromised patients, IgG2 < ref. range 35 (64.8) 19 (35.2) .752 we found lower levels of IgG2 in bacterial vs viral CAP. Still, the Data presented as means and ± standard deviation or No. (%). Group comparison per- formed with t test or χ test, as appropriate. Data on CURB-65 severity score are missing IgG2 associations with bacterial CAP in the present cohort may in 5 patients.  be regarded as modest, and therefore in line with results from Abbreviations: CURB-65, Confusion, Urea, Respiratory rate, Blood pressure, Age ≥65; Ig, immunoglobulin. an Australian CAP study [11], where no single pathogen was Assessed as dichotomous variables. associated with low IgG subclass levels, illustrating an uncertain impact of IgG2 deficiency. Antibodies to polysaccharide anti- gens of encapsulated bacteria are largely, but not entirely, of the admission was 1.  She was treated with intravenous antibiotics IgG2 subclass, while antibodies to protein antigens of viruses at a general ward for 5 days before discharge. The microbial eti- are IgG1 and IgG3 [29]. Previously, increased susceptibility to ology of CAP was not identified. infections caused by encapsulated bacteria in patients with low MBL Deficiency in Relation to Microbial Etiology, Disease Severity, and IgG2 has been demonstrated [14, 15, 30], suggesting that inher- Outcome ently IgG2-deficient patients have a reduced ability to mount MBL-deficient serum samples were not related to microbial an antibody response to certain polysaccharide antigens, lead- etiology, disease severity, or short-term or long-term outcome ing to an inadequate defense against invading pathogens like (Supplementary Table  3, A–D). A  similar pattern was seen S.  pnuemoniae and H.  inu fl enzae. Yet, an appropriate immune when excluding immunocompromised patients, rendering response may remain intact in patients with low IgG2 levels, as 31/212 (15%) patients with MBL deficiency (data not shown). the cause of reduced levels remains unclear. Another possible Adjustment for clinically significant comorbidities (CVD, reason for low IgG2 levels may be consumption of antibodies COPD, active malignancy, and renal disease) did not affect in the acute phase of CAP, with low levels subsequently seen at results for disease severity, short-term outcome, or long-term hospital admission. outcome. e c Th auses and clinical importance of our IgG and IgG2 find- ings are therefore uncertain. Several recent studies have reported an association between Table  3. Univariate Logistic Regression Analysis of Serum low Ig levels, disease severity, and unfavorable outcome in Immunoglobulin Levels at Hospital Admission and Association to ICU patients with sepsis [8]. In CAP, however, this association has Admission/30-Day Mortality in 257 Hospitalized Patients With Community- Acquired Pneumonia not been explored to the same extent. Feldman et al. could not find any differences in IgG subclass  levels between 66 non- Immunoglobulins OR (95% CI) P ICU and ICU patients with CAP [31]. By contrast, a recent IgM 1.16 (0.69–1.93) .579 Spanish study of 418 CAP patients showed a significant asso- IgA 0.95 (0.77–1.18) .632 ciation between low Ig levels (IgG/IgG1) in patients with a IgG 0.94 (0.84–1.06) .315 CURB-65 severity score of 4 and 5, in ICU patients vs non- IgG1 0.99 (0.87–1.12) .843 ICU patients (IgG/IgG1/IgG2), and with 30-day mortality IgG2 0.85 (0.64–1.11) .232 IgG3 0.99 (0.33–3.03) .993 (IgG/IgG1/IgG2) [13]. Low levels of IgG2 have been observed IgG4 1.07 (0.63–1.82) .811 in patients with severe H1N1 influenza in China [32] and IgG < ref. range 1.64 (0.68–3.94) .268 Australia [10, 11]. Of note, in the Chinese study, the lowest IgG2 < ref. range 1.42 (0.69–2.91) .340 IgG2 levels were seen in seriously ill influenza patients with a Abbreviations: CI; confidence interval; ICU, intensive care unit; Ig, immunoglobulin; OR, bacterial co-infection [32]. In our study, low serum levels of odds ratio. Assessed as dichotomous variables. Igs at admission were associated neither with disease severity Low Immunoglobulin and Complement in CAP • OFID • 5 Downloaded from https://academic.oup.com/ofid/article-abstract/5/2/ofy002/4791230 by Ed 'DeepDyve' Gillespie user on 16 March 2018 250 200 150 0 0 0 Classical pathway activity, % Alternative pathway activity, % Lectin pathway activity, % Figure  2. Serum total complement activity for the classical pathway (CP), alternative pathway (AP), and lectin pathway (LP) at hospital admission in 257 hospitalized patients with community-acquired pneumonia. Values are given in percentage related to a standard serum defined to contain 100% activity. Low levels were defined as <10% activity for CP, <10% for AP, and <10% for LP. nor with ICU admission and 30-mortality. The low number MBL deficiency and CAP severity and outcome may exist, even of severely ill patients may have influenced our observations though our results do not support an association. regarding outcome. Nonetheless, the relationship between low MASP-2, a part of the MASP family, is a protease essential for admission Ig levels and adverse short-term outcome does not activation of the lectin complement pathway by cleavage of C4 seem to be as close in CAP as in sepsis, at least not in patients and C2 [18]. Defects of MASP-2 have been suggested to be asso- with a nonsevere clinical course. ciated with infectious diseases [39], but with an uncertain clin- Despite the considerable morbidity in primary hypogam- ical penetrance [40]. We identified a patient with a homozygous maglobulinemia, especially recurrent respiratory infections [6], MASP-2 deficiency, to our knowledge the first case described in the impact on the long-term outcome of a transient