26-Year-Old Woman With Recurrent Upper Respiratory Infections.

A 26-year-old woman presented with a chief complaint of recurrent upper respiratory and sinus infections. She reported that during the last 2 years, she had experienced 4 sinus infections lasting longer than 1 week requiring antibiotic therapy and multiple sinopulmonary infections during the spring and fall. Before this, she denied any history of recurrent sinus infection, upper respiratory tract infection, acute otitis media, diarrhea, pneumonia, or other infection. Review of systems was negative for fevers, chills, unexplained weight loss, rashes, warts, other skin concerns, or any current symptoms except for anxiety. Medical history was significant for migraine headaches, bipolar 2 disorder, syncope, and premature ventricular complexes. Medications were oxcarbazepine, lamotrigine, venlafaxine, and metoprolol. There was no known family history of immunodeficiency. Physical examination revealed a nondistressed female adult with the following vital signs: temperature of 36.1 °C, heart rate of 78 beats/min, blood pressure of 117/73 mm Hg, and body mass index of 30.4 kg/m2. Examination of the head, eyes, ears, nose, and throat revealed clear tympanic membranes, normal conjunctiva, moist oral mucosa without lesions, and nonerythematous nasal mucosa without polyps or lesions. There was no lymphadenopathy in the anterior or posterior cervical chains. Lungs were clear to auscultation, and cardiac examination revealed a normal rate and regular rhythm. Abdominal examination revealed a soft, nontender, and nondistended abdomen. Integumentary examination revealed warm skin without lesions or rash. Findings on chest radiography were normal, and laboratory tests were ordered.1.Given this patient’s presentation, which arm of the immune system is most likely affected?a.Both cellular and humoral immunityb.Innate immunityc.Complement-mediated immunityd.Phagocytosise.Humoral immunity Severe combined immunodeficiency syndrome (SCID) is the prototype condition that impairs both cellular and humoral immunity.1Tangye S.G. Al-Herz W. Bousfiha A. et al.Human Inborn Errors of Immunity: 2019 update on the classification from the International Union of Immunological Societies Expert Committee.J Clin Immunol. 2020; 40 (Published correction appears in J Clin Immunol. 2020;40(1):65): 24-64Crossref PubMed Scopus (743) Google Scholar Multiple genotypes are associated with the phenotype of SCID. Children born with SCID appear normal but develop multiple severe infections, failure to thrive, and cutaneous manifestations, such as eczema, are common. Evaluation for SCID is part of the standard newborn screening, and thus it is identified early in life. Defects in the innate immune system lead to increased susceptibility to viral, bacterial, and fungal infections. Deficits in natural killer cells lead to increased infections with herpes simplex virus, Epstein-Barr virus, and cytomegalovirus.1Tangye S.G. Al-Herz W. Bousfiha A. et al.Human Inborn Errors of Immunity: 2019 update on the classification from the International Union of Immunological Societies Expert Committee.J Clin Immunol. 2020; 40 (Published correction appears in J Clin Immunol. 2020;40(1):65): 24-64Crossref PubMed Scopus (743) Google Scholar Sequence variations in the autoimmune regulator (AIRE) or STAT proteins can lead to predisposition to mycologic infections, including candidiasis.1Tangye S.G. Al-Herz W. Bousfiha A. et al.Human Inborn Errors of Immunity: 2019 update on the classification from the International Union of Immunological Societies Expert Committee.J Clin Immunol. 2020; 40 (Published correction appears in J Clin Immunol. 2020;40(1):65): 24-64Crossref PubMed Scopus (743) Google Scholar Complement deficiencies can lead to recurrent infections with encapsulated organisms, such as Neisseria, and are associated with other conditions including systemic lupus erythematosus and hereditary angioedema.1Tangye S.G. Al-Herz W. Bousfiha A. et al.Human Inborn Errors of Immunity: 2019 update on the classification from the International Union of Immunological Societies Expert Committee.J Clin Immunol. 2020; 40 (Published correction appears in J Clin Immunol. 