The complement system plays an important role in the innate and adaptive immune response against pathogens. It is essential for removing damaged cells, avoiding infections by enhancing the ability of clearing microorganisms and helping the modulation of the immune response . Complement deficiencies are rare, with a worldwide prevalence of 0.03%  , and predispose bacterial infection and/or autoimmune diseases. Individuals with abnormalities in the early components of the complement (especially C1q, C2 and C4) have a minimum risk of infection but a high risk of developing autoimmune diseases such as systemic lupus erythematosus (SLE) and rheumatoid arthritis. Increased susceptibility to these diseases is related to the inefficient removal of immune complexes  , and C4, part of the classical complement pathway, is closely linked to the removal of these complexes and of apoptotic debris .
In patients with C4 deficiency, the main treatment is based in the use of immunoglobulin, which helps reducing the frequency and severity of infections. Intravenous preparations start with 400 - 600 mg/kg every 3 to 4 weeks and are almost exclusively made of IgG  . Monitoring of IgG levels should be performed every 3 months and should remain above 500 mg/dL. Most adverse effects are related to infusion rate, most commonly being fever, tremors, arthralgia, myalgia, abdominal pain, nausea and headache. Fatal events are rare and can be prevented by careful medical supervision and early management  .
We report a case of a pregnant woman with C4 deficiency with multiple previous gestational losses. She progressed during the puerperium to septic pelvic thrombophlebitis and necrotizing fasciitis in the abdominal surgical wound. She had a good evolution and was discharged without sequelae. This case involves two rare pathologies, without previous reports in literature of simultaneous occurrence and survival: immunodeficiencies of complement factors and necrotizing fasciitis. In reporting the case, we intend to help management of similar cases that may occur. The case occurred in the Hospital de Clínicas de Porto Alegre, in the state of Rio Grande do Sul, Brazil―a public-private institution linked to the Universidade Federal do Rio Grande do Sul.
2. Case Report
Patient has consented to the disclosure of her case for academic and scientific purposes. Pregnant woman, 29 years old, white. Obstetric history of six pregnancies―two vaginal deliveries and three abortions. The two vaginal deliveries had neonatal death, weighting 498 grams (gestational age of 22 weeks) and 650 grams (gestacional age of 25 weeks). In both cases, she was hospitalized after rupture of the membranes and labor was induced. The abortions occurred in the first pregnancy trimester. Cerclage was performed in the third and fourth gestation, however they both evolved with ovular infection and gestational loss after two weeks. The patient hadn’t used immunoglobulin in any previous gestation. She had a sister with history of multiple gestational losses and a father which died of sepsis after thoracic trauma. Both of them had C4 deficiency.
First prenatal consult happened at 15 weeks, when progesterone 200 mg/day was prescribed and serial measurements of the uterine cervix by transvaginal ultrasound were programmed. The uterine cervix was measured biweekly until 22 weeks, being initially 37 mm and progressing to 24 mm, when Ingamed® cervical pessary was inserted.
The patient was hospitalized at 21 weeks due to a vaginal infection, receiving clindamycin, azithromycin and metronidazole, Use of vaginal progesterone was maintained and a 5-day pulse of intravenous immunoglobulin was initiated. The patient’s evolution followed as described in the table below.
W: weeks; D: days; IV: intravenous; ICU: Intensive Care Unit.
The patient used warfarin for three months and after four months the color of the skin returned to its usual color and the surgical scar was in the final stage of healing (Figure 5 & Figure 6). After 1 year, she returned without complications and her skin color had returned to its normal.
The newborn remained 53 days in the neonatal ICU, requiring mechanical ventilation and a nasogastric tube. He was discharged in good general condition along with the mother. He maintained follow-up visits, evolving without sequelae. Currently, he has a palatal hemangioma in regression.
During pregnancy, the innate and adaptive immune system must be regulated to ensure the survival of the mother and the fetus. The complement system is a part
Figure 1. Initial wound infection.
Figure 2. Patient with necrotizing fasciitis after first debridement.
Figure 3. Abdominal ultrasound with heterogeneous contents in the uterine cavity.
Figure 4. Patient with occlusive dressing after debridement.
Figure 5. Operative wound with granulation tissue after 40 days of puerperium. Dullness of the patient’s color due to the prolonged use of antibiotics.
