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Primary Immune Deficiency Disorder

Primary Immunodeficiency

Patients diagnosed with primary immune deficiency disorder may show any one of several gene defects that cause the immune system to fail. Contrary to secondary immunodeficiencies, environmental factors triggering symptom onset cannot be identified.

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Presentation

Many PIDD patients have a family history of immunodeficiency or associated autoimmune disease, but may not even be aware of it. Pointed questioning may be required to reveal evidence of a hereditary disease. Moreover, patients may not report determined complaints if these are considered irrelevant [3].

As a rule of thumb, T cell deficiencies manifest shortly after birth, B cell and antibody deficiencies within the first year of life after cessation of protection by maternal antibodies. Complement disorders and other PIDD may manifest at any age [10]. The most common symptom of PIDD is an increased susceptibility to infection. Because cell populations and components of the immune system fulfill distinct functions regarding defense against pathogens, the predominance of determined infectious agents may imply the nature of the underlying disorder. Patients suffering from T cell disorders present with recurrent opportunistic infections (e.g., Mycobacterium spp., enterovirus, Candida albicans), while disturbances of humoral immunity - B cell and antibody deficiencies - result in proneness to infections with encapsulated bacteria like Haemophilus influenzae and Streptococcus pneumoniae. Infections with Neisseria spp. are characteristic of complement disorders. Any organ system may be compromised, but sinusitis, otitis media, upper respiratory infection and pneumonia are most commonly observed among patients with this disorder [11]. Gastrointestinal disorders, primarily manifesting in form of diarrhea, may bother up to 50% of PIDD patients [5]. While neither recurrent sinusitis nor diarrhea are likely to be triggered by PIDD, co-occurrence of frequent infections of more than one organ system and gastrointestinal discomfort are highly suspicious of an immunodeficiency. In many cases, PIDD take a progressive course and depletion of immune cells and other factors becomes more severe as the patients gets older [11].