2020;40(1):65): 24-64Crossref PubMed Scopus (743) Google Scholar Whereas the range of presentation of diseases of the innate immune system is vast, these syndromes typically are manifested at birth, making this an unlikely diagnosis for our patient. Phagocytosis is a cellular process used by many cells in the immune system to engulf and digest a target organism. A prototypical congenital deficit in phagocytosis is chronic granulomatous disease (CGD), which is characterized by recurrent pneumonias and abscesses with catalase-positive organisms including Staphylococcus aureus, Candida sp, Aspergillus sp, and Pseudomonas sp. The gene that is most commonly mutated in CGD, CYBB, is X-linked and thereby unlikely in our female patient. Standard treatment is with antimicrobial prophylaxis with trimethoprim-sulfamethoxazole, itraconazole, and interferon; bone marrow transplant can be considered.1Tangye S.G. Al-Herz W. Bousfiha A. et al.Human Inborn Errors of Immunity: 2019 update on the classification from the International Union of Immunological Societies Expert Committee.J Clin Immunol. 2020; 40 (Published correction appears in J Clin Immunol. 2020;40(1):65): 24-64Crossref PubMed Scopus (743) Google Scholar These syndromes also are manifested in childhood. Humoral immune system deficits refer to defects in B-cell antibody production. B cells differentiate into plasma cells and produce IgM antibodies and through isotype switching can change into IgG-, IgA-, or IgE-producing cells. Antibody deficiencies are classically manifested as recurrent sinopulmonary infections, as seen in our patient. Humoral immunodeficiency can be primary (present from birth) or secondary. The likelihood of primary immunodeficiency being the pathogenesis of the recurrent infections is unlikely, given the recent onset of her symptoms. Secondary humoral immunodeficiency is an acquired state of humoral deficiency due to nongenetic reasons. Based on her history, the appropriate test was ordered.2.Which one of the following tests is the most likely to yield a diagnosis for our patient?a.Complete blood count (CBC) with differentialb.Quantitative immunoglobulin level (IgA, IgG, IgM)c.Dihydrorhodamine flow cytometryd.Total hemolytic complement assaye.Non–contrast-enhanced computed tomography imaging of the chest A CBC with differential provides quantitation of the 3 major blood cell types—erythrocytes (red blood cells), leukocytes (white blood cells), and platelets—as well as of other white blood cell subtypes, including neutrophils, lymphocytes, monocytes, basophils, and eosinophils. The CBC with differential is an important screening test for immunodeficiency as it can detect pathologic decreases or increases in white blood cell levels. For example, neutropenia may indicate a congenital disorder, and lymphopenia may suggest a T-cell disorder. Although important as a screening tool, the CBC is not specific enough to yield an immunodeficiency diagnosis. A quantitative immunoglobulin assay measures the serum concentration of the 3 most common gamma globulins—immunoglobulins G, A, and M. Immunoglobulins are produced by plasma B cells, and both increases and decreases in their levels are informative. An increased IgM level coupled with decreased IgA and IgG levels can indicate a class switch recombination deficit (hyper-IgM syndrome). Selective IgA deficiency is relatively common (about 1 in 300 Americans) and is notable for increasing risk of anaphylaxis with blood transfusion. Reduction in multiple gamma globulins is referred to as hypogammaglobulinemia. Common variable immunodeficiency (CVID) is characterized by reduction in IgG and IgA and sometimes IgM.1Tangye S.G. Al-Herz W. Bousfiha A. et al.Human Inborn Errors of Immunity: 2019 update on the classification from the International Union of Immunological Societies Expert Committee.J Clin Immunol. 2020; 40 (Published correction appears in J Clin Immunol. 2020;40(1):65): 24-64Crossref PubMed Scopus (743) Google Scholar The quantitative immunoglobulin assay is the “gold standard” test to initially evaluate for humoral immunodeficiency and should be performed when a patient has been without infection; if the result is abnormal, the test should be repeated in 4 to 6 weeks for confirmation. There are many specialized immune function assays to help in the diagnosis of immunodeficiencies. For example, dihydrorhodamine flow cytometry can identify an NADPH oxidase defect and can help diagnose CGD, and the total hemolytic complement assay can identify defects in the activation of the classical complement pathway. Neither of these assays would help in the diagnosis of a humoral immunodeficiency. Whereas chest computed tomography is appropriate for evaluation of atypical pneumonia, it will not provide any diagnostic information about this patient’s immune system. Our patient’s quantitative immunoglobulin assay demonstrated the