decrease in Norway. This patient was without tendency to recurrent infec- Igs during infections like pneumonia is not clear. In the present tions and did not present with a severe form of CAP, in accord- cohort, we did not find significant associations between low lev- ance with previous findings [37]. els of Igs at hospital admission and 5-year all-cause mortality, Limitations suggesting a less important role of low admission Ig levels per The following limitations should be considered. First, our study se on long-term immune responses. was performed at a single hospital, thereby possibly limiting its Although deficiency of the pattern recognition molecule generalizability. Second, blood samples were not obtained be- MBL has been associated with respiratory infections in cystic fi- yond the 6-week follow-up; thus we do not know the time frame brosis [20] and CVID [21], a consistent predisposition to pneu- of the decrease in IgG/IgG2 levels in 39 patients in this CAP monia in MBL-deficient or -insufficient patients has not been cohort. Third, the outcome measure short-term outcome was documented. A  meta-analysis indicated that MBL-deficient defined as a composite of ICU admission and 30-day mortality. patients were predisposed to invasive pneumococcal infections A  majority of patients (39/49, 80%) were categorized with the [33], but in 3 CAP studies of low MBL, including a more re- softer ICU survivor outcome parameter. cent meta-analysis, no associations to S.  pneumoniae or other Conclusion pathogens in CAP have been found [34–36]. In our study popu- In summary, neither low admission immunoglobulin levels nor lation, MBL deficiency was not associated with microbial eti- MBL deficiency was associated with microbial etiology, disease ology. Consequently, our observations support the hypothesis severity, short-term outcome, or long-term outcome in hospi- that MBL deficiency is not an important factor for microbial talized patients with CAP. vulnerability in CAP [37, 38]. A large Spanish study of 848 CAP patients found MBL Supplementary Data insufficiency to be associated with severe sepsis, multiorgan Supplementary materials are available at Open Forum Infectious Diseases online (http://ofid.oxfordjournals.org). dysfunction syndrome, ICU admission, and 90-day mortality, but not 28-day mortality [37]. In later studies, however, these Acknowledgments findings have not been reproduced [36, 38]. Similarly, an associ- We gratefully thank Kåre Bø, o Th mas Skrede, Anita Johansen, and Britt ation between MBL deficiency and disease severity or outcome Hiaasen for collection of patient data; Ola Bjørang, Helvi H. Samdal, Carina Thilesen, and Mette Bogen for excellent laboratory assistance; and Nihal measures was not seen in our CAP cohort, but in our cohort Perera for contributing to the design of the database. fewer patients had a very high CURB-65 score and the short- Financial support. This work was supported by Vestre Viken Hospital term mortality rate was fairly low. Thus, the study populations Trust, Norway. The funder had no role in the study design, data collection are not completely comparable. In conclusion, a link between and analysis, decision to publish, or preparation of the manuscript. 6 • OFID • Siljan et al Downloaded from https://academic.oup.com/ofid/article-abstract/5/2/ofy002/4791230 by Ed 'DeepDyve' Gillespie user on 16 March 2018 <10 10-50 50-100 >100 <10 10-50 50-100 >100 <10 10-50 50-100 >100 Patients, No. Patients, No. Patients, No. 20. Garred P, Pressler T, Madsen HO, et  al. Association of mannose-binding lectin Potential conifl cts of interest. All authors: no reported conflicts of gene heterogeneity with severity of lung disease and survival in cystic fibrosis. J interest. All authors have submitted the ICMJE Form for Disclosure of Clin Invest 1999; 104:431–7. Potential Conflicts of Interest. Conflicts that the editors consider relevant to 21. Fevang B, Mollnes TE, Holm AM, et al. Common variable immunodeficiency and the content of the manuscript have been disclosed. the complement system; low mannose-binding lectin levels are associated with bronchiectasis. Clin Exp Immunol 2005; 142:576–84. References 22. Holter JC, Müller F, Bjørang O, et al. Etiology of community-acquired pneumonia 1. Wunderink RG, Waterer GW. Community-acquired pneumonia. N Engl J Med and diagnostic yields of microbiological methods: a 3-year prospective study in 2014; 370:1863. Norway. BMC Infect Dis 2015; 15:64. 2. Trotter CL, Stuart JM, George R, Miller E. Increasing hospital admissions for 23. Holter JC, Ueland T, Jenum PA, et  al. Risk factors for long-term mortality after pneumonia, England. Emerg Infect Dis 2008; 14:727–33. hospitalization for community-acquired pneumonia: a 5-year prospective fol- 3. Woodhead M, Welch CA, Harrison DA, et al. Community-acquired pneumonia low-up study. PLoS One 2016; 11:e0148741. on the intensive care unit: secondary analysis of 17,869 cases in the ICNARC Case 24. Seelen MA, Roos A, Wieslander J, et al. Functional analysis of the classical, alter- Mix Programme Database. Crit Care 2006; 10(Suppl 2):S1. native, and MBL pathways of the complement system: standardization and vali- 4. Letourneau AR, Issa NC, Baden LR. Pneumonia in the immunocompromised dation of a simple ELISA. J Immunol Methods 2005; 296:187–98. host. Curr Opin Pulm Med 2014; 20:272–9. 25. Csuka D, Munthe-Fog L, Skjoedt MO, et al. A novel assay to quantitate MASP-2/ 5. Schroeder HW Jr, Cavacini L. Structure and function of immunoglobulins. J ficolin-3 complexes in serum. J Immunol Methods 2013; 387:237–44. Allergy Clin Immunol 2010; 125:S41–52. 