Splenomegaly
  • Splenomegaly and generalized lymphadenopathy are present in many patients with common variable immunodeficiency (CVID). Recurrent infections Permanent damage to the bronchi may occur, resulting in bronchiectasis.[emedicine.medscape.com]
  • Hepatomegaly and splenomegaly may be detected in the abdomen. In infants, crusting around the anus may be a sign of chronic diarrhoea. Delayed developmental milestones or ataxia may be evident.[patient.info]
  • He presented in respiratory failure at our institution with anasarca, 3 pitting edema in all extremities, clubbing of all digits, splenomegaly, and petechiae.[acphospitalist.org]
  • On physical examination, patients with this subtype often have splenomegaly and bronchiectasis.[emedicine.medscape.com]
  • Combined immunodeficiency due to caspase-8 deficiency presents with recurrent sinopulmonary bacterial infections, poor growth, lymphadenopathy and splenomegaly, asthma , and herpesvirus infection.[emedicine.medscape.com]
Recurrent Infection
  • Some will suffer recurrent infections from infancy.[immunodeficiency.ca]
  • Abstract: Patients with primary immunodeficiency diseases most often are recognized because of their increased susceptibility to infection (chronic or recurrent infections without other explanation, infection with an organism of low virulence, or infection[asmscience.org]
  • PIDs are associated with recurrent infections that often appear in early childhood and are caused by weakly virulent microorganisms.[clinchem.aaccjnls.org]
  • A child with recurrent infections in a single anatomic location is more likely to have an anatomic defect than an immunodeficiency. If recurrent infections are present in two or more sites, however, an immunodeficiency disease can be suspected.[aafp.org]
  • Primary immune deficiencies should be suspected whenever anyone has: serious infections (ones that requires hospitalization, or IV antibiotics or antivirals) recurrent infections (infections that reoccur frequently), or opportunistic or unusual infections[primaryimmune.stanford.edu]
Anemia
  • In other patients – adults as well as children and infants – weight loss, chronic gastrointestinal infections, and autoimmune disease such as immune thrombocytopenia, hemolytic anemia, vitiligo, or pernicious anemia may signal a disorder of the immune[mountsinai.org]
  • ., hemolytic anemia, inflammatory bowel disease, vasculitis, or systemic lupus erythematosus) or as part of a syndrome complex (Table 1).[asmscience.org]
  • […] symptoms of primary immunodeficiency can include: Frequent and recurrent pneumonia, bronchitis, sinus infections, ear infections, meningitis or skin infections Inflammation and infection of internal organs Blood disorders, such as low platelet counts or anemia[fortishealthcare.com]
Candidiasis
  • Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy. J Clin Endocrinol Metab. 2006;91:2843–50. CrossRef PubMed Google Scholar 9. Husebye ES, Perheentupa J, Rautemaa R, Kampe O.[link.springer.com]
  • Recent studies in patients with other primary immune deficiency disorders , including autoimmune polyendocrinopathy, candidiasis and ectodermal dystrophy syndrome, CD25 deficiency, STAT5b deficiency, and Wiskott–Aldrich syndrome, have added to our understanding[journals.lww.com]
  • Less Common Categories of Primary Immunodeficiencies Syndrome (% of primary immunodeficiencies)* Clinical presentation Examples Well-defined disorders (15.12) Child with syndromic features Chronic mucocutaneous candidiasis DNA repair defects: ataxia-telangiectasia[aafp.org]
  • * C7 deficiency 4 * C9 deficiency 1 Other immunodeficiencies * Severe Combined Immunodeficiency (SCID) 2 * Chronic Granulomatous Disease 3 * Wiskott-Aldrich syndrome 2 * Natural killer cell deficiency 2 * DiGeorge syndrome 3 * Chronic Mucocutaneous Candidiasis[irishhealth.com]
  • Chronic Mucocutaneous Candidiasis and Susceptibility to Fungal Infections Due to Defects in CARD9 and Dectin-1 Bodo Grimbacher 23. Severe Combined Immunodeficiency Due to Absent Coronin-1A Lawrence R. Shiow, Kenneth Paris and Jennifer M. Puck 24.[oxfordmedicine.com]
Inflammation
  • Impaired acute, granulocytic inflammation results in impaired clearance of bacteria and debris from the gut wall, itself resulting in chronic, granulomatous inflammation.[jem.rupress.org]
  • Stanford Alliance for Primary Immunodeficiencies and Rare Immune Diseases (SAPI) Primary Immunodeficiencies (PI) are rare diseases of the immune system that affects children and adults and increases the susceptibility to infection, allergy, auto-inflammation[primaryimmune.stanford.edu]
  • Signs and symptoms of primary immunodeficiency can include: Frequent and recurrent pneumonia, bronchitis, sinus infections, ear infections, meningitis or skin infections Inflammation and infection of internal organs Blood disorders, such as low platelet[fortishealthcare.com]
Weight Loss
  • […] of an underlying PI disorder and a possible PI diagnosis. 2 Two or more new ear infections within one year Two or more new sinus infections within one year, in the absence of allergy One pneumonia per year for more than one year Chronic diarrhea with weight[immunedisease.com]
  • In other patients – adults as well as children and infants – weight loss, chronic gastrointestinal infections, and autoimmune disease such as immune thrombocytopenia, hemolytic anemia, vitiligo, or pernicious anemia may signal a disorder of the immune[mountsinai.org]
  • Gastrointestinal complaints such as abdominal pain, bloating, nausea, vomiting, diarrhea, and weight loss can occur in people with CVID.[immunedisease.com]
