Dirk N. Darnell

Pulmonary Nontuberculous Mycobacterial Disease: Prospective Study of a Distinct Preexisting Syndrome

RATIONALE Pulmonary nontuberculous mycobacterial (PNTM) disease is increasing, but predisposing features have been elusive. OBJECTIVES To prospectively determine the morphotype, immunophenotype, and cystic fibrosis transmembrane conductance regulator genotype in a large cohort with PNTM. METHODS We prospectively enrolled 63 patients with PNTM infection, each of whom had computerized tomography, echocardiogram, pulmonary function, and flow cytometry of peripheral blood. In vitro cytokine production in response to mitogen, LPS, and cytokines was performed. Anthropometric measurements were compared with National Health and Nutrition Examination Survey (NHANES) age- and ethnicity-matched female control subjects extracted from the NHANES 2001-2002 dataset. MEASUREMENTS AND MAIN RESULTS Patients were 59.9 (+/-9.8 yr [SD]) old, and 5.4 (+/-7.9 yr) from diagnosis to enrollment. Patients were 95% female, 91% white, and 68% lifetime nonsmokers. A total of 46 were infected with Mycobacterium avium complex, M. xenopi, or M. kansasii; 17 were infected with rapidly growing mycobacteria. Female patients were significantly taller (164.7 vs. 161.0 cm; P < 0.001) and thinner (body mass index, 21.1 vs. 28.2; P < 0.001) than matched NHANES control subjects, and thinner (body mass index, 21.1 vs. 26.8; P = 0.002) than patients with disseminated nontuberculous mycobacterial infection. A total of 51% of patients had scoliosis, 11% pectus excavatum, and 9% mitral valve prolapse, all significantly more than reference populations. Stimulated cytokine production was similar to that of healthy control subjects, including the IFN-gamma/IL-12 pathway. CD4(+), CD8(+), B, and natural killer cell numbers were normal. A total of 36% of patients had mutations in the cystic fibrosis transmembrane conductance regulator gene. CONCLUSIONS Patients with PNTM infection are taller and leaner than control subjects, with high rates of scoliosis, pectus excavatum, mitral valve prolapse, and cystic fibrosis transmembrane conductance regulator mutations, but without recognized immune defects.

Long-Term Interferon-γ Therapy for Patients with Chronic Granulomatous Disease

BACKGROUND Chronic granulomatous disease (CGD) is a rare disorder of phagocytes in which absent production of superoxide and hydrogen peroxide in phagocytes predisposes patients to bacterial and fungal infections. Infections are dramatically reduced by prophylaxis with antibiotics, antifungals, and interferon- gamma (IFN-gamma ). METHODS Seventy-six patients with CGD were enrolled in an uncontrolled, open-label follow-up study to assess the long-term clinical safety and efficacy of IFN-gamma therapy. Patients received IFN-gamma subcutaneously 3 times per week. RESULTS We observed patients for up to 9 years, for a total observation period of 328.4 patient-years. The incidence of serious infections was 0.30 infections per patient-year; for serious bacterial infections, the incidence was 0.18 cases per patient-year, and for serious fungal infections, it was 0.12 cases per patient-year. Thirty-seven percent of patients reported an adverse event, the most common of which was fever. Twenty-six patients withdrew from the study (3 because of adverse events, 15 because of patient preference, and 8 because of transfer to another trial). There were no life-threatening IFN-gamma-related adverse events and no discernible effects on growth. The overall mortality rate was 1.5% per patient-year. CONCLUSION IFN-gamma prophylaxis for CGD appears to be effective and well tolerated over a prolonged period of time.

