Age: 3.0
Sex: M
Vaccine: HIBV
Symptoms: Biopsy kidney normal, Blood pressure normal, Complement factor C3 decreased, Complement factor abnormal, Full blood count normal
Clinical narrative: he exhibited nonprotective IgG titers to Hemophilus influenzae type B; 3-year-old boy received a repeat immunization to H influenzae type B.  This literature marketed report has been received from the authors of a published literature article, titled as stated above and refers to a 3-year-old, male patient (boy), with a history of infections: recurrent acute otitis media and one occurrence of pneumonia, that required hospitalization.  Complement factor I (CFI) deficiency was a rare disorder with 38 reported cases worldwide. The immune system had adaptive and innate pathways. The complement system was part of the innate pathway, which, through proteolytic reactions, cleared immune complexes and opsonized and kills microbial pathogens. The deficiency of CFI led to complement dysregulation through C3 convertase overactivation and low C3 levels, resulting in decreased bacterial opsonization, phagocytosis, and macrophage activation complex killing. In addition, CFI deficiency caused increased susceptibility to autoimmune/autoinflammatory ailments such as systemic lupus erythematosus, atypical hemolytic uremic syndrome (aHUS), glomerulonephritis, encephalitis, and macular degeneration.  On an unknown date before the presentation, the patient was vaccinated with Haemophilus b Conjugate Vaccine (Meningococcal Protein Conjugate) (manufacturer unknown) (dose, strength, route of administration, anatomical location, lot # and expiration date were not reported) for prophylaxis.  On an unspecified date, the patient presented to the immunology clinic for decreased complement component 3 (C3) levels with glomerulonephritis. Previously, during evaluation for chronic constipation, he was found to have microscopic hematuria. He had normal kidney function, complete blood cell count, and blood pressure. A pediatric nephrology evaluation revealed, that he had low levels of C3 at 28 to 36 mg/dL on 3 different laboratory samples. Notably, antinuclear (ANA) antibody, antistreptolysin O, and C4 were normal. Renal biopsy result was also normal, thus excluding glomerulopathy or C3 nephritic factor as diagnoses. It was reported, that the patient's mother had ulcerative colitis and asthma. There was no other family history of atopic disease, immunodeficiencies, or autoimmune disorders.   At the presentation time, immunologic evaluation revealed normal serum levels of immunoglobulin G (IgG), immunoglobulin A, and immunoglobulin M. He had normal IgG antibody titers to diphtheria toxoid and tetanus toxoid. He exhibited nonprotective IgG titers to Hemophilus influenzae type B (antibody test abnormal) and Streptococcus pneumoniae. Flow cytometry revealed normal memory and class-switched B cells. The patient had a decreased C3 level of 36 mg/dL and undetectable levels in total hemolytic complement (CH50) and serum complement, alternate pathway (AH50) assays. The C4 level was normal. An evaluation performed at the laboratory revealed decreased complement components 5, 8, and 9 (C5, C8, and C9) and complement factors B, H, and I, indicating a likelihood of alternative pathway overactivation. The results were as followed (microgram/mL): C1q of 111, C1r of 73, C1s of 117, C2 of 21.5, C5 of below 17 (low (L)), C6 of 31, C7 of 97.8, C8 of 36 (L), C9 of 17 (L), factor B of below 114 (L), factor D of 2.32, factor H of 75 (L), factor I of below 13 (L). Other results included: C3 of 36 (mg/dL) (L), C4 of 20 (mg/dL), CH50 of below 17 (U/mL) (L) and AH50 of 0 (U/mL) (L).   Subsequently, genetic studies of C5 and factors I, B, and H, identified compound heterozygous mutations of complement factor 1 (CFI), c1253A >T (p.his418leu) and c.772G >A (p.ala258thr), which have been previously reported as pathogenic. The c.1253A >T mutation in exon 11 caused reduced protein expression, whereas the c.772G4A mutation of exon 5 led to erroneous mRNA. Thus, the patient's clinical, laboratory, and genetic manifestations confirmed a CFI deficiency. On an unknown date, the patient was prescribed daily amoxicillin, as prophylaxis for infection.  