following (reference ranges provided parenthetically): IgG, 382 mg/dL (767 to 1590 mg/dL); IgA, 33 mg/dL (61 to 356 mg/dL); and IgM, 33 mg/dL (37 to 286 mg/dL). Results of her CBC with differential were normal, including: white blood cell count, 5.7 × 109/L (3.4 to 9.6 × 109/L); neutrophil count, 3.70 × 109/L (1.56 to 6.45 × 109/L); and lymphocyte count, 1.52 × 109/L (0.95 to 3.07 × 109/L).3.Which one of the following is the most appropriate first-line treatment strategy?a.Hematopoietic stem cell transplantb.Intravenous immune globulin (IVIG) administrationc.Medication adjustmentd.Long-term antibiotic suppressive therapye.Subcutaneous immune globulin (SCIG) administration Hematopoietic stem cell transplant is a potentially curative treatment of SCID and myeloid disorders that cause immunodeficiency, such as multiple myeloma.2Castagnoli R. Delmonte O.M. Calzoni E. Notarangelo L.D. Hematopoietic stem cell transplantation in primary immunodeficiency diseases: current status and future perspectives.Front Pediatr. 2019; 7: 295Crossref PubMed Scopus (112) Google Scholar However, hematopoietic stem cell transplant is an expensive procedure that can lead to morbidity and mortality and should be considered only in select patients with life-threatening immunodeficiency states.2Castagnoli R. Delmonte O.M. Calzoni E. Notarangelo L.D. Hematopoietic stem cell transplantation in primary immunodeficiency diseases: current status and future perspectives.Front Pediatr. 2019; 7: 295Crossref PubMed Scopus (112) Google Scholar Intravenous immune globulin therapy provides exogenous donor immunoglobulins and is used to treat symptomatic hypogammaglobulinemia.3Perez E.E. Orange J.S. Bonilla F. et al.Update on the use of immunoglobulin in human disease: a review of evidence.J Allergy Clin Immunol. 2017; 39: S1-S46Abstract Full Text Full Text PDF Scopus (377) Google Scholar However, the cause of hypogammaglobulinemia should first be ascertained because secondary hypogammaglobulinemia states often respond to removal of the offending agent or pathologic state. Given our patient’s use of lamotrigine for treatment of bipolar disorder and the clinical history compatible with a secondary immunodeficiency, the decision was made to first attempt a medication adjustment by removing lamotrigine, the suspected offending medication. Patients with immunodeficiency states that lead to recurring bacterial infections may be candidates for long-term antibiotic suppressive therapy. For example, patients with CGD are given antimicrobial prophylaxis. The risks and benefits of long-term antibiotic use must be carefully weighed as antibiotic resistance is an increasing concern globally.3Perez E.E. Orange J.S. Bonilla F. et al.Update on the use of immunoglobulin in human disease: a review of evidence.J Allergy Clin Immunol. 2017; 39: S1-S46Abstract Full Text Full Text PDF Scopus (377) Google Scholar For the same reasons as for IVIG, SCIG, a subcutaneous version of immunoglobulin, is incorrect. Her medication regimen was adjusted by discontinuation of the offending agent, lamotrigine.4.Which one of the following answers is correct regarding the anticipated time of recovery for our patient’s immunoglobulin levels?a.Immediate recoveryb.Recovery within 3 to 5 daysc.Recovery within months to yearsd.Recovery within decadese.No anticipated recovery Both immediate recovery and recovery within 3 to 5 days after lamotrigine discontinuation are unlikely. In addition to the time necessary for the medication to be metabolized and eliminated, it takes time for B cells to resume antibody production for reasons that are not completely understood. A partial answer may be found in recent research in model organisms reporting that lamotrigine affects the transcription of genes involved in inflammation and immune system activation and regulation.4Mochol M. Whatmore P. Taubøll E. et al.Lamotrigine effects on immune gene expression in larval zebrafish.Epilepsy Res. 2021; 178106823Crossref PubMed Scopus (1) Google Scholar Patients with secondary hypogammaglobulinemia typically have an excellent prognosis if the offending agent can be removed. For antiepileptic medications such as lamotrigine, immunoglobulin levels typically respond in a period of months to years, and a clinical response of reduced infection frequency often occurs before the immunoglobulin levels return to laboratory normal ranges.5Ozaras N. Goksugur N. Eroglu S. Tabak O. Canbakan B. Ozaras R. Carbamazepine-induced hypogammaglobulinemia.Seizure. 