Galen O. Joe

High Prevalence of Osteonecrosis of the Femoral Head in HIV-Infected Adults

Context Osteonecrosis (avascular necrosis) of the hip is an uncommon but painful and disabling condition that sometimes requires total hip replacement. Contribution This large survey showed that an unusually high percentage of HIV-infected adults (4.4% [95% CI, 2.5% to 7.2%]) had osteonecrosis of the hip, as detected by magnetic resonance imaging. Implications Although screening asymptomatic HIV-infected patients is not warranted, osteonecrosis should be considered in HIV-infected patients with persistent groin or hip pain. The Editors The natural history of HIV infection has changed substantially with the wide use of highly active antiretroviral regimens that include potent protease inhibitors or non-nucleoside reverse transcriptase inhibitors (1). The incidence of HIV-related deaths and HIV-associated opportunistic infections has decreased dramatically. As survival and quality of life have improved, the focus of health care providers has shifted to management of the increasingly complex drug regimens and their associated drug interactions and toxicities. Previously unrecognized or underrecognized complications related to HIV infection or therapies for HIV infection, such as lactic acidosis, hyperlipidemia, and fat redistribution, are increasingly being recognized (2). Osteonecrosis of the hip (also known as avascular necrosis) is a disabling condition that frequently requires total hip replacement (3-5). Osteonecrosis in HIV-infected patients was first reported in 1990 (6). Subsequent anecdotal reports have suggested that osteonecrosis is being diagnosed with increasing frequency in the setting of HIV infection (7-31). Between May 1999 and November 2000, six HIV-infected patients followed at the Warren Grant Magnuson Clinical Center of the U.S. National Institutes of Health (NIH) presented with groin or hip pain and received a diagnosis of osteonecrosis. The first two of these patients received their diagnosis within a 4-day period and were the first HIV-infected patients ever to receive such a diagnosis at the NIH Clinical Center. We also learned that an increasing number of cases of osteonecrosis were being reported to the U.S. Food and Drug Administrations Adverse Event Reporting System. We were concerned that osteonecrosis might be becoming a major HIV-related complication. We hypothesized that, if this were true, additional patients may have developed clinically silent osteonecrosis. Because magnetic resonance imaging (MRI) has been used to study asymptomatic osteonecrosis of the hip in other high-risk populations (32-37), we undertook a prospective MRI-based study to determine the prevalence of and evaluate possible risk factors for asymptomatic osteonecrosis of the hip in a sample of HIV-infected patients. Methods Participant Recruitment and Questionnaire Between 1 June and 15 December 1999, adults who were enrolled in studies of the treatment or natural history of HIV infection at the NIH Clinical Center or who were receiving health care services at the National Naval Medical Center in Bethesda, Maryland, were invited to participate in an MRI-based screening study of osteonecrosis of the hip. All patients seen in the outpatient clinics of the National Institute of Allergy and Infectious DiseasesNIH Clinical Center HIV program during the study period were informed of the protocol and encouraged to participate. Because this study focused on asymptomatic patients, we excluded persons with current groin or hip pain. Because the incidence of osteonecrosis was unknown, we considered several possible sample sizes (100 to 300 patients) and estimations of the 95% CI for low prevalence rates of asymptomatic osteonecrosis (0.1% to 3.5%). We determined that a sample size of at least 300 HIV-infected participants would be reasonable and attainable. Before undergoing MRI, participants completed a standard questionnaire on joint symptoms; medical history; medication use; and personal habits, including ethanol use, cigarette smoking, and routine exercise regimens. Questions related to medication use made a clear distinction between corticosteroids and other types of steroids, such as androgenic and anabolic steroids. Patients were asked why corticosteroids were prescribed and the route, frequency, and duration of use. The Institutional Review Board of the National Institute of Allergy and Infectious Diseases approved the protocol. All participants gave written