  • In other patients – adults as well as children and infants – weight loss, chronic gastrointestinal infections and autoimmune diseases, such as immune thrombocytopenia, hemolytic anemia, vitiligo or pernicious anemia, may signal a disorder of the immune[kcallergycenter.com]
  • Diagnosis by exclusion Case 1: A 33-year-old woman was in generally good health until she presented with acute-onset prolonged flu-like symptoms followed by hepatitis secondary to Epstein-Barr virus (EBV), significant weight loss, and recurrent fevers[acphospitalist.org]
Diarrhea
  • Gastrointestinal disorders, primarily manifesting in form of diarrhea, may bother up to 50% of PIDD patients.[symptoma.com]
  • […] possible presence of an underlying PI disorder and a possible PI diagnosis. 2 Two or more new ear infections within one year Two or more new sinus infections within one year, in the absence of allergy One pneumonia per year for more than one year Chronic diarrhea[immunedisease.com]
  • Gastrointestinal complaints such as abdominal pain, bloating, nausea, vomiting, diarrhea, and weight loss can occur in people with CVID.[immunedisease.com]
  • Diarrhea, failure to thrive, opportunistic infections, and severe routine infections in a child younger than three months should raise suspicion for SCID.[aafp.org]
Failure to Thrive
  • Affected children suffer from recurrent sinusitis, otitis media, upper respiratory infection and pneumonia, but also from developmental defects and failure to thrive.[symptoma.com]
  • Diarrhea, failure to thrive, opportunistic infections, and severe routine infections in a child younger than three months should raise suspicion for SCID.[aafp.org]
  • PIDs should be suspected in patients with: recurrent sinus or ear infections or pneumonias within a 1 year period; failure to thrive; poor response to prolonged use of antibiotics; persistent thrush or skin abscesses; or a family history of PID.[aacijournal.biomedcentral.com]
  • Common gastrointestinal symptoms include diarrhoea, malabsorption and failure to thrive or losing weight.[patient.info]
  • Since early childhood, I’ve suffered from a list of maladies; failure to thrive, pneumonia, bronchitis, asthma, chronic ear infections and hearing loss, bladder and kidney infections and swollen lymph nodes.[globalgenes.org]
Nausea
  • Mild or moderate pain Redness Swelling Itching The most common side effects of HYQVIA are: Headache Fatigue Nausea Fever Vomiting These are not all the possible side effects.[hyqvia.com]
  • Gastrointestinal complaints such as abdominal pain, bloating, nausea, vomiting, diarrhea, and weight loss can occur in people with CVID.[immunedisease.com]
  • […] recurrent pneumonia, bronchitis, sinus infections, ear infections, meningitis or skin infections Inflammation and infection of internal organs Blood disorders, such as low platelet counts or anemia Digestive problems, such as cramping, loss of appetite, nausea[fortishealthcare.com]
Chronic Diarrhea
  • diarrhea with weight loss Recurrent viral infections (colds, herpes, warts, condyloma) Recurrent need for intravenous antibiotics to clear infections Recurrent, deep abscesses of the skin or internal organs Persistent thrush or fungal infection on the[immunedisease.com]
  • In one case study from the Hacettepe University in Turkey, Kiliç et al [ 34 ] reported a 12-year-old boy who had recurrent respiratory tract infections and chronic diarrhea since age 2 years.[emedicine.medscape.com]
  • Others affect the gastrointestinal system, triggering symptoms such as chronic diarrhea. Left untreated, a PIDD can permanently damage infected parts of the body.[massgeneral.org]
  • Patients with SCID usually present within the first year of life with chronic diarrhea and failure to thrive; severe, recurrent infections with opportunistic pathogens (e.g., Candida albicans [thrush], Pneumocystis jiroveci , or cytomegalovirus); and[aacijournal.biomedcentral.com]
  • diarrhea, failure to thrive, lymphadenopathy, eosinophilia, hepatosplenomegaly, and elevated serum IgE levels.[merckmanuals.com]
Loss of Appetite
  • Frequent and recurrent pneumonia, bronchitis, sinus infections, ear infections, meningitis or skin infections Inflammation and infection of internal organs Blood disorders, such as low platelet counts or anemia Digestive problems, such as cramping, loss[fortishealthcare.com]
Hepatosplenomegaly
  • […] patients 10 yr), varicella-zoster virus infection, herpesvirus infection *Omenn syndrome is an autosomal recessive form of severe SCID causing erythroderma, desquamation, alopecia, chronic diarrhea, failure to thrive, lymphadenopathy, eosinophilia, hepatosplenomegaly[merckmanuals.com]
  • […] the authors identified a C57BL/10 mouse with a spontaneous mutation in and reduced activity of RAG1 . [3] Mice bred from this animal exhibited major symptoms of Omenn syndrome, including having high numbers of memory-phenotype T cells, experiencing hepatosplenomegaly[emedicine.medscape.com]
  • Hepatosplenomegaly and lymphadenopathy are frequently found in patients with CVID and cellular immune deficiency. Cutaneous fungal infections suggest defects in cellular immunity. Furuncles and soft tissue abscesses are seen in phagocytic disorders.[worldallergy.org]
  • […] type Ichthyosis-follicular atrophoderma-hypotrichosis-hypohidrosis syndrome Ichthyosis-follicular atrophoderma-hypotrichosis syndrome Ichthyosis follicularis-alopecia-photophobia syndrome Ichthyosis follicularis-atrichia-photophobia syndrome Ichthyosis-hepatosplenomegaly-cerebellar[orpha.net]
Platyspondyly
Petechiae
  • He presented in respiratory failure at our institution with anasarca, 3 pitting edema in all extremities, clubbing of all digits, splenomegaly, and petechiae.[acphospitalist.org]