On an unspecified date, he also received a repeat immunization to Haemophilus influenzae (H. influenzae) type B with Haemophilus b Conjugate Vaccine (Meningococcal Protein Conjugate) (manufacturer unknown) (dose, strength, route of administration, anatomical location, lot # and expiration date were not reported) (inappropriate schedule of vaccine administered). The patient also received his first pneumococcal polysaccharide vaccine (reported as PNEUMOCOCCAL VACCINE, POLYVALENT (23-VALENT) (Injection,  , ) (PNEUMOVAX23) or "PPSV23") and unspecified "meningococcal conjugate vaccine".  After immunizations, he exhibited protective antibody titers to H. influenzae type B and Streptococcus pneumoniae. He had regular follow-ups with the pediatric immunology and nephrology clinic and was monitored closely for infections, progressive renal disease, and in particular, atypical hemolytic uremic syndrome (aHUS). The outcome of the event of antibody test abnormal was recovered/resolved.  The CFI deficiency was a rare primary immunodeficiency, that led to increased susceptibility to encapsulated bacterial infections and non-infectious presentations such as rheumatologic, renal, dermatologic, and neurologic disease. The CFI gene was located on chromosome 4q25 and generates a 88 kDa glycoprotein, that was principally produced by the liver. Furthermore, CFI was an acute-phase reactant, and it's expression was up-regulated by interleukin-6 in hepatocytes. The patients with CFI deficiency were susceptible to invasive bacterial infections, with up to 81 % of affected individuals presenting in such a manner. Among genetically confirmed cases, there was a slight preponderance in women (2.2:1) and childhood onset. No clear relationship currently existed between CFI mutations and the resulting clinical phenotype of CFI deficiency. Of note, there were cases of siblings, who shared a CFI genotype, but even though the proband developed pathogenic manifestations, the sibling remained asymptomatic. Autoimmune ailments were associated with CFI deficiency, some of which could be life-threatening. An example of such an ailment was aHUS, which was characterized by hemolytic anemia, thrombocytopenia, and acute kidney injury resulting from microthrombi in the small blood vessels. The penetrance of aHUS in patients with CFI mutations was approximately 50 %. The prognosis for aHUS was extremely poor, with approximately 60 % of patients progressing to end-stage renal failure. Renal transplantation in patients with aHUS who had CFI mutations has been associated with a high recurrence rate and especially poor prognosis. In CFI deficiency, there was unregulated activation of the alternative complement pathway, that subsequently activated the terminal complement pathway, with C5 activation and generation of C5a and C5b-9 membrane attack complex (MAC), leading to elevations in plasma levels of C5a and C5b-9. The C5b-9 MAC complex might have been caused inflammation, endothelial cell activation, neutrophil activation, hemolysis, or thrombosis. Eculizumab is a humanized anti-C5 monoclonal antibody that binds to the alfa chain of C5 and prevents the generation of C5a and C5b by the C5 convertase, causing down-regulation of C5a anaphylatoxin and C5b-C9 MAC, thereby decreasing inflammation. The eculizumab has been approved for the treatment of aHUS.  Currently, the treatment for CFI deficiency was limited to antimicrobial prophylaxis through vaccination against encapsulated bacterial pathogens. Although there was no empirical evidence demonstrating the effectiveness of antibiotic prophylaxis in CFI deficiency, this was commonly used to prevent serious infections. Direct replacement of CFI using fresh frozen plasma or purified CFI had resulted in transient correction of in vitro assays of complement activity. However, fresh frozen plasma infusions were associated with anaphylaxis, and long-term clinical outcomes have not been reported. Bone marrow transplantation was not a potentially curative strategy given that CFI synthesis occurred in the liver. Of note, CFI deficiency was a rare but likely underdiagnosed cause of primary immunodeficiency and/or immune dysregulation. The diagnosis of CFI deficiency should be considered in patients with recurrent infections and/or renal, dermatologic, rheumatologic, neurologic disturbances, along with low C3 levels. Early identification was important, because it allowed for the initiation of prophylactic measures to prevent severe infections and other systemic sequelae. The causality between the suspect vaccination and the event of antibody test abnormal was assessed by the authors to be related.  A copy of the published article is attached as further documentation of the patient's experience.