26. Weiss G, Madsen HO, Garred P. A novel mannose-binding lectin-associated ser- 6. Notarangelo LD. Primary immunodeficiencies. J Allergy Clin Immunol 2010; ine protease 1/3 gene variant. 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Mannose-binding immunoglobulin allotype and human antibody response and susceptibility to lectin and mannose-binding lectin-associated serine protease 2 in susceptibility, polysaccharide encapsulated bacteria. J Clin Invest 1985; 75:1935–42. severity, and outcome of pneumonia in adults. J Allergy Clin Immunol 2008; 16. Dunkelberger JR, Song WC. Complement and its role in innate and adaptive 122:368–74, 374.e1–2. immune responses. Cell Res 2010; 20:34–50. 38. Endeman H, Herpers BL, de Jong BA, et al. Mannose-binding lectin genotypes in 17. Skattum L, van Deuren M, van der Poll T, Truedsson L. Complement deficiency susceptibility to community-acquired pneumonia. Chest 2008; 134:1135–40. states and associated infections. Mol Immunol 2011; 48:1643–55. 39. Stengaard-Pedersen K, Thiel S, Gadjeva M, et  al. Inherited deficiency of 18. Garred P, Genster N, Pilely K, et al. A journey through the lectin pathway of com- mannan-binding lectin-associated serine protease 2. N Engl J Med 2003; plement-MBL and beyond. Immunol Rev 2016; 274:74–97. 349:554–60. 19. Garred P, Madsen HO, Kurtzhals JA, et al. Diallelic polymorphism may explain 40. García-Laorden MI, García-Saavedra A, de Castro FR, et  al. Low clinical pen- variations of the blood concentration of mannan-binding protein in Eskimos, but etrance of mannose-binding lectin-associated serine protease 2 deficiency. J not in black Africans. Eur J Immunogenet 1992; 19:403–12. Allergy Clin Immunol 2006; 118:1383–6. Low Immunoglobulin and Complement in CAP • OFID • 7 Downloaded from https://academic.oup.com/ofid/article-abstract/5/2/ofy002/4791230 by Ed 'DeepDyve' Gillespie user on 16 March 2018 http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Open Forum Infectious Diseases Oxford University Press

Low Levels of Immunoglobulins and Mannose-Binding Lectin Are Not Associated With Etiology, Severity, or Outcome in Community-Acquired Pneumonia

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Open Forum Infectious Diseases MAJOR ARTICLE Low Levels of Immunoglobulins and Mannose-Binding Lectin Are Not Associated With Etiology, Severity, or Outcome in Community-Acquired Pneumonia 1,2,3 1,2,3,a 2,3 1,3 2,3,4 5 6 7 William W. Siljan, Jan C. Holter, Ståle H. Nymo, Einar Husebye, Thor Ueland, Lillemor Skattum, Vidar Bosnes, Peter Garred, 2,3,8 4,9,10,11 2,3,8,10 1,3 Stig S. Frøland, Tom E. Mollnes, Pål Aukrust, and Lars Heggelund 1 2 Department of Internal Medicine, Drammen Hospital, Vestre Viken Hospital Trust, Drammen, Norway; Research Institute of Internal Medicine, Oslo University Hospital Rikshospitalet, Oslo, 3 4 Norway; Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway; Research Laboratory, Nordland Hospital, Bodø, and Faculty of Health Sciences, K.G. Jebsen TREC, University of Tromsø, Tromsø, Norway; Department of Laboratory Medicine, Section of Microbiology, Immunology and Glycobiology, Lund University and Clinical Immunology and Transfusion 6 7 Medicine, Region Skåne, Lund, Sweden; Department of Immunology, Section of Medical Immunology, Oslo University Hospital Ullevaal, Oslo, Norway; Laboratory of Molecular Medicine, Department of Clinical Immunology, Rigshospitalet and Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark; Section of Clinical Immunology and Infectious 9 10 Diseases, Oslo University Hospital Rikshospitalet, Oslo, Norway; Department of Immunology, Faculty of Medicine, University of Oslo, Oslo, Norway; K.G. Jebsen Inflammatory Research Center, University of Oslo, Oslo, Norway; Centre of Molecular Inflammation Research, Norwegian University of Science and Technology, Trondheim, Norway. Background. Disease severity and outcome in community-acquired pneumonia (CAP) depend on the host and on the challenge of the causal microorganism(s). We measured levels of immunoglobulins (Igs) and complement in 257 hospitalized adults with CAP and examined the association of low levels of Igs or complement to microbial etiology, disease severity, and short-term and long-term outcome. Methods. Serum Igs were analyzed in blood samples obtained at admission and at 6 weeks postdischarge if admission levels were low. Serum complement deficiencies were screened with a total complement activity enzyme-linked immunosorbent assay (ELISA), with further analyzes performed if justified. Disease severity was assessed by the CURB-65 severity score. Short-term outcome was defined as a composite end point of intensive care unit (ICU) admission and 30-day mortality, and long-term outcome as 5-year all-cause mortality. Results. At admission, 87 (34%) patients had low levels of at least 1 Ig, with low IgG2 as the most prevalent finding (55/21%). IgG levels were lower in bacterial than viral CAP (8.48 vs 9.97 g/L, P = .023), but low Igs were not associated with microbial etiology. Fifty-five (21%) patients had low lectin pathway activity, of which 33 (13%) were mannose-binding lectin (MBL) deficient. Low ad- mission levels of any Ig or MBL were not associated with disease severity, short-term outcome, or long-term outcome. Excluding patients defined as immunocompromised from analysis did not substantially ae ff ct these results. Conclusion. In hospitalized adults with CAP, low admission levels of Igs or complement were in general not associated with microbial etiology, disease severity, short-term outcome, or long-term outcome. Keywords. complement; etiology; immunoglobulin; mannose-binding lectin; mannose-binding protein-associated serine pro- teases; mortality; pneumonia. Community acquired-pneumonia (CAP) still has high mor- Immunoglobulins (Igs) are fundamental mediators of bidity and mortality worldwide despite advances in its man- humoral immunity by neutralization, opsonization, and agement [1], resulting in an increasing number of hospital phagocytosis of pathogens and by contributing to comple- and intensive care unit (ICU) admissions [2, 3]. Patients with ment activation [5]. Deficiencies in this antibody-mediated primary or secondary immunodeficiencies are more suscepti- immune system implicate a significant risk of recurrent infec- ble to pulmonary infections, and the occurrence of secondary tions, in particular those caused by encapsulated bacteria in immunodeficiencies is rising, caused by wider use of immuno- the respiratory tract [6, 7]. In the acute phase of infectious suppressive medications [4]. diseases such as sepsis and severe influenza, low levels of Igs have been associated with an unfavorable outcome [8–10]. Correspondingly, an association between subnormal levels of Received 27 September 2017; editorial decision 21 December 2017; accepted 3 January 2018. Present affiliation: Department of Microbiology, Oslo University Hospital Ullevaal, Oslo, Norway Igs, predominantly total IgG and IgG1/2 subclasses, and dis- Correspondence: W.  W. Siljan, MD,  Department of Internal Medicine, Drammen Hospital, ease severity has been reported in CAP and influenza A H1N1 Vestre Viken Hospital Trust, NO-3004 Drammen, Norway (williasi@ulrik.uio.no). cohorts [11–13]. However, the relevance of Ig levels in relation Open Forum Infectious Diseases © The Author(s) 2018. Published by Oxford University Press on behalf of Infectious Diseases to microbial etiology in CAP is less clear, although it is well Society of America. This is an Open Access article distributed under the terms of the Creative known that IgG and in particular IgG2 are of major impor- Commons Attribution-NonCommercial-NoDerivs licence (http://creativecommons.org/licenses/ by-nc-nd/4.0/), which permits non-commercial reproduction and distribution of the work, in any tance for the pulmonary defense against encapsulated bacteria medium, provided the original work is not altered or transformed in any way, and that the work [14, 15]. Furthermore, whereas an association has been estab- is properly cited. For commercial re-use, please contact journals.permissions@oup.com DOI: 10.1093/ofid/ofy002 lished in primary hypogammaglobulinemia, the significance of Low Immunoglobulin and Complement in CAP • OFID • 1 Downloaded from https://academic.oup.com/ofid/article-abstract/5/2/ofy002/4791230 by Ed 'DeepDyve' Gillespie user on 16 March 2018 a transient decrease in IgG/IgG2 levels during infections like In the current study, patients with missing Ig and comple- CAP is more uncertain. ment analyses at hospital admission (n  =  10) were excluded, e co Th mplement system is a key part of immune defense, leaving a sample of 257 (ie, analysis cohort). (The inclusion constituting a functional bridge between innate and humoral process is summarized in Supplementary Appendix.) Patients immunity [16]. Complement may be activated through 3 major were invited to an outpatient follow-up approximately 6 weeks pathways; the classical, lectin, and alternative, with consider- aer h ft ospital discharge (convalescent phase, n  =  220). When able crosstalk between the pathways and with other branches of analyzing associations with long-term outcome, patients who the immune system. Complement deficiencies have been asso- died were considered responders at their death dates, and those ciated with increased susceptibility to bacterial infections [17]. who survived aer t ft he closing date were considered censored; e m Th ost prevalent deficiencies of the complement system are patients who died within 30  days aer h ft ospital admission mannose-binding lectin (MBL) and complement component 2 (n = 10) were excluded. Patients lost to follow-up were censored (C2), and it has been shown that individuals with C2 deficiency at the time of last contact. are more prone to infections and severe outcome in pneumo- Of the 257 patients in this study, 45 were considered im- nia [17]. MBL is a soluble pattern recognition molecule, mainly munocompromised. An immunocompromised host included exerting its effects through opsonization of pathogens and the occurrence of (i) primary or secondary immunodeficiency, subsequent activation of the lectin complement pathway [18]. defined as antibody deficiency, human immunodeficiency virus Genetically determined MBL deficiency is very prevalent, as (HIV), organ transplant, and/or receiving chemotherapy and/ complete deficiency ae ff cts 5% to 10% and low levels are seen in or radiation therapy within the past 3 months; (ii) active malig- up to 30% of the Caucasian population [19]. With the exception nancy, defined as any cancer except basal—or squamous—cell of patients with cystic fibrosis [20] and, potentially, common cancer of the skin that was active at the time of presentation variable immunodeficiency (CVID) [21], the significance of or diagnosed within 1  year of presentation; or (iii) immuno- MBL deficiency in relation to CAP remains unclear. suppressive drug use, defined as any use of systemic steroids, We have previously reported that by using extended diagnos- Azathioprine, TNF inhibitor, Cyclosporine, Cyclophosphamide, tics, a high microbial yield was achieved in a well-defined co- or Methotrexate within the past 3 months. hort of patients with CAP [22]. The objective of this study was All patients provided written informed consent. The study to assess the presence of low Ig levels and decreased activation was approved by the Regional Committee for Medical and of the 3 major complement