Pulmonary nontuberculous mycobacterial disease: prospective study of a distinct preexisting syndrome

Richard D Kim, David E Greenberg, Mary E Ehrmantraut, Shireen V Guide, Li Ding, Yvonne Shea, Margaret R Brown, Milica Chernick, Wendy K Steagall, Connie G Glasgow, JingPing Lin, Clara Jolley, Lynn Sorbara, Mark Raffeld, Suvimol Hill, Nilo Avila, Vandana Sachdev, Lisa A Barnhart, Victoria L Anderson, Reginald Claypool, Dianne M Hilligoss, Mary Garofalo, Alan Fitzgerald, Sandra Anaya-O'Brien, Dirk Darnell, Rosamma DeCastro, Heather M Menning, Stacy M Ricklefs, Stephen F Porcella, Kenneth N Olivier, Joel Moss, Steven M Holland, Richard D Kim, David E Greenberg, Mary E Ehrmantraut, Shireen V Guide, Li Ding, Yvonne Shea, Margaret R Brown, Milica Chernick, Wendy K Steagall, Connie G Glasgow, JingPing Lin, Clara Jolley, Lynn Sorbara, Mark Raffeld, Suvimol Hill, Nilo Avila, Vandana Sachdev, Lisa A Barnhart, Victoria L Anderson, Reginald Claypool, Dianne M Hilligoss, Mary Garofalo, Alan Fitzgerald, Sandra Anaya-O'Brien, Dirk Darnell, Rosamma DeCastro, Heather M Menning, Stacy M Ricklefs, Stephen F Porcella, Kenneth N Olivier, Joel Moss, Steven M Holland

Abstract

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.

Figures

Figure 1.
Figure 1.
(Left panel) Schematic depiction of the anthropometrics of the women with pulmonary nontuberculous mycobacterial (PNTM) (n = 60) compared with (right panel) National Health and Nutrition Examination Survey age-, sex-, and race-matched control subjects. *P < 0.001.
Figure 2.
Figure 2.
Pulmonary function tests are shown for patients with PNTM infection. Data are given as percent predicted values. FEF25–75 = forced expiratory flow between 25 and 75% of FVC; DlCO = diffusing capacity for carbon monoxide.
Figure 3.
Figure 3.
(A–F) Cytokine stimulation and response for peripheral blood mononuclear cells in 55 patients. Dark boxes, patients; open boxes, controls. In each box plot, the median value is indicated by the thick horizontal line, and the 25th and 75th percentiles are indicated by the upper and lower margins of the box, respectively. The whiskers denote the last value that is inside 1.5 times the interquartile range. Extreme values, if any, have been hidden to preserve the scale of each chart. Only P values that are below 0.05 are shown. Stimulation of (A) IFN-γ, (B) IL-12; (C) TNF-α, (D) IL-1b, (E) IL-10, and (F) IL-6.
Figure 3.
Figure 3.
(A–F) Cytokine stimulation and response for peripheral blood mononuclear cells in 55 patients. Dark boxes, patients; open boxes, controls. In each box plot, the median value is indicated by the thick horizontal line, and the 25th and 75th percentiles are indicated by the upper and lower margins of the box, respectively. The whiskers denote the last value that is inside 1.5 times the interquartile range. Extreme values, if any, have been hidden to preserve the scale of each chart. Only P values that are below 0.05 are shown. Stimulation of (A) IFN-γ, (B) IL-12; (C) TNF-α, (D) IL-1b, (E) IL-10, and (F) IL-6.
Figure 3.
Figure 3.
(A–F) Cytokine stimulation and response for peripheral blood mononuclear cells in 55 patients. Dark boxes, patients; open boxes, controls. In each box plot, the median value is indicated by the thick horizontal line, and the 25th and 75th percentiles are indicated by the upper and lower margins of the box, respectively. The whiskers denote the last value that is inside 1.5 times the interquartile range. Extreme values, if any, have been hidden to preserve the scale of each chart. Only P values that are below 0.05 are shown. Stimulation of (A) IFN-γ, (B) IL-12; (C) TNF-α, (D) IL-1b, (E) IL-10, and (F) IL-6.
Figure 3.
Figure 3.
(A–F) Cytokine stimulation and response for peripheral blood mononuclear cells in 55 patients. Dark boxes, patients; open boxes, controls. In each box plot, the median value is indicated by the thick horizontal line, and the 25th and 75th percentiles are indicated by the upper and lower margins of the box, respectively. The whiskers denote the last value that is inside 1.5 times the interquartile range. Extreme values, if any, have been hidden to preserve the scale of each chart. Only P values that are below 0.05 are shown. Stimulation of (A) IFN-γ, (B) IL-12; (C) TNF-α, (D) IL-1b, (E) IL-10, and (F) IL-6.
Figure 3.
Figure 3.
(A–F) Cytokine stimulation and response for peripheral blood mononuclear cells in 55 patients. Dark boxes, patients; open boxes, controls. In each box plot, the median value is indicated by the thick horizontal line, and the 25th and 75th percentiles are indicated by the upper and lower margins of the box, respectively. The whiskers denote the last value that is inside 1.5 times the interquartile range. Extreme values, if any, have been hidden to preserve the scale of each chart. Only P values that are below 0.05 are shown. Stimulation of (A) IFN-γ, (B) IL-12; (C) TNF-α, (D) IL-1b, (E) IL-10, and (F) IL-6.
Figure 3.
Figure 3.
(A–F) Cytokine stimulation and response for peripheral blood mononuclear cells in 55 patients. Dark boxes, patients; open boxes, controls. In each box plot, the median value is indicated by the thick horizontal line, and the 25th and 75th percentiles are indicated by the upper and lower margins of the box, respectively. The whiskers denote the last value that is inside 1.5 times the interquartile range. Extreme values, if any, have been hidden to preserve the scale of each chart. Only P values that are below 0.05 are shown. Stimulation of (A) IFN-γ, (B) IL-12; (C) TNF-α, (D) IL-1b, (E) IL-10, and (F) IL-6.

Source: PubMed

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