Figure 6. Patient 4 months after surgery. The color of the skin returned to its usual color.
of the immune system that consists of a set of proteins that act sequentially, providing a rapid and powerful defense to the body by identifying and destroying pathogens. Its inadequate activation can cause a number of complications.
More than 50 proteins constitute the complement system, and C4 is part of the classical complement route. IgG and IgM antibodies bind to antigens and initiate a cascade of events, where the C1 factor cleaves C4 and C2 in C4b and C2b, respectively. These factors interact and form C3 convertase, which converts C3 to C3a (that produces inflammatory response) and C3b (that has an opsonization function). The addition of C3b to C3 convertase generates C5 convertase, which cleaves C5 to C5a and C5b. C5b then connects to C6 and C7, forming a complex that binds to the membrane. The C5bC6C7 complex binds to C8 and multiple C9, forming the membrane attack complex (MAC). This complex forms a channel that allows the free diffusion of substance, disrupting the cellular osmotic balance and leading to death of the invading organism .
Inherited complement deficiencies are rare  , corresponding to 4.9% of all primary immunodeficiencies . The most common one is C1 deficiency, occurring in 0.01% of the population . Severe deficiencies of complement proteins predispose to infections, mainly by encapsulated bacteria such as Streptococcus pneumoniae. In addition, C1, C2, and C4 deficiencies may predispose to autoimmune diseases, primarily collagen vascular diseases and systemic lupus erythematosus. This is due to failure in removing immune complexes and necrotic material. More than 75% of patients with C4 deficiency have some manifestation of autoimmunity . Studies have shown that patients with C4 deficiency have a decrease in regulatory T cells, which are important to prevent the appearance of aberrant autoimmune responses . Complete homozygosity for C4 deficiency is rare. The C4 gene is located on chromosome 6p21.3, and there are two isotypes of the gene product (C4A and C4B5). Healthy individuals usually have two copies of each of the isotypes, while those with less than four copies of C4 are more likely to develop autoimmune diseases  .
Pregnancy alone can increase infection by suffering various mechanical and physiological adaptations and by creating an immunosuppressive state. These changes in a patient with deficiency of complement factors―important in regulating the immune response―play a prominent role in severe infections and subsequent sepsis . Infections are the fifth leading cause of maternal death .
Necrotizing fasciitis (NF) is an invasive and potentially lethal soft tissue infection. It is characterized by necrosis of the subcutaneous tissue, superficial fascia and other adjacent tissues. The infection can involve epidermis, dermis, subcutaneous tissue, fascia and muscle. It is considered a surgical emergency, with mortality exceeding 40%  and increasing incidence in recent years . Pregnancy, delivery and gynecological procedures are important risk factors for NF. Other risk factors are those that predispose infections, such as peripheral vascular disease, diabetes mellitus, impaired immune system, and surgical procedures that compromise skin integrity. In a retrospective study with 23 patients with NF in lower abdomen or pelvis, 34.7% had diabetes . Obesity, which increases the infection risk during pregnancy and cesarean delivery, is also an important risk factor .
The fasciitis can be divided considering microbiology or presence of gas in the tissues. Polymicrobial fasciitis is caused by anaerobic and aerobic bacteria, with typically at least one isolated anaerobic (Bacteroides, Clostridium or Peptostreptococcus) in combination with enterobacteria (Escherichia coli, Enterobacter, Klebsiella, Proteus). Monomicrobial fasciitis is usually caused by Staphylococcus, or group A and other beta hemolytic Streptococcus. Pure myonecrosis by Clostridium perfringens has a more homogenous muscle invasion and a higher rate of mortality, being the only one that needs to be differentiated from other necrotizing soft tissue infections . The incidence of this type of NF varies from 0.3 to 15 per 100,000 people.
Main manifestations of NF include severe pain, edema, erythema, fever, crepitation and epithelial necrosis. The disease has rapid onset and progression, involving mainly the vulva, perineum, lower limbs and abdominal wall. Skin involvement is usually smaller than the extent of necrosis in the underlying tissue, turning the differentiation between NF and cellulitis difficult . Definitive diagnosis occurs after surgical debridement, with microbiological and histological evaluation of the infected tissues. Imaging findings precede skin involvement, aiding in diagnosis. Magnetic Resonance imaging can determine the extent of inflammation in the fascia and necrosis of infectious tissue . Crepitation, presence of gas in soft tissue or bubble formation in imaging have a good sensitivity for diagnosis . Among laboratory tests, base deficit and blood lactate are often elevated. Without rapid and efficient intervention, NF quickly leads to septic shock, multiple organ failure and death. Most of the time, this illness requires long hospitalization, days in ICU and high hospital expenses .