Common Severe Infections in Chronic Granulomatous Disease

BACKGROUND Chronic granulomatous disease (CGD) is due to defective nicotinamide adenine dinucleotide phosphate oxidase activity and characterized by recurrent infections with a limited spectrum of bacteria and fungi as well as inflammatory complications. To understand the impact of common severe infections in CGD, we examined the records of 268 patients followed at a single center over 4 decades. METHODS All patients had confirmed diagnoses of CGD, and genotype was determined where possible. Medical records were excerpted into a standard format. Microbiologic analyses were restricted to Staphylococcus, Burkholderia, Serratia, Nocardia, and Aspergillus. RESULTS Aspergillus incidence was estimated at 2.6 cases per 100 patient-years; Burkholderia, 1.06 per 100 patient-years; Nocardia, 0.81 per 100 patient-years; Serratia, 0.98 per 100 patient-years, and severe Staphylococcus infection, 1.44 per 100 patient-years. Lung infection occurred in 87% of patients, whereas liver abscess occurred in 32%. Aspergillus incidence was 55% in the lower superoxide-producing quartiles (quartiles 1 and 2) but only 41% in the higher quartiles (rate ratio, <0.0001). Aspergillus and Serratia were somewhat more common in lower superoxide producing gp91phox deficiency. The median age at death has increased from 15.53 years before 1990 to 28.12 years in the last decade. Fungal infection carried a higher risk of mortality than bacterial infection and was the most common cause of death (55%). Gastrointestinal complications were not associated with either infection or mortality. CONCLUSIONS Fungal infections remain a major determinant of survival in CGD. X-linked patients generally had more severe disease, and this was generally in those with lower residual superoxide production. Survival in CGD has increased over the years, but infections are still major causes of morbidity and mortality.

Brain Abnormalities in Patients With Hyperimmunoglobulin E Syndrome

OBJECTIVES. Hyperimmunoglobulin E syndrome is a multisystem disorder with abnormalities of the immunologic, connective tissue, and skeletal tissue systems. Central nervous system abnormalities have not been considered a feature of hyperimmunoglobulin E syndrome. We aimed to determine whether central nervous system abnormalities detected on brain MRI exist in hyperimmunoglobulin E syndrome and to characterize any identified abnormalities. PATIENTS AND METHODS. Fifty patients aged from 3 to 52 years (mean: 24 years) with established diagnoses of hyperimmunoglobulin E syndrome had MRI of the brain as part of an hyperimmunoglobulin E syndrome natural history protocol. Abnormalities were described, measured, counted, and mapped. Patient charts were reviewed for neurologic findings and blood pressure measurements. RESULTS. Focal brain lesions exhibiting high signal intensities on flow-attenuated inversion recovery and on T2-weighted techniques were found in 35 of the 50 patients. The focal hyperintensities were predominantly in the white matter of the cerebral hemispheres, and the number ranged from 2 to >50. The hyperintensities occurred more frequently in adults than in children, and no association with elevated blood pressure was found. Five patients had lacunar infarctions. Chiari type 1 malformations were found in 9 of 50 patients. Two patients had infectious complications presenting on MRI as cerebritis in 1 patient and as a hemorrhagic infarct in the other; both were found on autopsy to be fungal. Neurologic abnormalities were present in 1 patient with a lacunar infarction, the 2 patients with infectious complications, and in 1 patient with a subarachnoid hemorrhage secondary to a berry aneurysm. CONCLUSIONS. Central nervous system abnormalities are common in hyperimmunoglobulin E syndrome. Focal T2 hyperintensities, not appreciated previously, represent a prominent feature of this rare disease that may assist in diagnosis. The etiology and clinical implications of these abnormalities remain to be investigated.

Pneumocystis jiroveci Infection in Patients With Hyper–Immunoglobulin E Syndrome

The hyper–immunoglobulin E syndrome is a primary immunodeficiency characterized by recurrent pyogenic skin and lung abscesses, dermatitis, and elevated serum immunoglobulin E levels. Pneumocystis jiroveci (formerly Pneumocystis carinii) is not typically associated with hyper–immunoglobulin E syndrome. We identified 7 patients with hyper–immunoglobulin E syndrome with P jiroveci detected in respiratory or pulmonary pathology specimens. In 5 patients it was the sole pathogen, and in 2 other patients it contributed to a polymicrobial etiology. No consistent prophylaxis was given, and there have been no recurrences on long-term follow-up. Our experience suggests that P jiroveci can cause pneumonia in patients with hyper–immunoglobulin E syndrome both with and without chronic lung disease.

Sarcoidosis in Chronic Granulomatous Disease

In addition to increased susceptibility to infections in patients with chronic granulomatous disease (CGD), a higher incidence of sterile inflammatory disorders in these patients has been noted. However, sarcoidosis has not been reported previously in CGD. In this report, we describe two patients who have CGD and a disorder consistent with sarcoidosis on the basis of unequivocal clinical-radiographic presentations, their responses to treatment, and serum angiotensin-converting enzyme levels. Serum angiotensin-converting enzyme levels were measured in 26 other patients with CGD to establish an appropriate reference range. A possible relationship between CGD and sarcoidosis is discussed.