Workup

Workup usually starts with routine analyses of blood samples, that may reveal abnormal leukocyte counts. Differential blood counts, assessment of serum levels of complement factors and individual types of immunoglobulins by immunoelectrophoresis are also indispensable. However, qualitative are more important than quantitative studies [3], and in this context, more or less specific tests like the ImmuKnow cell function assay (evaluates the activity of CD4+ T cells), the CH50 and AH50 assays (provide information about the activation of the classical and alternative complement pathway, respectively), and molecular biological procedures (e.g., to assess cytokine and receptor expression), among others, may be helpful [12] [13] [14]. The patient's ability to produce antibodies may be evaluated by measuring antibody titers after immunization. Many PIDD are confirmed by means of genetic screens, but the scope of potential differential diagnoses needs to be narrowed down before a target-oriented approach to gene analysis is possible.

Also, SIDD should be ruled out. Anamnestic data are of utmost importance to that end, but additional measures may be required to determine if the patient is infected with the human immunodeficiency virus, or if they lose immunoglobulins due to a protein-losing enteropathy or nephropathy. Also, susceptibility to infection may be the result of severe congenital neutropenia or cyclic neutropenia, diseases that may be diagnosed after bone marrow examinations.

Treatment

Substitution of IgG is the most common therapeutic approach to PIDD, since this type of immunoglobulin protects against infection with a broad range of pathogens [8]. Furthermore, considerable shares of PIDD patients receive antibiotics, both in order to prevent infections and to treat pre-existing ones. However, continuous antimicrobial therapy is not without side effects and resistance development may severely restrict the choice of antibiotics in case of life-threatening infections. Immunosuppressive therapy aims at counteracting aberrant immune responses that either trigger PIDD (autoimmune disease) or result from PIDD. On the other hand, proliferation of depleted cell pools may be enhanced by application of growth factors. Such therapies may bear the risk of malignant degeneration. Hematopoietic stem cell transplantation is usually carried out in non-responders to alternative treatments and may indeed be the only curative approach to many hereditary immunodeficiencies.

Prognosis

Life expectancy of PIDD patients depends on the underlying disease, but has been stated to be 1 to 49 years [8]. However, PIDD are presumably underdiagnosed and it is to be expected that mild forms of the disease don't significantly reduce the patient's life expectancy. In fact, other studies report many PIDD patients to have a near-normal lifespan [9].

The overall poor prognosis associated with moderate to severe PIDD is due to them being caused by gene defects that often have no cure. Here, treatment comprises preventive and supportive measures, but most patients will eventually die from severe infections, sepsis or malignancies. However, improvements in hematopoietic stem cell transplantation render this procedure a treatment option that is more available for patients afflicted with PIDD. Hopefully, morbidity and mortality will continue to decrease due to this treatment modality.

Etiology

It is beyond the scope of this article to address each disorder classified as PIDD and the interested reader is referred to the extensive list compiled by the International Union of Immunological Societies Expert Committee for Primary Immunodeficiency [2]. The following list may merely give an impression of the heterogeneity of PIDD.

  • They may affect either or both of innate and adaptive immunity.
  • With regards to adaptive immunity, either cellular or humoral immunity may be disturbed.
  • PIDD may comprise quantitative and qualitative alterations of immune cells, antibodies and complement factors.
  • Regulatory mechanisms may be impaired, which may lead to deficient or excess immune responses.
  • Most PIDD result from gene defects, i.e., failures in transcription, translation or post-translational modification may lead to the synthesis of defective gene products; other deficiencies are caused by autoimmune reactions against determined components of the immune system.

Of course, PIDD may fulfill several of the aforementioned criteria, e.g., a genetic predisposition for autoimmune-mediated PIDD has been shown for various diseases [4]. In fact, such a combined etiology is assumed for one of the most common PIDD, for common variable immunodeficiency (CVID). Despite considerable research efforts, the precise triggers of CVID remain largely unknown. This also applies to selective IgA immunodeficiency (SIgAD), an even more common type of PIDD. Although considered a genetic disorder, CVID may develop from SIgAD, suggesting partial overlaps in their etiology.