Prognosis in NF depends on rapid diagnosis and aggressive multidisciplinary management, involving deep debridement of all necrotic tissue, intravenous antibiotics, appropriate analgesia and intensive care in ICU . Antibiotics are administered empirically before culture results and can be adjusted later according to the antibiogram. It should cover gram positive cocci, enteric gram negative rods and anaerobics. Daily evaluation of the open wound and surgical debridement until the infection is no longer perceived decreases mortality . Normally, the procedure is repeated every 2 days until there is no evidence of necrotic tissue. Closure of the wounds begins as soon as possible, just when the viable tissue allows the skin to be re-approximated or grafted . Hyperbaric oxygen therapy has been used adjuvantly, and although it does not decrease mortality, it can accelerate wound closure. This technique improves oxygen supply to compromised ischemic tissue, increases phagocytosis of polymorphonuclear cells, acts as a bactericidal agent for anaerobic organisms and can disrupt the production of alpha toxin. However, studies validating this therapy are still lacking .
The use of IV Immunoglobulin also appears to be beneficial for the survival of patients with NF . Human Immunoglobulin can be beneficial in primary immunodeficiencies, such as those caused by absence of B cells or inefficient production of antibodies, and primary defects with hypogammaglobulinemia. Currently, there is sufficient clinical evidence showing that Immunoglobulin decreases frequency and severity of infections and of hospitalizations in patients with primary immunodeficiencies. However, much of this evidence refers to immunodeficiencies that compromise the production of antibodies (the most prevalent ones). There are no studies showing benefits of using IV Immunoglobulin in patients with complement deficiency; however, the lack of other treatments for this disease and the good results in other immunodeficiencies justify its use in patients with C4 deficiency.
The appropriate dose of immunoglobulin for primary immunodeficiencies is still being studied. An initial dose of 400 - 600 mg/kg is advised every 3 to 4 weeks. The frequency of adverse effects ranges from 0.6% to 30%, being higher in the presence of infections or at the first infusion . This is due to the formation of antigen-antibody complexes, which can be reduced if the patient is afebrile or using antimicrobials. To reduce adverse effects, infusion should be slow and by infusion pump. During the infusion, most common symptoms include tremors and fevers (mimicking infection), abdominal pain, nausea and headache. In these cases, the infusion should be discontinued and the symptoms managed.
In necrotizing fasciitis, IV Immunoglobulin also appears to be beneficial. It is supposedly able to inhibit the mitogenic activity of bacteria, especially gram positive. In addition, Immunoglobulin can block T lymphocytes activation by bacterial antigens, decreasing the production of inflammatory cytokines  .
Complement deficiencies are extremely rare conditions that are associated with the development of autoimmune diseases. In pregnancy, an immunosuppressive state alone, they can cause numerous adverse outcomes. Necrotizing fasciitis is an infection that has immunosuppressive states as an important risk factor. The reported case shows how immunocompromised pregnant women need follow-up in high-risk prenatal care and, if possible, the use of prophylactic IV Immunoglobulin. In cases of infection, rapid diagnosis and multidisciplinary therapy, with a surgical approach and use of antibiotics, are important. We emphasize the importance of immunoglobulin use for the patient’s excellent outcome and the relevance of knowing family history and efficacy of immunoglobulin use in other relatives. A clear understanding of the role of the complement system in pregnancy―and its possible deficiencies―is necessary to prevent adverse outcomes. No cases of patients with both necrotizing fasciitis and C4 immunodeficiency have survived. We believe that future cases may benefit from the successful management of this patient using immunoglobulin.
We would like to express our deepest gratitude to the participants for their time and patience throughout this study.
The authors have no financial relationships relevant to this article to disclose.
 Macedo, A.C.L. and Isaac, L. (2016) Systemic Lupus Erythematosus and Deficiencies of Early Components of the Complement Classical Pathway. Frontiers in Immunology, 7, 55.
