Published online April 16, 2007
PEDIATRICS Vol. 119 No. 5 May 2007, pp. e1203-e1205 (doi:10.1542/peds.2006-2396)

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EXPERIENCE & REASON

Diagnosis of Common Variable Immunodeficiency in a Patient With Primary Ciliary Dyskinesia

Edward W. Skorpinski, MD^a, Shiang-Ju Kung, MD^b, Ejaz Yousef, MD^c,d and Stephen J. McGeady, MD^c,d

^a Berkshire Allergy & Asthma Center, Wyomissing, Pennsylvania
^b Allergy Section, Division of Immunologic and Infectious Diseases, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania
^c Division of Allergy and Clinical Immunology, Alfred I. duPont Hospital for Children, Nemours Children's Clinic, Wilmington, Delaware
^d Division of Allergy and Clinical Immunology, Thomas Jefferson University, Philadelphia, Pennsylvania

ABSTRACT

In this case report we describe the first account in the literature of a patient with primary ciliary dyskinesia and common variable immunodeficiency. A 17-year-old boy with previously diagnosed Kartagener syndrome and stable lung disease developed a deteriorating clinical course that prompted the search for a secondary diagnosis. Although both of these rare conditions can result in similar lung pathology, they require different management strategies, which illustrates the need to consider associated diagnoses in complicated clinical situations.

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Key Words: Kartagener syndrome • bronchiectasis • primary ciliary dyskinesia • common variable immunodeficiency

Abbreviations: KS, Kartagener syndrome • PCD, primary ciliary dyskinesia • CVID, common variable immunodeficiency • CT, computed tomography • Ig, immunoglobulin • IVIG, intravenous immunoglobulin • non-CF, non–cystic fibrosis related

First described in 1933, Kartagener syndrome (KS) consists of the clinical triad of situs inversus, bronchiectasis, and recurrent sinusitis.¹ In the 1970s, with the use of electron microscopy, the physiologic defect of KS was determined to be nonfunctioning cilia caused by absence of inner and outer dynein arms on the ciliary structure.^2,3 Since that time, the term "primary ciliary dyskinesia" (PCD) has been used to describe the larger group of patients with recurrent infections and improperly functioning cilia, of which 50% have situs inversus. PCD is felt to be an autosomal recessive disorder with an occurrence rate of 1 in 12000 to 40000 live births.⁴ Common variable immunodeficiency (CVID) is an immune disorder that consists of hypogammaglobulinemia and impaired antibody response; although a TACI (transmembrane activator and calcium modulator and cyclophilin ligand interactor) receptor genetic mutation accounts for 10% of cases, the underlying defect among the rest is yet to be identified and may be multifactorial.^5,6 Patients may present at any age, but the average reported age at onset of symptoms is 23 and 28 years for men and women, respectively.⁷ Despite its name, CVID occurs in only 1 in 25000 to 60000 persons, but it has been shown to be inherited as an autosomal recessive condition in some families.⁸ To our knowledge, there has never been a comorbidity consisting of PCD and CVID described in the literature.

CASE REPORT

A 17-year-old white boy was seen in consultation after hospitalization for the third time in 2 months with fever, malaise, chest tightness, emesis, and diarrhea. An offspring of nonconsanguineous parents delivered after a 32-week-gestation pregnancy, he was diagnosed with situs inversus at birth. After treatment for recurrent episodes of sinusitis and otitis media during the first 2 years of life, he underwent nasal biopsy, which showed abnormal ciliary structure on electron microscopy, consistent with a clinical picture of KS and PCD. Ultimately, the patient underwent myringotomy tube placement 6 times, adenoidectomy twice, and nasal septoplasty with polyp removal. Recurrent pneumonias were treated on an outpatient basis, and chest computed tomography (CT) at age 13 showed no evidence of bronchiectasis. The patient was up-to-date with respect to immunizations and experienced no adverse effects when immunized with live-virus vaccines. His growth patterns were reportedly normal. His family history was negative for immunodeficiency, and he denied tobacco use. His first hospitalization ever at age 15 was for pneumonia with pleural effusion, and his sputum culture grew ceftriaxone-resistant Streptococcus pneumoniae, and repeat chest CT revealed left lower-lobe bronchiectasis.

Two months before this admission, while hospitalized for fever, emesis, diarrhea, and dehydration, the patient was noted to have significant splenomegaly accompanied by mild pancytopenia. Results of Epstein-Barr virus, cytomegalovirus, and toxoplasma studies were negative, and he was referred for a pediatric hematology/oncology evaluation of the pancytopenia and splenomegaly. He was readmitted to the hospital 1 week later with fever, cough, dyspnea, and pallor, and his chest CT now demonstrated significant bilateral interstitial consolidation, prominent mediastinal lymph nodes, and bilateral bronchiectasis. Bronchoscopy revealed copious tracheal secretions, and results of a bronchoalveolar lavage culture were positive for nonmucoid Pseudomonas aeruginosa. Bone marrow analysis was normal, and the patient's pancytopenia was felt to be secondary to hypersplenism, which was present as a result of chronic infection.