Epidemiology

There are more than 150 PIDD and they vary widely with regards to incidence and prevalence, predilection for determined patient groups and age distribution. The most common PIDD is SIgAD, and its prevalence has been estimated to be about 1 in 600 inhabitants in the western world. Interestingly, prevalence rates in East Asia are much lower and may only amount to 1 in 18,000 persons [4]. In contrast, other PIDD, such as Job syndrome, affect less than 1 in 1,000,000 people.

Sex distribution
Age distribution

Pathophysiology

PIDD is a general term that comprises a heterogenous group of disorders sharing the common feature of immunodeficiency. However, the underlying gene defects (or autoimmune responses) may induce further complaints, e.g., neurological deficits, cardiovascular and pulmonary disorders and cutaneous lesions, to name a few, and these are sometimes referred to as syndromic features. Gastrointestinal disorders are rather common, too, and may be observed both in CVID and SIgAD patients. Celiac disease and diarrhea is often associated with the former, inflammatory bowel disease-like lesions have been related to the latter [5]. The mucous membranes of the gastrointestinal tract are continuously exposed to bacterial, viral and fungal pathogens, to parasites, to non-pathogenic antigens, and to physical stimuli. Accordingly, this organ system has evolved to become one of the largest immune organs in the human body. It relies on innate mucosal immunity as well as adaptive immune responses mediated by lymphocytes, macrophages, and dendritic cells. In CVID and SIgAD, the adaptive immune system is disturbed. Pediatric chronic granulomatous disease shall serve as an example for malfunction of impairment of innate immunity [6].

Although an increased susceptibility to infection is the hallmark of many PIDD, the immune system's role in anti-mutagenesis and anti-carcinogenesis should not be underestimated. Indeed, PIDD patients may be prone to develop neoplasms. Ataxia telangiectasia shall serve as an example for PIDD predisposing for malignancies. This disease is inherited with an autosomal recessive trait and is provoked by mutations of the ATM (ataxia telangiectasia mutated) gene, whose gene product senses DNA double-strand breaks. Consequently, cell cycle arrest induction due to DNA damage is reduced and cells with nucleic acid anomalies may proliferate. Individuals affected by this disease are prone to acute lymphoblastic leukemia, Hodgkin lymphoma, non-Hodgkin lymphoma and carcinoma [7].

Prevention

PIDD may develop due to gene defects or autoimmune responses against components of the immune system, and both pathophysiological events are of unknown etiology. Thus, no specific measures can be recommended to prevent PIDD. However, the mode of inheritance is known for many diseases associated with primary immunodeficiency and affected families may be advised to seek genetic counselling. Also, psychological support may be offered in counselling sessions. Prenatal diagnosis of PIDD by means of chorionic villus sampling or amniocentesis should be considered.

Summary

Primary immune deficiency disorder (PIDD) is a general term that refers to malfunctions of the immune system that are not triggered by an identifiable cause, e.g., by any other disease, drugs or environmental factors. Should that be the case, the respective patient would be diagnosed with secondary immune deficiency disorder (SIDD).

Most PIDD are congenital diseases, which differentiates them from SIDD. Still, PIDD comprise a very heterogeneous group of more than 150 diseases [1] [2]. PIDD may be difficult to be determined; single molecules that form part of the innate or adaptive immune system, such as a particular cytokine, or may affect large cell populations, e.g., all cells originating from lymphoid progenitor cells in the bone marrow. The precise defect underlying PIDD determines the severity of the disease and renders the patient susceptible to certain pathogens or noxious agents. Because exposure to those stimuli occurs early in life, PIDD-associated symptoms usually manifest shortly after birth or after cessation of protection by maternal antibodies. Autoimmune-mediated PIDD may be an exception to this rule. Here, components of the immune system are destroyed due to an autoimmune response against those structures, and this may occur at any age.

Besides an increased susceptibility to infection, many PIDD are associated with developmental defects, failure to thrive and growth retardation and development of malignancies. Symptoms of often non-specific and don't raise the suspicion of PIDD, that requires a detailed workup to identify both quantitative and functional alterations of a subpopulations of cells, antibodies and mediators [3]. Only then can the broad spectrum of differential diagnoses be narrowed down. Still, the etiology of many PIDD remains poorly understood and this fact further complicates their diagnosis.