2012; 21: 229-231Abstract Full Text Full Text PDF PubMed Scopus (20) Google Scholar A full recovery is expected well before a decade. However, patients who must continue to take the offending agent, such as transplant patients who require ongoing immunosuppression, may experience ongoing hypogammaglobulinemia. Two months after discontinuation of lamotrigine, our patient demonstrated immunoglobulin levels of 416 mg/dL for IgG, 34 mg/dL for IgA, and 46 mg/dL for IgM, all of which were improved from previously but still below reference range. She reported resolution of recurrent infections within 5 months.5.If the patient’s immunoglobulin levels did not respond to the removal of lamotrigine, which one of the following tests would be appropriate to investigate our patient’s immune function in a follow-up visit?a.Pneumococcal vaccine responseb.Serial CBC with differentialc.Serial CD4+ countd.Delayed-type hypersensitivity skin testinge.Genetic testing Measurement of responsiveness to Tdap or pneumococcal vaccination is an excellent surrogate of humoral immune function. A thorough vaccination history should be obtained before testing. Tdap immunization is used to measure antibody response to a protein antigen, and pneumococcal polysaccharide vaccine (PPSV-23) immunization is used to test antibody responsiveness to a polysaccharide immunogen. Two patterns of antibody deficiency exist: polysaccharide antibody deficiency, typical of hypogammaglobulinemia; and deficiency of antibodies to both polysaccharides and proteins but not protein alone, as seen in SCID and CVID. Antibody titers should be determined 4 to 6 weeks after vaccination.6Orange J.S. Ballow M. Stiehm E.R. et al.Use and interpretation of diagnostic vaccination in primary immunodeficiency: a working group report of the Basic and Clinical Immunology Interest Section of the American Academy of Allergy, Asthma & Immunology.J Allergy Clin Immunol. 2012; 130: S1-S24Abstract Full Text Full Text PDF PubMed Scopus (325) Google Scholar A positive response to pneumococcal vaccination is defined as titers greater than 1:3 in more than 70% of the antigens, and an absence of response with normal immunoglobulin levels is seen in specific antibody deficiency.7Bonilla F.A. Khan D.A. Ballas Z.K. et al.Practice parameter for the diagnosis and management of primary immunodeficiency.J Allergy Clin Immunol. 2015; 136: 1186-1205.e1-78Abstract Full Text Full Text PDF PubMed Scopus (418) Google Scholar Serial CBC is not likely to yield any prognostic information in this case as the white blood cell count does not yield specific information on B-cell numbers or function. Whereas serial CD4 count is useful in monitoring the effectiveness of antiretroviral therapy in patients living with HIV infection, it is not appropriate for management of hypogammaglobulinemia. Delayed-type hypersensitivity skin testing is a measurement of cellular immunity, performed by injection of an antigen from either Candida or Trichophyton species, with an induration response measured in 48 hours.7Bonilla F.A. Khan D.A. Ballas Z.K. et al.Practice parameter for the diagnosis and management of primary immunodeficiency.J Allergy Clin Immunol. 2015; 136: 1186-1205.e1-78Abstract Full Text Full Text PDF PubMed Scopus (418) Google Scholar It is less commonly used today because of availability of other test modalities and would not be helpful in determining whether a patient has recovered antibody production. Genetic testing is appropriate in the evaluation of primary immunodeficiencies. Unfortunately, our patient did not present for planned follow-up pneumococcal titers. Immunodeficiency is a complex medical presentation that should be approached foremost with a detailed history. A comprehensive history will help determine primary vs secondary immunodeficiency, which functions of the immune system may be involved, and possible secondary causes that are present.8McCusker C. Upton J. Warrington R. Primary immunodeficiency.Allergy Asthma Clin Immunol. 