activation pathways at hospital ad- Health Research Ethics in South-Eastern Norway (ref. number mission and, if present, examine their association to microbial S-06266a), and a waiver of consent was obtained from the com- etiology, disease severity, and short-term and long-term out- mittee to link patient data to death certificates (2012/467 A). come. We hypothesized that low Ig levels, especially low IgG2, Data Collection and Definitions and decreased complement activation at admission would be Baseline data collection and definitions have been described associated with bacterial etiology and unfavorable outcome elsewhere [22, 23]. In brief, demographic, clinical, and labora- in CAP. tory data were collected within 48 hours of admission. The mean time from hospital admission to study inclusion was MATERIALS AND METHODS 0.6  ±  0.5  days, and 250 of 257 (97%) patients were included Study Population and Design within 24 hours. The microbial etiology of CAP was established The study was performed in an acute care 270-bed general by use of comprehensive microbiological testing (ie, bacterial hospital in Drammen, Vestre Viken Hospital Trust, in South- cultures, serology, urinary antigen tests, and polymerase chain Eastern Norway between January 1, 2008, and January 31, 2011; reaction [PCR]). 267 patients aged ≥18  years admitted with suspected pneu- Blood Sampling monia to the Department of Internal Medicine were consecu- Blood samples were obtained at hospital admission and at the tively included. Patients were screened for eligibility within the scheduled 6-week follow-up, with serum and plasma samples first 48 hours of hospital admission by determining presence drawn into pyrogen-free vacutainer tubes. Tubes for plasma of CAP criteria, defined by (i) a new pulmonary infiltrate on samples contained ethylenediaminetetraacetic acid (EDTA) chest radiograph, (ii) rectal temperature >38.0°C, and (iii) at as anticoagulant. Serum or plasma was separated from whole least 1 of the following symptoms or signs: cough (productive blood within 60 minutes by refrigerated centrifugation at 2000 g or nonproductive), dyspnea, respiratory chest pain, crackles, for 12 minutes and stored in several aliquots at –80ºC. Samples or reduced respiratory sounds. If the chest radiographic exam- were thawed only once. ination uncovered noninfectious causes such as pulmonary infarction, tumor, or bronchiectasis, or if the patient had been Ig and Complement Analyses hospitalized within the past 2 weeks, the patient was excluded Serum levels of IgM, IgA, IgG, and IgG subclasses (IgG1, from the study. IgG2, IgG3, IgG4) at hospital admission were quantified by 2 • OFID • Siljan et al Downloaded from https://academic.oup.com/ofid/article-abstract/5/2/ofy002/4791230 by Ed 'DeepDyve' Gillespie user on 16 March 2018 immunonephelometr y (BN ProSpec nephelometer, Siemens AG, logistic regressions were used to assess the association be- Germany, and Cobas 8000 analyzer, Roche AG, Switzerland). tween Ig or complement parameters and short-term outcome. The reference values are given in Supplementary Appendix. In Adjusted Cox regression analysis was used to assess the asso- patients with levels of IgG or IgG2 below reference range at ciation between Ig or complement parameters and long-term hospital admission, samples from the 6-week follow-up were outcome. A  2-sided P value <.05 was considered significant. analyzed. Statistical analyses were performed using STATA, version 14.0, Complement deficiencies were screened in serum with a for Windows (Stata Corp LP, College Station, TX) and SPSS, total complement activity enzyme-linked immunosorbent version 23.0, for Windows (IBM Corp, Armonk, NY). assay (ELISA; Complement system Screen, Wieslab, Euro RESULTS Diagnostica, Malmö, Sweden). The method includes classical pathway (CP), lectin pathway (LP), and alternative pathway Ig Levels Below Reference Range (AP) activity with a common readout for terminal pathway ac- At hospital admission, 87 (34%) patients had levels below the tivity and has been described in detail previously [24]. The val- reference range of at least 1 Ig (IgM, IgA, IgG, IgG1, IgG2, IgG3, ues are given in percentage related to a standard serum defined or IgG4), with low IgG2 levels as the most prevalent finding (55 to contain 100% activity. e Th reference ranges are given in the patients/21%) (Figure  1). At the 6-week follow-up, IgG levels Figure 2 legend. Patients with indications of complement defi- remained low in more than one-third of patients with sub- ciency from the screening were further analyzed for the com- normal levels at admission (12 patients, 40%). In particular, plement proteins described below. 39 out of the 50 (78%) patients with low IgG2 at admission (2 MBL was quantified using an ELISA described in detail pre- deceased, 3 missing samples) had levels below the reference viously [19]; low levels were defined as <50  ng/mL. C1q and range at the 6-week follow-up (Figure 1). We found no increase C2 were quantified at Region Skåne, Lund, Sweden, and C3 and in comorbidities (cardiovascular disease [CVD], chronic ob- C4 at Oslo University Hospital, Oslo, Norway, using standard structive pulmonary disease [COPD], autoimmune disease, immunochemical techniques. diabetes mellitus, renal disease, neurological disease) among In brief, mannose-binding lectin–associated serine protease patients with low IgM, IgA, IgG, or IgG2 levels compared with 1 and 2 (MASP-1 and MASP-2, respectively) deficiencies were the rest of the study population. identified by genotyping for MASP1 G426E (rs28945068) and Ig Levels in Relation to Microbial Etiology MASP2 D120G (rs72550870), while analysis of MASP-2 bind- Low