On examination for the most recent admission, the patient appeared fatigued, pale, and chronically ill, with bilateral rales auscultated on pulmonary examination and the spleen tip palpable 5 cm below the right costal margin. A chest radiograph revealed left lower-lobe consolidation and right lower-lobe discoid atelectasis. The blood culture grew S pneumoniae, a complete blood count showed lymphopenia (absolute lymphocyte count: 1000 cells per µL), mild anemia (hemoglobin: 11.8 g/dL), and mild thrombocytopenia (120000 platelets per µL), and quantitative immunoglobulin (Ig) values were IgA < 10 mg/dL, IgG < 50 mg/dL, and IgM < 10 mg/dL, with similar values on repeat determination. Subsequent outpatient workup showed nonprotective antibody titers to diphtheria, tetanus, and 12 pneumococcal serotypes, and only antidiphtheria antibodies showed minimal response after booster immunizations with tetanus and diphtheria and 23-valent pneumococcal vaccines. A lymphocyte-enumeration study reflected the overall lymphopenia, but relative numbers of CD3, CD4, CD8, CD19, and CD16/56 cells were of normal proportion, and results of lymphocyte-proliferation studies to 3 mitogens were normal; HIV serology was negative, complement levels were normal, and stool giardia antigen was negative. Monthly intravenous immunoglobulin (IVIG) therapy was initiated.

DISCUSSION

Absent dynein arm structure leading to immotile cilia is the most common defect underlying the clinical features of KS, although other ciliary structural and functional defects have been identified.⁹ Absent ciliary function during embryogenesis is believed to result in situs inversus in 50% of cases, and male patients produce immotile sperm. Poor mucociliary clearance is deemed to be the primary reason behind recurrent sinopulmonary infections in KS and the broader classification of PCD, and the average age at diagnosis of PCD is 4.4 years.¹⁰ Although patients with PCD have been thought to be intact immunologically, a case report of an individual with KS and a neutrophil chemotactic defect,¹¹ however, prompted Neffen et al¹² to measure humoral and cellular immunity in a series of 6 patients with KS. In their study, immunoglobulin levels, complement assays, lymphocyte enumeration, and in vitro lymphoproliferative responses were essentially normal; however, an absent in vivo delayed hypersensitivity response to purified protein derivative and fungal antigens was observed in the majority of the patients. No other description of immunodeficiencies in patients with KS or PCD was identified during literature searches.

It has been found that recurrent pulmonary infections of several etiologies can lead to bronchiectasis. A study of 136 children with non–cystic fibrosis–related (non-CF) bronchiectasis reported PCD as the third most common etiology (15%), behind idiopathic (26%) and chronic (18%) aspiration. Although those with immunodeficiencies of all types comprised 35% of the study population, CVID was the most common individual immunodeficiency and was the fourth most common etiology (10%) of non-CF bronchiectasis overall.¹³ Other studies of non-CF bronchiectasis have shown similar statistics for PCD, although the prevalence of CVID ranged from 2% to 4%.^14,15 Because of substantial overlap in the patterns of bronchiectasis seen in PCD and CVID, it is not possible to determine the etiology of bronchiectasis by chest CT findings alone.¹¹ It has been noted, however, that pulmonary function in patients with PCD remains fairly constant if the condition is treated properly.^16–18 A review of sequential pulmonary-function studies showed that our patient began to exhibit a decline after several years of stability. Meanwhile, a study of 248 patients with CVID described a 21% prevalence of gastrointestinal disease with a variety of pathologic findings on biopsy.⁵ Symptoms at 2 of our patient's hospitalizations included emesis, diarrhea, and abdominal pain on presentation, and the persistence of these symptoms eventually led to the performance of upper and lower endoscopy. His biopsy specimens showed active esophagitis and mild active duodenitis. Although it has not been widely used clinically, analysis of exhaled nitric oxide and nasal nitric oxide showed significantly lower levels of both in patients with PCD compared with healthy controls, whereas subjects with non-CF bronchiectasis had higher levels than controls.¹⁹ Such testing was not available for our patient.

CONCLUSIONS

This case illustrates the need to consider associated diagnoses in complicated clinical situations. Although there was no available record of any humoral immunity evaluation having been performed during our patient's early childhood, results of such testing more than likely would have been normal given the fact that the usual age of onset of CVID is in the third decade of life. Once the relatively rare diagnosis of PCD was established, however, the possibility of an associated, equally rare immunodeficiency was considered only after a few years of clinical deterioration had occurred. Although the management of PCD includes early and aggressive use of antibiotics and immunization, the diagnosis of CVID is approached with antibiotics and IVIG replacement therapy. Immunizations are ordinarily of little benefit to patients with CVID, and live vaccines, in particular, can be harmful (and should be avoided).²⁰ It is not possible to know the time of onset of CVID or whether immunoglobulin replacement earlier in this patient's life might have delayed the progression of the structural lung disease; however, his clinical course improved after monthly IVIG administration. As this case illustrates, when faced with a deteriorating clinical picture, the clinician must consider comorbidities that require different or additional management strategies.

FOOTNOTES

Accepted Nov 14, 2006.

Address correspondence to Edward W. Skorpinski, MD, Berkshire Allergy & Asthma Center, 2210 Ridgewood Rd, Suite 100, Wyomissing, PA 19610. E-mail: eskorpinski{at}comcast.net

The authors have indicated they have no financial relationships relevant to this article to disclose.

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PEDIATRICS (ISSN 1098-4275). ©2007 by the American Academy of Pediatrics

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This Article Abstract Full Text (PDF) Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services E-mail this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Add to My File Cabinet Download to citation manager Request Permissions Citing Articles Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Skorpinski, E. W. Articles by McGeady, S. J. Search for Related Content PubMed PubMed Citation Articles by Skorpinski, E. W. Articles by McGeady, S. J. Related Collections Infectious Disease & Immunity Social Bookmarking                         What's this?