2018; 14: 61Crossref PubMed Scopus (102) Google Scholar Warning signs that should trigger an immunodeficiency evaluation include the following: 4 or more infections, such as otitis, bronchitis, pneumonia, or sinuitis, requiring antibiotics within 1 year; recurring infections or infections requiring prolonged antibiotics; 2 or more serious bacterial infections, such as osteomyelitis, meningitis, and septicemia; 2 or more radiologically proven pneumonias within 3 years; unusual infections or infections in unusual locations; and a family history of immunodeficiency (ESID.org). Questions should be asked about number and sites of infections within the last year, hospitalizations, causal organisms, vaccine history, family history for immunodeficiency, and past medical and surgical histories. Social history should include assessment of risk factors for malnutrition and exposure to HIV, including comprehensive substance use and sexual histories. Childhood history of recurrent infections and sites of infection should be assessed. The most common primary hypogammaglobulinemia is CVID, although other disorders including X-linked agammaglobulinemia can likewise lead to antibody production deficits.1Tangye S.G. Al-Herz W. Bousfiha A. et al.Human Inborn Errors of Immunity: 2019 update on the classification from the International Union of Immunological Societies Expert Committee.J Clin Immunol. 2020; 40 (Published correction appears in J Clin Immunol. 2020;40(1):65): 24-64Crossref PubMed Scopus (743) Google Scholar Children with recurrent infections suggestive of primary immunodeficiency should be referred for specialty evaluation by an immunologist to facilitate diagnosis and appropriate management. Initiation of treatment for primary hypogammaglobulinemia syndromes, including IVIG and SCIG when appropriate, reduces the rate of serious infections and improves quality of life.9Ghafoor A. Joseph S.M. Making a diagnosis of common variable immunodeficiency: a review.Cureus. 2020; 12e6711PubMed Google Scholar Secondary hypogammaglobulinemia states are known to be due to infections, malignant neoplasms, protein-losing states, and medications. Anticonvulsants including lamotrigine, carbamazepine, phenytoin, and valproate are well documented as causing hypogammaglobulinemia and CVID-like syndromes.7Bonilla F.A. Khan D.A. Ballas Z.K. et al.Practice parameter for the diagnosis and management of primary immunodeficiency.J Allergy Clin Immunol. 2015; 136: 1186-1205.e1-78Abstract Full Text Full Text PDF PubMed Scopus (418) Google Scholar IgA is the most affected antibody isotype in anticonvulsant-mediated hypogammaglobulinemia, although multiple isotypes can be affected. The mechanism of anticonvulsant-induced immunosuppression is not fully known, and individual patients may experience different time courses and severity of immunosuppression.5Ozaras N. Goksugur N. Eroglu S. Tabak O. Canbakan B. Ozaras R. Carbamazepine-induced hypogammaglobulinemia.Seizure. 2012; 21: 229-231Abstract Full Text Full Text PDF PubMed Scopus (20) Google Scholar Glucocorticoids and other immunosuppressants can likewise lead to secondary hypogammaglobulinemia through their on-target effects. For example, rituximab can precipitate hypogammaglobulinemia as this medication depletes CD20-positive cells including B-cell populations.10Roberts D.M. Jones R.B. Smith R.M. et al.Rituximab-associated hypogammaglobulinemia: incidence, predictors and outcomes in patients with multi-system autoimmune disease.J Autoimmun. 2015; 57: 60-65Crossref PubMed Scopus (186) Google Scholar It is therefore important to consider the possibility that medications may decrease antibody production in both their on-target and off-target effects. More than 30 medications are associated with hypogammaglobulinemia, many of which are antineoplastic agents, and we encourage multidisciplinary consultation with pharmacy or immunology specialists if questions arise about the culpability of specific medicines in a patient’s immunodeficiency state.11Patel S.Y. Carbone J. Jolles S. The expanding field of secondary antibody deficiency: causes, diagnosis, and management.Front Immunol. 2019; 10: 33Crossref PubMed Scopus (103) Google Scholar Hypogammaglobulinemia is often an overlooked diagnostic entity in medicine. Up to 1 in 10,000 individuals in the United States are affected by a primary immunodeficiency, and secondary hypogammaglobulinemia is significantly more common than primary hypogammaglobulinemia.12Azar A.E. Ballas Z.K. Evaluation of the adult with suspected immunodeficiency.Am J Med. 2007; 120: 764-768Abstract Full Text Full Text PDF PubMed Scopus (30) Google Scholar Medical trainees and primary care physicians are well positioned to identify secondary hypogammaglobulinemia using history, physical examination, and high-yield laboratory testing. By correctly identifying patients at risk for secondary immunodeficiency who present with warning signs of antibody deficiency, providers can reduce the morbidity from this underdiagnosed and undertreated condition and help reduce the burden of secondary humoral immunodeficiency. The authors report no competing interests.