 Picard, C., Al-Herz, W., Bousfiha, A., et al. (2015) Primary Immunodeficiency Diseases: an Update on the Classification from the International Union of Immunological Societies Expert Committee for Primary Immunodeficiency. Journal of Clinical Immunology, 35, 696.
 Li, N., Zhang, J., Liao, D., Yang, L., Wang, Y. and Hou, S. (2017) Association between C4, C4A, and C4B Copy Number Variations and Susceptibility to Autoimmune Diseases: A Meta-Analysis. Scientific Reports, 7, 42628.
 Costa-Carvalho, B.T., Solé, D., Condino-Neto, A. and Rosário Filho, N. (2010) I Consenso Brasileirosobre o Uso de Imunoglobulina Humana em Pacientes com Imunodeficiências Primárias. Revista brasileira de alergia e imunopatologia, 33, 104-116.
 Turley, A.J., Gathmann, B., Bangs, C., Bradbury, M., Seneviratne, S., Gonzalez-Granado, L.I., et al. (2015) Spectrum and Management of Complement Immunodeficiencies (Excluding Hereditary Angioedema) across Europe. Journal of Clinical Immunology, 35, 199-205.
 Arason, G.J., Jorgensen, G.H. and Ludviksson, B.R. (2010) Primary Immunodeficiency and Autoimmunity: Lessons from Human Diseases. Scandinavian Journal of Immunology, 71, 317-328.
 Cheng, H.-B., Chen, R.-Y., Wu, J.-P., et al. (2015) Complement C4 Induces Regulatory T Cells Differentiation through Dendritic Cell in Systemic Lupus Erythematosus. Cell & Bioscience, 5, 73.
 Robinson, D.P. and Klein, S.L. (2012) Pregnancy and Pregnancy-Associated Hormones Alter Immune Responses and Disease Pathogenesis. Hormones and Behavior, 62, 263-271.
 Oud, L. and Watkins, P. (2014) Necrotizing Fasciitis Associated with Pregnancy: A Population-Based Cohort Study. Infectious Diseases and Therapy, 3, 307-320.
 Gallup, D.G., Freedman, M.A., Meguiar, R.V., Freedman, S.N. and Nolan, T.E. (2002) Necrotizing Fasciitis in Gynecologic and Obstetric Patients: A Surgical Emergency. American Journal of Obstetrics and Gynecology, 187, 305-311.
 Nikolaou, M., Zampakis, P., Vervita, V., et al. (2014) Necrotizing Fasciitis Complicating Pregnancy: A Case Report and Literature Review. Case Reports in Obstetrics and Gynecology, 2014, Article ID: 505410.
 Elliott, D.C., Kufera, J.A. and Myers, R.A.M. (1996) Necrotizing Soft Tissue Infections: Risk Factors for Mortality and Strategies for Management. Annals of Surgery, 224, 672-683.
 Brothers, T.E., Tagge, D.U., Stutley, J.E., Conway, W.F., Del Schutte Jr., H. and Byrne, T.K. (1998) Magnetic Resonance Imaging Differentiates between Necrotizing and Non-Necrotizing Fasciitis of the Lower Extremity. Journal of the American College of Surgeons, 187, 416-421.
 Brennan, V.M., Salomé-Bent, L. and Chapel, H.M. (2003) Immunology Nurses Study. Prospective Audit of Adverse Reactions Occurring in 459 Primary Antibody-Deficient Patients Receiving Intravenous Immunoglobulin. Clinical & Experimental Immunology, 133, 247-251.
 Kaul, R., McGeer, A., Norrby-Teglund, A., Kotb, M., Schwartz, B., O’Rourke, K., Talbot, J. and Low, D.E. (1999) The Canadian Streptococcal Study Group; Intravenous Immunoglobulin Therapy for Streptococcal Toxic Shock Syndrome—A Comparative Observational Study. Clinical Infectious Diseases, 28, 800-807.
 Kaul, R., et al. (1997) Population-Based Surveillance for Group A Streptococcal Necrotizing Fasciitis: Clinical Features, Prognostic Indicators, and Microbiologic Analysis of Seventy-Seven Cases. Ontario Group A Streptococcal Study. The American Journal of Medicine, 103, 18-24.