levels of any Ig at hospital admission were not related to ing to MBL or ficolins was performed in serum with an assay a specific group of microbial etiology. However, serum levels from Hycult Biotech (HM2190-IA, Uden, the Netherlands) [25, of IgG differed significantly between the groups of etiology 26]. Plasma levels of MASP-2 were quantified by an ELISA kit (P  =  .027), with lower levels seen in bacterial than viral CAP (Hycult Biotech), with a reference range of 170–1196 ng/mL. (P = .023). For IgA, IgM, or any of the IgG subclasses, no rela- Outcome Measures tion to microbial etiology was seen (Table  1). Additionally, in Based on the etiology, patients were categorized into 4 groups: patients with low levels of any Ig, CAP caused by encapsulated (i) bacterial, (ii) viral, (iii) viral-bacterial, and (iv) unknown. bacteria (S. pneumoniae and H. Influenzae) did not occur more In addition, patients with Streptococcus pneumoniae or frequently (P = .734). Haemophilus influenzae were studied separately. Disease sever- Ig Levels in Relation to Disease Severity, Short-term Outcome, and Long- ity was evaluated by the validated CURB-65 scoring system term Outcome [27]; patients with a CURB-65 score of <3 were classified into a Patients with low IgG or IgG2 at both time points did not pres- low-risk group and ≥3 into a high-risk group. Short-term out- ent with a higher CURB-65 severity score (P = .594) than other come was defined as a composite end point of ICU admission CAP patients. Moreover, there were no differences in Ig levels and 30-day mortality [28]. Long-term outcome was defined as between patients with high (≥3) vs low (< 3) CURB-65 severity 5-year all-cause mortality. score (Table 2). Statistical Analysis In all, 39 (15%) patients were survivors requiring ICU admis- Categorical variables were expressed as counts (percentages), sion, while 10 (4%) patients died within 30  days of hospital and continuous variables were presented as mean (standard admission. In univariate logistic regression analysis, Igs were deviation) for normally distributed data or median (25th–75th not associated with an adverse short-term outcome when percentiles) for visually skewed data. Continuous variables were assessed as continuous variables (Table 3). Similarly, Igs below analyzed using a t test, and comparison of categorical variables the reference range were not associated with an adverse short- were compared using the χ test or 1-way ANOVA, where ap- term outcome (Table 3). propriate, whereas Tukey’s test was performed for post hoc test Excluding patients who died within 30  days of hospital of differences between pair of groups. Univariate and adjusted admission, 5-year mortality was 26% (65/246 patients, 1 lost Low Immunoglobulin and Complement in CAP • OFID • 3 Downloaded from https://academic.oup.com/ofid/article-abstract/5/2/ofy002/4791230 by Ed 'DeepDyve' Gillespie user on 16 March 2018 Ig levels below reference range Admission 6 weeks 7 7 IgM IgA IgG IgG1 IgG2 IgG3 IgG4 Figure  1. Patients with serum immunoglobulin levels below reference range at hospital admission and 6-week follow-up in 257 hospitalized patients with communi- ty-acquired pneumonia. Data are presented as numbers. Only patients with low IgG or IgG2 at hospital admission were analyzed at 6-week follow-up. Abbreviation: Ig, immunoglobulin. Complement Deficiencies to follow-up). In age- and gender-adjusted Cox regression ana- Screening of serum samples documented 55 (21%) patients lysis, low levels of Igs were not associated with increased 5-year with low or undetectable lectin pathway activity, of which 3 also mortality (Supplementary Table  2). Adjustment for clinically had a defective classical pathway activity (Figure 2). One of the significant comorbidities (CVD, COPD, active malignancy, and 3 patients had an MBL deficiency, was quantified for C1q, and renal disease) did not ae ff ct results for disease severity, short- had only a slightly reduced level. The other 2 had normal MBL term outcome, or long-term outcome. and were quantified for C2 and C4, both with normal levels. Ig Results Excluding Immunocompromised Patients Abnormalities in functional activity of the alternative pathway Forty-five patients were defined as immunocompromised at were not observed in our patient cohort (Figure 2). study inclusion, leaving 212 patients in the study population MASP-2 Deficiency when excluding these. In this assumed nonimmunocompro- One patient with a lectin pathway deficiency, normal MBL lev- mised group, Ig levels at hospital admission differed signifi- els (1134 ng/mL), and normal classical and alternative pathway cantly between groups of microbial etiology for IgA (P = .048) activity was found to be homozygote MASP-2 deficient. MASP-2 and IgG2 (P  =  .021), with lower levels seen in bacterial than in serum did not form complexes with MBL or ficolins. Protein in viral-bacterial CAP for IgA (mean 2.55  ±  1.13  g/L vs quantification of MASP-2 was in accordance with a defect, being 3.34 ± 2.13 g/L, P = .039) and in bacterial vs viral CAP for IgG2 63 and 29  ng/mL at hospital admission and 6-week follow-up, (mean 2.51 ± 0.99 g/L vs 3.22 ± 1.45 g/L, P = .018). By contrast, respectively, well below the reference range of 170–1196  ng/ low levels of any Ig were not associated with a higher CURB- mL. The patient was a previously healthy female aged 66  years 65 severity score. The number of adverse outcomes in this sub- without tendency to infection. The CURB-65 severity score at group was too low to perform outcome analyses. Table 1. Serum Immunoglobulin Levels (g/L) and Number of Patients With Serum Immunoglobulin Levels Below Reference Range at Hospital Admission in 257 