A 36-year-old Caucasian male was admitted to the hospital on August 2006 with a history of a 15-day low grade fever, weight loss, nonproductive cough, and progressive dyspnea. His previous personal and family history were unremarkable. He was not smoking and was not receiving any medications on a regular basis. Review of systems revealed frequent episodes of respiratory infections over the past 5 years without the need for hospitalization. Physical examination showed bilateral crackles and rales involving all lung fields bilaterally and no significant lymphadenopathy, hepatosplenomegaly, or any abnormalities from the skin and cardiovascular system.
The initial white blood cell (WBC) count was normal but severe lymphocytopenia (<200 cells/muL) was noted. The patient deteriorated clinically and a decline of WBCs, platelet count, and hematocrit was noted while total lymphocyte count decreased to <60 cells/muL. On presentation, the erythrocyte sedimentation rate and C-reactive protein were elevated and lactic dehydrogenase levels were 1485 U/L. Among other markers of inflammation, ferritin levels were within normal limits and the levels of fibrinogen were increased (687 mg/dL). Due to depression of all cell lines in the periphery, bone marrow biopsy was undertaken. Bone marrow was hypercellular with mild dysplastic changes, and it contained macrophages with increased phagocytic activity, revealing hemophagocytic syndrome. The initial chest X-ray (CXR) showed bilateral diffuse infiltrates arising from the perihilar regions (Figure 1(a)). Initial Gram stains and cultures from sputum were negative. At that point, antibiotics against pathogens of community-acquired pneumonia were administered and the patient underwent bronchoscopy.
While waiting for bronchoscopy results, he developed worsening hypoxemia and respiratory failure that required intubation and transfer to the hospital's intensive care unit (ICU). Bronchoalveolar lavage (BAL) analysis revealed Pneumocystis jiroveci (PJP) and high-dose trimethoprim-sulfamethoxazole (TMP-SMX) along with corticosteroids was added to broad-spectrum antibiotics. Examination for other pathogens, including Mycobacterium tuberculosis, atypical mycobacteria, cytomegalovirus (CMV), Cryptococcus, and Aspergillus species, was unrevealing.
The patient showed no significant clinical improvement. New blood and sputum cultures sent 5 days after his ICU admission revealed multiresistant Pseudomonas aeruginosa (P. aeruginosa), sensitive only to amikacin and colistin and intermediately sensitive to piperacillin-tazobactam. Colistin and amikacin were added to meropenem, intravenous pentamidine was added to TMP-SMX, and granulocyte colony stimulating factor was administered.
Laboratory evaluation for immunodeficiency had already begun. Serum antibody assays for HIV-1 and -2 were negative. Serum immunoglobulin levels were markedly reduced: IgM 0.259 g/L (normal range: 0.4-2.8 g/L), IgG 3.9 g/L (normal range: 7-17 g/L), IgG1 2.81 g/L, IgG2 0.426 g/L, IgG3 0.331 g/L, and IgG4 0.0198 g/L. Immunofixation that performed as a standard laboratory procedure, excluded a subsequent overproduction of an IgA monoclonal paraprotein. When those results became available, intravenous immunoglobulin infusions (IVIG) were administered, with the regimen Pentaglobin at a dose of 400 mg/kg/day for 5 days.
While the patient was receiving the above-described therapy and was showing minimal improvement, his CXR was evolving and showed ground-glass opacification and bullous-type lesions at the upper lung fields bilaterally (Figure 1(b)). The patient's clinical condition improved significantly almost 2 weeks after appropriate antimicrobial and adjunctive therapy (Figure 1(c)). At that time (approximately 4 weeks after the onset of respiratory failure), PJP full therapy was substituted by secondary prophylaxis and broad-spectrum antibiotics were discontinued.