Patient Information

Immunodeficiency refers to malfunctions of the immune system that render the patient susceptible to infections. Many diseases are associated with immunodeficiency, with acquired immunodeficiency syndrome (AIDS) due to infection with the human immunodeficiency virus (HIV) probably being the one best known. Because AIDS is the result of an infection with HIV, the corresponding immunodeficiency is classified as secondary immune deficiency disorder (SIDD). This also applies to defective immunity due to other infectious diseases, the intake of drugs, tumors of immune organs, etc. In contrast, if no trigger can be identified, immunodeficiencies are referred to as primary immune deficiency disorder (PIDD). PIDD are most commonly induced by gene defects and are thus present at birth. They don't necessarily manifest within the first year of life, but most PIDD do. Affected children suffer from recurrent sinusitis, otitis media, upper respiratory infection and pneumonia, but also from developmental defects and failure to thrive. Components of the immune system may also be the target of autoimmune responses, i.e., attacks of the patient's immune cells against their own tissues. In that case, PIDD may manifest at any age. Symptoms are similar to those mentioned before. There is a total of 150 PIDD known to date, and common variable immunodeficiency and selective IgA immunodeficiency are the most prevalent ones. PIDD is usually diagnosed through blood tests and clinical features. Treatment is generally directed at restoring the normal function of the immune system through immunoglobulin therapy, growth factor therapy or hematopoietic stem cell transplantation for refractory cases.

References

Article

  1. Arason GJ, Jorgensen GH, Ludviksson BR. Primary immunodeficiency and autoimmunity: lessons from human diseases. Scand J Immunol. 2010; 71(5):317-328.
  2. Picard C, Al-Herz W, Bousfiha A, et al. Primary Immunodeficiency Diseases: an Update on the Classification from the International Union of Immunological Societies Expert Committee for Primary Immunodeficiency 2015. J Clin Immunol. 2015; 35(8):696-726.
  3. Buckley RH. Primary immunodeficiency or not? Making the correct diagnosis. J Allergy Clin Immunol. 2006; 117(4):756-758.
  4. Arkwright PD, Abinun M, Cant AJ. Autoimmunity in human primary immunodeficiency diseases. Blood. 2002; 99(8):2694-2702.
  5. Agarwal S, Mayer L. Diagnosis and treatment of gastrointestinal disorders in patients with primary immunodeficiency. Clin Gastroenterol Hepatol. 2013; 11(9):1050-1063.
  6. Uzzan M, Ko HM, Mehandru S, et al. Gastrointestinal Disorders Associated with Common Variable Immune Deficiency (CVID) and Chronic Granulomatous Disease (CGD). Curr Gastroenterol Rep. 2016; 18(4):17.
  7. Suarez F, Mahlaoui N, Canioni D, et al. Incidence, presentation, and prognosis of malignancies in ataxia-telangiectasia: a report from the French national registry of primary immune deficiencies. J Clin Oncol. 2015; 33(2):202-208.
  8. Gathmann B, Grimbacher B, Beaute J, et al. The European internet-based patient and research database for primary immunodeficiencies: results 2006-2008. Clin Exp Immunol. 2009; 157 Suppl 1:3-11.
  9. Wood P, Stanworth S, Burton J, et al. Recognition, clinical diagnosis and management of patients with primary antibody deficiencies: a systematic review. Clin Exp Immunol. 2007; 149(3):410-423.
  10. Cooper MA, Pommering TL, Koranyi K. Primary immunodeficiencies. Am Fam Physician. 2003; 68(10):2001-2008.
  11. de Vries E, Driessen G. Educational paper: Primary immunodeficiencies in children: a diagnostic challenge. Eur J Pediatr. 2011; 170(2):169-177.
  12. Zeevi A, Lunz J. Cylex ImmuKnow Cell Function Assay. Methods Mol Biol. 2013; 1034:343-351.
  13. Costabile M. Measuring the 50% haemolytic complement (CH50) activity of serum. J Vis Exp. 2010; (37).
  14. Clay TM, Hobeika AC, Mosca PJ, et al. Assays for monitoring cellular immune responses to active immunotherapy of cancer. Clin Cancer Res. 2001; 7(5):1127-1135.

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Last updated: 2018-06-21 17:47