Hospitalized Patients With Community-Acquired Pneumonia, Stratified by Etiology Total Bacterial Viral-Bacterial Viral Unknown (n = 257) (n = 73) (n = 49) (n = 39) (n = 96) P IgM 0.86 ± 0.53 0.91 ± 0.59 0.84 ± 0.51 0.81 ± 0.41 0.95 ± 0.66 .657 IgA 2.83 ± 1.64 2.57 ± 1.09 3.16 ± 2.09 2.91 ± 1.82 2.43 ± 1.25 .139 IgG 9.08 ± 2.87 8.48 ± 2.71 9.26 ± 2.82 9.97 ± 3.04 8.72 ± 2.81 .027 IgG1 6.44 ± 2.53 6.01 ± 2.14 6.51 ± 2.51 7.16 ± 3.06 6.25 ± 2.29 .071 IgG2 2.70 ± 1.23 2.49 ± 1.10 2.81 ± 1.18 2.96 ± 1.46 2.49 ± 1.22 .123 IgG3 0.45 ± 0.31 0.44 ± 0.25 0.48 ± 0.37 0.46 ± 0.33 0.38 ± 0.23 .764 IgG4 0.55 ± 0.55 0.56 ± 0.56 0.51 ± 0.40 0.59 ± 0.68 0.57 ± 0.60 .762 IgG < ref. range 30 (100) 13 (36.7) 3 (10.0) 3 (10.0) 11 (43.3) .099 IgG2 < ref. range 55 (100) 17 (30.9) 6 (10.9) 7 (12.7) 25 (45.5) .313 Data are presented as means and ± standard deviation or No. (%). Group comparison performed with 1-way analysis of variance or χ test as appropriate. Patients with unknown etiology excluded from statistical analysis. Abbreviations: Ig, immunoglobulin. Assessed as dichotomous variables. 4 • OFID • Siljan et al Downloaded from https://academic.oup.com/ofid/article-abstract/5/2/ofy002/4791230 by Ed 'DeepDyve' Gillespie user on 16 March 2018 Patients, No. Table  2. Serum Immunoglobulin Levels (g/L) or Number of Patients DISCUSSION With Low Immunoglobulin Levels at Hospital Admission Stratified by In the present study, admission Ig levels below reference range CURB-65 <3 vs CURB-65 ≥3 in 257 Hospitalized Patients With Community- Acquired Pneumonia were not associated with a specific group of microbial etiology in CAP, but IgG and IgG2 levels were significantly lower in bac- CURB-65 < 3 CURB-65 ≥3 terial than in viral CAP. Second, Ig levels below the reference Immunoglobulin (n = 157) (n = 95) P range at hospital admission were not associated with disease se- IgM 0.91 ± 0.53 0.88 ± 0.66 .737 verity, short-term outcome, or long-term outcome. Third, MBL IgA 2.64 ± 1.67 2.74 ± 1.19 .610 deficiency was not associated with microbial etiology, disease IgG 8.74 ± 2.88 9.17 ± 2.77 .249 IgG1 6.19 ± 2.54 6.56 ± 2.22 .241 severity, or outcome measures. IgG2 2.59 ± 1.23 2.67 ± 1.23 .601 Even though admission Ig levels below the reference range IgG3 0.42 ± 0.24 0.44 ± 0.35 .454 were not associated with a specific microbial etiology in our IgG4 0.53 ± 0.54 0.59 ± 0.59 .409 study, IgG levels were significantly lower in bacterial than in IgG < ref. range 20 (66.7) 10 (33.3) .690 a viral CAP, and when excluding immunocompromised patients, IgG2 < ref. range 35 (64.8) 19 (35.2) .752 we found lower levels of IgG2 in bacterial vs viral CAP. Still, the Data presented as means and ± standard deviation or No. (%). Group comparison per- formed with t test or χ test, as appropriate. Data on CURB-65 severity score are missing IgG2 associations with bacterial CAP in the present cohort may in 5 patients.  be regarded as modest, and therefore in line with results from Abbreviations: CURB-65, Confusion, Urea, Respiratory rate, Blood pressure, Age ≥65; Ig, immunoglobulin. an Australian CAP study [11], where no single pathogen was Assessed as dichotomous variables. associated with low IgG subclass levels, illustrating an uncertain impact of IgG2 deficiency. Antibodies to polysaccharide anti- gens of encapsulated bacteria are largely, but not entirely, of the admission was 1.  She was treated with intravenous antibiotics IgG2 subclass, while antibodies to protein antigens of viruses at a general ward for 5 days before discharge. The microbial eti- are IgG1 and IgG3 [29]. Previously, increased susceptibility to ology of CAP was not identified. infections caused by encapsulated bacteria in patients with low MBL Deficiency in Relation to Microbial Etiology, Disease Severity, and IgG2 has been demonstrated [14, 15, 30], suggesting that inher- Outcome ently IgG2-deficient patients have a reduced ability to mount MBL-deficient serum samples were not related to microbial an antibody response to certain polysaccharide antigens, lead- etiology, disease severity, or short-term or long-term outcome ing to an inadequate defense against invading pathogens like (Supplementary Table  3, A–D). A  similar pattern was seen S.  pnuemoniae and H.  inu fl enzae. Yet, an appropriate immune when excluding immunocompromised patients, rendering response may remain intact in patients with low IgG2 levels, as 31/212 (15%) patients with MBL deficiency (data not shown). the cause of reduced levels remains unclear. Another possible Adjustment for clinically significant comorbidities (CVD, reason for low IgG2 levels may be consumption of antibodies COPD, active malignancy, and renal disease) did not affect in the acute phase of CAP, with low levels subsequently seen at results for disease severity, short-term outcome, or long-term hospital admission. outcome. e c Th auses and clinical importance of our IgG and IgG2 find- ings are therefore uncertain. Several recent studies have reported an association between Table  3. Univariate Logistic Regression Analysis of Serum low Ig levels, disease severity, and unfavorable outcome in Immunoglobulin Levels at Hospital Admission and Association to ICU patients with sepsis [8]. In CAP, however, this association has Admission/30-Day Mortality in 257 Hospitalized Patients With Community- Acquired Pneumonia not been explored to the same extent. Feldman et al. could not find any differences in IgG subclass  levels between 66 non- Immunoglobulins OR (95% CI) P ICU and ICU patients with CAP [31]. By contrast, a recent IgM 1.16 (0.69–1.93) .579 Spanish study of 418 CAP patients showed a significant asso- IgA 0.95 (0.77–1.18) .632 ciation between low Ig levels (IgG/IgG1) in