Study Participants: We performed an unbiased review of all complement levels measured at our hospital from 2002–2018 (n = 5876, from 1643 total patients). Patients clinically diagnosed with SLE or CTD were captured in our pediatric dataset as quarterly complement testing is usual standard practice at our center. A total of 70 subjects met inclusion criteria, based on an undetectable complement measurement during the observation period. Both patients with primary complement deficiency (n = 18) and those with acquired complement deficiency (n = 52) were included in the cohort (Table 1). Manual chart review identified total number of subjects with each diagnosis screened in our dataset. Primary complement deficiencies in this cohort included C1q deficiency (n = 3), C2 deficiency (n = 11), C6 deficiency (n = 3), and C8 deficiency (n = 1). Acquired complement deficiencies included SLE/CTD-related disorders (n = 45), which represented 27% of the SLE patients [n = 43 of 155], 11% of pediatric Sjögren’s [n = 1 of 9] and 3.7% of MCTD patients [n = 1 of 27]. Two patients had C3 and/or C5 nephritic factors and 5 patients had infection-related complement consumption. Median period of observation was 10.83 years (IQR, 4.12–16.12) for primary complement deficiency followed from date of birth and 4.33 years (IQR, 2.7–6.5) for secondary complement disorders followed from diagnosis. Demographic characteristics and diagnoses are summarized in Table 1.
Table 1
Demographic and Clinical Characteristics
Variable† | SLE/CTD | PCD |
Total | 45 | 18 |
Female, n. (%) | 42 (93) | 4 (22) |
Age§ (year) | 14.7 (IQR: 12.8–16.4) | 10.8 (IQR: 4.1–16.1) |
Observation Period (year) | 4.8 (IQR: 2.7–6.5) | 10.8 (IQR: 4.1–16.1) |
SLE + Nephritis,n | 23 | |
SLE, n | 20 | |
Other CTDs, n | 2 | |
LOI ‡ | | |
LOI 0 n. (%) | 1 (2) | |
LOI 1 n. (%) | 6 (13) | |
LOI 2 n. (%) | 10 (22) | |
LOI 3 n. (%) | 5 (11) | |
LOI 4 n. (%) | 23 (51) | |
| | |
Rate of SBI/yr | 0.06 (IQR: 0-0.40) | 0.15 (IQR: 0.07–0.48) |
PCD, primary complement deficiency; SLE/CTD, systemic lupus erythematosus/ |
connective tissue disease (SLEwN: with nephritis; SLE: without nephritis); LOI, level of |
immunosuppression. |
† For interval variables, the medians and interquartile ranges are presented. For |
categorical variables, the total number and percentages are presented. |
‡ LOI is the level of immunosuppression: 0 (HCQ) 1: Prednisone and/or methotrexate, |
2: Azathioprine, and/or mycophenolate, 3: Methylprednisolone, 4: Rituximab, |
cyclophosphamide and/or tacrolimus. |
Serious Bacterial Infections: To examine the risk of SBI among patients with acquired complement deficiency, we first established the rate of SBI in our cohort of primary complement deficiencies with a known risk for encapsulated bacterial infections: annual rate of approximately 0.15 SBI/year (IQR, 0.07–0.48). The annual rate of SBI in patients with SLE/CTD diagnoses used the lowest C3 recorded for each patient as the starting point of their observation period. SLE/CTD patients had a lower median annual rate of SBI of 0.06 (IQR, 0-0.40) following lowest C3 level, although severe hypocomplementemia was transient. Overall, 27 SBIs were recorded in our SLE/CTD cohort with 14 of 43 SLE/CTD patients (32%) having at least one SBI event during their observation period including pneumonia (33%), bacteremia (22%), sepsis (11%), intraabdominal infection (11%) and soft tissue infections requiring parenteral antibiotics (7%). Streptococcus pneumoniae and Staphylococcus aureus were the most frequently isolated microorganisms. Equivalent rates of vaccination for PCV13 and MCV4 were observed in the subjects with or without SBI, as well as rates of PPVS23 (albeit only roughly 40% of the SLE/CTD patients were fully immunized).
Complement Levels: A total of 1197 serum measurements were collected over the observation period for the SLE/CTD cohort with a median of 5.32 separate serum measurements (IQR 3.73–6.35) per year collected per patient with a vast majority of the serum measurements reporting both C3 and C4 levels. Patients with the diagnosis of SLE/CTD all had either an undetectable (89%) or low C4 level (range, 2–6 mg/dL) (11%), at some point during their disease course. C3 levels were normal in 9% (n = 4) of the SLE/CTD cohort. We found trough C3 levels were lower in patients with SBI (35 mg/dL +/- 21) compared with patients without SBI (55 mg/dL +/- 24) (P = 0.01).
We then utilized every C3 measurement for the SLE/CTD patients as a new observation (n = 1,150) and assessed the 30-day probability of having an SBI based upon level. Lupus nephritis and immunosuppression has been associated with SBI in SLE cohorts, thus these were included as covariates. We excluded C3 levels drawn on the same day as the SBI diagnosis. We also categorically examined the risk of an infection in patients with low C3 (C3 < 83 mg/dL per reference range) compared to those with a normal C3 level. In our cohort of SLE/CTD patients with a history of at least one measurement with undetectable complement, we found a correlation between a low C3 level and the probability of being diagnosed with an SBI within 30 days (Fig. 1). Further, our model suggests that patients with a very low to undetectable C3 level have an approximately 15% chance of being diagnosed with an SBI within 30 days. Logistic regression showed that patients with a low C3 measurement have a significantly higher risk of infection than those with a normal C3 level (OR 5.34 [95% CI, 1.88–15.16]) (Table 2). Given that infection itself may be a causal event for undetectable complement, a secondary analysis excluded any C3 levels drawn within 30 days following an SBI and we found similar results.
Table 2
Logistic Regression Analysis of SLE/CTD-related Secondary Complement Deficiency: Odds of SBI following trough C3 level in patients with SCD
Serious Bacterial Infection (SBI) | Odds Ratio | Std. Err. | Z | P>|z| | 95% Conf. Interval |
C3 (Low) | 5.34 | 2.84 | 3.15 | 0.002 | (1.88–15.16) (0.95–13.57) (0.53–4.32) |
LOI | 3.60 | 2.43 | 1.89 | 0.059 |
LN Present | 1.51 | 0.81 | 0.77 | 0.44 |
| | | | |
LOI, level of immunosuppression; LN, lupus nephritis. |