X-linked carriers of chronic granulomatous disease: Illness, lyonization, and stability

Background: Chronic granulomatous disease (CGD) is characterized by recurrent life‐threatening bacterial and fungal infections and aberrant inflammation. Mutations in CYBB cause X‐linked CGD and account for 65% to 70% of cases in Western countries. Objective: We sought to understand the clinical manifestations associated with the X‐linked CGD carrier state. Methods: We undertook a comprehensive retrospective study of 162 affected female subjects. We examined dihydrorhodamine 123 (DHR) oxidation data for percentage of X‐chromosome inactivation. We correlated lyonization (%DHR+) with clinical features. Where possible, we followed %DHR+ values over time. Results: Clinical data were available for 93 female subjects: %DHR+ values were 46% (mean) and 47% (median; SD, 24). Using the %DHR+ value as the criterion for X inactivation, 78% of patients had levels of inactivation of 20% to 80%, suggesting random inactivation that was independent of age. In contrast, carriers with CGD‐type infections had median %DHR+ values of 8% (n = 14; range, 0.06% to 48%), and those with only autoimmune or inflammatory manifestations had median %DHR+ values of 39% (n = 31; range, 7.4% to 74%). Those with both infections and autoimmunity had low %DHR+ values (n = 6; range, 3% to 14%). A %DHR+ value of less than 10% was strongly associated with infections (odds ratio, 99). Strong association persisted when %DHR+ values were less than 20% (odds ratio, 12). Autoimmunity was not associated with %DHR+ values. In 2 sets of identical twins, the %DHR+ populations tracked closely over time. Although the %DHR+ populations were very similar between sisters, those between mothers and daughters were unrelated. Conclusions: A low %DHR+ value strongly predicts infection risk in X‐linked CGD carriers, and the carrier state itself is associated with autoimmunity.

Progressive Multifocal Leukoencephalopathy in Primary Immune Deficiencies: Stat1 Gain of Function and Review of the Literature

BACKGROUND Progressive multifocal leukoencephalopathy (PML) is a rare, severe, otherwise fatal viral infection of the white matter of the brain caused by the polyomavirus JC virus, which typically occurs only in immunocompromised patients. One patient with dominant gain-of-function (GOF) mutation in signal transducer and activator of transcription 1 (STAT1) with chronic mucocutaneous candidiasis and PML was reported previously. We aim to identify the molecular defect in 3 patients with PML and to review the literature on PML in primary immune defects (PIDs). METHODS STAT1 was sequenced in 3 patients with PML. U3C cell lines were transfected with STAT1 and assays to search for STAT1 phosphorylation, transcriptional response, and target gene expression were performed. RESULTS We identified 3 new unrelated cases of PML in patients with GOF STAT1 mutations, including the novel STAT1 mutation, L400Q. These STAT1 mutations caused delayed STAT1 dephosphorylation and enhanced interferon-gamma-driven responses. In our review of the literature regarding PML in primary immune deficiencies we found 26 cases, only 54% of which were molecularly characterized, the remainder being syndromically diagnosed only. CONCLUSIONS The occurrence of PML in 4 cases of STAT1 GOF suggests that STAT1 plays a critical role in the control of JC virus in the central nervous system.

Familial immunodeficiency with cutaneous vasculitis, myoclonus, and cognitive impairment.

We report a family with five of six siblings (including identical male twins) with a novel constellation of immunologic and neurologic impairments. Affected subjects experienced severe dermatitis starting around 9 months of age, Stevens–Johnson syndrome in early childhood, and extreme elevations of IgE (9,400–43,000 IU/ml). The oldest sibling died at age 27 of respiratory failure following recurrent, severe pneumonias. All four surviving affected siblings have had chronic sinusitis or otitis, cutaneous vasculitis, and recurrent bacterial pneumonias leading to bronchiectasis. Neurologic features in all five siblings included oral motor deficits, dysarthria, low average IQ (70–80), and essential myoclonus. Four had documented ataxia and/or mild sensory loss with increased patellar but diminished ankle reflexes. The nonconsanguineous parents and one sibling had none of the above findings, consistent with autosomal recessive inheritance. This primary immunodeficiency with distinctive neurological impairments represents a new syndrome. Published 2003 Wiley‐Liss, Inc.