patients with a IgG 0.94 (0.84–1.06) .315 CURB-65 severity score of 4 and 5, in ICU patients vs non- IgG1 0.99 (0.87–1.12) .843 ICU patients (IgG/IgG1/IgG2), and with 30-day mortality IgG2 0.85 (0.64–1.11) .232 IgG3 0.99 (0.33–3.03) .993 (IgG/IgG1/IgG2) [13]. Low levels of IgG2 have been observed IgG4 1.07 (0.63–1.82) .811 in patients with severe H1N1 influenza in China [32] and IgG < ref. range 1.64 (0.68–3.94) .268 Australia [10, 11]. Of note, in the Chinese study, the lowest IgG2 < ref. range 1.42 (0.69–2.91) .340 IgG2 levels were seen in seriously ill influenza patients with a Abbreviations: CI; confidence interval; ICU, intensive care unit; Ig, immunoglobulin; OR, bacterial co-infection [32]. In our study, low serum levels of odds ratio. Assessed as dichotomous variables. Igs at admission were associated neither with disease severity Low Immunoglobulin and Complement in CAP • OFID • 5 Downloaded from https://academic.oup.com/ofid/article-abstract/5/2/ofy002/4791230 by Ed 'DeepDyve' Gillespie user on 16 March 2018 250 200 150 0 0 0 Classical pathway activity, % Alternative pathway activity, % Lectin pathway activity, % Figure  2. Serum total complement activity for the classical pathway (CP), alternative pathway (AP), and lectin pathway (LP) at hospital admission in 257 hospitalized patients with community-acquired pneumonia. Values are given in percentage related to a standard serum defined to contain 100% activity. Low levels were defined as <10% activity for CP, <10% for AP, and <10% for LP. nor with ICU admission and 30-mortality. The low number MBL deficiency and CAP severity and outcome may exist, even of severely ill patients may have influenced our observations though our results do not support an association. regarding outcome. Nonetheless, the relationship between low MASP-2, a part of the MASP family, is a protease essential for admission Ig levels and adverse short-term outcome does not activation of the lectin complement pathway by cleavage of C4 seem to be as close in CAP as in sepsis, at least not in patients and C2 [18]. Defects of MASP-2 have been suggested to be asso- with a nonsevere clinical course. ciated with infectious diseases [39], but with an uncertain clin- Despite the considerable morbidity in primary hypogam- ical penetrance [40]. We identified a patient with a homozygous maglobulinemia, especially recurrent respiratory infections [6], MASP-2 deficiency, to our knowledge the first case described in the impact on the long-term outcome of a transient decrease in Norway. This patient was without tendency to recurrent infec- Igs during infections like pneumonia is not clear. In the present tions and did not present with a severe form of CAP, in accord- cohort, we did not find significant associations between low lev- ance with previous findings [37]. els of Igs at hospital admission and 5-year all-cause mortality, Limitations suggesting a less important role of low admission Ig levels per The following limitations should be considered. First, our study se on long-term immune responses. was performed at a single hospital, thereby possibly limiting its Although deficiency of the pattern recognition molecule generalizability. Second, blood samples were not obtained be- MBL has been associated with respiratory infections in cystic fi- yond the 6-week follow-up; thus we do not know the time frame brosis [20] and CVID [21], a consistent predisposition to pneu- of the decrease in IgG/IgG2 levels in 39 patients in this CAP monia in MBL-deficient or -insufficient patients has not been cohort. Third, the outcome measure short-term outcome was documented. A  meta-analysis indicated that MBL-deficient defined as a composite of ICU admission and 30-day mortality. patients were predisposed to invasive pneumococcal infections A  majority of patients (39/49, 80%) were categorized with the [33], but in 3 CAP studies of low MBL, including a more re- softer ICU survivor outcome parameter. cent meta-analysis, no associations to S.  pneumoniae or other Conclusion pathogens in CAP have been found [34–36]. In our study popu- In summary, neither low admission immunoglobulin levels nor lation, MBL deficiency was not associated with microbial eti- MBL deficiency was associated with microbial etiology, disease ology. Consequently, our observations support the hypothesis severity, short-term outcome, or long-term outcome in hospi- that MBL deficiency is not an important factor for microbial talized patients with CAP. vulnerability in CAP [37, 38]. A large Spanish study of 848 CAP patients found MBL Supplementary Data insufficiency to be associated with severe sepsis, multiorgan Supplementary materials are available at Open Forum Infectious Diseases online (http://ofid.oxfordjournals.org). dysfunction syndrome, ICU admission, and 90-day mortality, but not 28-day mortality [37]. In later studies, however, these Acknowledgments findings have not been reproduced [36, 38]. Similarly, an associ- We gratefully thank Kåre Bø, o Th mas Skrede, Anita Johansen, and Britt ation between MBL deficiency and disease severity or outcome Hiaasen for collection of patient data; Ola Bjørang, Helvi H. Samdal, Carina Thilesen, and Mette Bogen for excellent laboratory assistance; and Nihal measures was not seen in our CAP cohort, but in our cohort Perera for contributing to the design of the database. fewer patients had a very high CURB-65 score and the short- Financial support. This work was supported by Vestre Viken Hospital term mortality rate was fairly low. Thus, the study populations Trust, Norway. The funder had no role in the study design, data collection are not completely comparable. 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