Three to four days later, the patient's respiratory status deteriorated again. New CXR and computed tomography (CT) scans revealed worsened dense infiltrates and bullous lesions (Figure 2(a)). Broad-spectrum antibiotics were reinstituted plus empiric antifungal and antituberculosis therapy. Repeated testing for Mycobacterium tuberculosis, Mycobacterium avium complex, and fungi via stains, cultures, and molecular detection by polymerase chain reaction (PCR) was negative. New bronchial cultures and BAL studies revealed the same pathogens:Pneumocystis jirovecii and P. aeruginosa. Anti-PJP therapy was reinstituted with TMP-SMX plus clindamycin at this stage, while empiric antifungal and antituberculous therapies were discontinued. Immunoglobulin infusions for 5 more days at the same regimen and dosage as previously were administered. Patient's CXR continued to evolve during therapy and P. aeruginosa was repeatedly isolated from bronchial secretions (Figures 2(b) and 2(c)). The patient responded clinically to his new regimen after 2-3 weeks and radiologically after almost 4-5 weeks (Figures 2(d) and 2(e)). Secondary PJP prophylaxis was again initiated.
Immunoglobulin level serial measurements during hospitalization and follow-up are depicted on Table 1.
Post test immunization (Haemophilus influenzae type b, polysaccharide antigen of Streptococcus pneumoniae, and tetanus toxin) specific antigenic responses were absent, indicative of defective antibody production.
Adenosine deaminase (ADA) enzymatic activity in red blood cells was normal.
Tumour necrosis factor receptor superfamily member 13B (TNFRSF13B, also known as TACI) expression on Beta lymphocytes, assessed by flow cytometry, was within normal range (8.7%) and no defect on TNFRSF13B gene encoding TACI protein was recognized by gene sequencing.
Lymphocyte proliferation in response to antigens (tetanus toxoid and Candida) was not impaired (impaired responses in 20-40% of CVID patients).
HLA-DR expression on CD3+ T lymphocytes (suggesting activation of T cells) was 56% soon after hospital discharge and 15.5% a few months later (measurements performed in different laboratories). Cytokines IL-2, IL-4, IL-5, IL-10, IL-12, and INF-gamma levels were measured and were found to be within normal range.
Initial immunophenotyping revealed marked lymphopenia (total lymphocytes: 320 cells/muL) and marked decreases of peripheral CD4+ T (16.4%), CD8+ T (8%), and CD19+ B lymphocytes (1.5%), while NK cell percentage was found elevated (60.3%). During follow-up, CD4+ T cells were persistently low, while CD8+ T cells and B cells gradually increased to normal levels, and NK cell percentage decreased to near-normal range. The percentage of naive CD4+ T cells (CD4+ CD45RA+) remained persistently low (Table 2).
Repeated serum antibody assays for HIV-1 and -2 and HTLV I and II as well as quantitative HIV-1 plasma RNA measurement were negative.
Further investigations: due to history of recurrent respiratory tract infections and the newly discovered hypogammaglobulinemia, further analysis for suspected immunodeficiency was undertaken. 
Based on the diagnostic criteria proposed by the European Society for Immunodeficiencies and Pan-American Group for Immunodeficiency (age older than 4 years, serum IgG level below the lower reference range, decreased serum IgM or IgA, and exclusion of an underlying cause), the patient's immune deficiency was labelled as CVID, while, according to the criteria proposed by Malphettes et al., he was placed at the LOCID category/variant.
After hospital discharge, the patient had been regularly monitored and did not develop any other OIs. An additional bone marrow examination, performed almost one year after initial presentation, was within normal limits with slightly reduced bone marrow cells. He received secondary prophylaxis against PJP due to persistently low CD4 count and immunoglobulin substitution therapy periodically with subcutaneous injections. He developed a chronic diffuse eczema-type rash attributed to autoimmunity. He had a few bouts of diarrhea without documented infectious etiology that progressed over time and were attributed to small bowel enteropathy similar to celiac disease. Unfortunately the patient died, five years after the initial presentation to us due to unremitted intestinal disease that progressed to ileus, bowel perforation, and septic shock.