informed consent. Data Collection We retrieved laboratory and clinical data from patient databases. Laboratory values obtained within 4 months of the MRI date were used in the analyses; for certain variables, we also analyzed the highest or lowest values recorded in a laboratory database that contained data back to 1984. Physiatrist Evaluation After approximately 150 patients were scanned and asymptomatic osteonecrosis was detected in 4 patients, we prospectively determined whether subtle physical findings might identify patients with MRI evidence of osteonecrosis of the hip. Patients enrolled after 12 July 1999 were asked (but not required) to be examined by a physiatrist who was unaware of the MRI results. The examination included evaluation of range of motion in the hip, which involved testing in all planes to end range with and without resistance and joint-loading maneuvers; pain was assessed in each test (38). MRI Scanning HIV-Infected Participants Magnetic resonance imaging was performed by using an LX Horizon 1.5-T MRI system (General Electric Medical Systems, Milwaukee, Wisconsin). We modeled the protocol for screening MRI on a previously described method for bilateral screening of the hips for osteonecrosis (37). Coronal T1-weighted spin-echo sequences were done with a repetition time of 400 ms and an echo time of 8 ms (using a 256 192 matrix). These were followed by coronal fatsuppressed T2-weighted fast spin-echo inversion recovery sequences with a repetition time of 3266 ms, an echo time of 38 ms, and an inversion time of 150 ms (256 224 matrix). Other variables used for both screening sequences included three excitations, a 40.0 40.0cm field of view, and 5-mm contiguous sections. All MRI scans were initially interpreted by one of the investigators. Positive scans were later intermixed with 35 randomly selected negative scans of HIV-infected participants and were reviewed by a second radiologist, who was unaware of the previous interpretation. Patients with osteonecrosis on the screening MRI underwent dedicated high-resolution MRI of the affected hip or the more abnormal hip. HIV-Negative Participants We assumed that asymptomatic osteonecrosis of the hip detectable only by MRI must occur infrequently in healthy adult humans with no known risk factors. To document this, we recruited persons without hip or groin pain who had no known risk factors for osteonecrosis. Exclusion criteria for this comparison group were a history of alcohol abuse, hip or leg fracture, pancreatitis, diabetes mellitus, hypertriglyceridemia (requiring therapy), systemic lupus erythematosus, blood-clotting disorders, or systemic corticosteroid use during the previous year or for greater than 1 month ever (total lifetime use). We recruited these participants from an NIH healthy volunteer database and by posting flyers at the NIH Clinical Center. The participants in the comparison group were approximately matched for age and sex to participants in the screening study HIV-infected patients; the comparison group underwent the MRI screening and consented to participate using the same protocol and procedures that were used in the HIV group. Hematologic Evaluation Participants with MRI evidence of osteonecrosis were evaluated for a possible hypercoagulable state by using the following assays: two assays for the presence of a lupus anticoagulant (DRVVT, American Diagnostica, Inc., Greenwich, Connecticut, and Staclot, Diagnostica Stago, Asnieres-Sur-Seine, France); assays for immunoglobulin (Ig)G and IgM anticardiolipin antibodies (Quantilite, Innova, San Diego, California); functional assays for protein C, protein S, and antithrombin III levels (Diagnostica Stago; an assay for thrombinantithrombin complex levels [Dade Behring Marburg, Marburg, Germany]; an assay for functional plasma activator inhibitor-1 levels (Biopool, Umea, Sweden); and routine laboratory assays for serum homocysteine and serum lipoprotein(a) levels. These patients were also evaluated for genetic predisposition to hypercoagulability by using restriction enzyme-based genetic tests for factor V Leiden, a prothrombin gene abnormality (G20210A), and for the heat-labile folate reductase (5,10 methylene tetrahydrofolate reductase) gene abnormality, which may lead to hyperhomocystinemia (39-41). For a comparison group, we measured anticardiolipin antibodies, lupus anticoagulant, and protein S levels in a sample of 50 controls with HIV infection who had no evidence of osteonecrosis on MRI. These controls were randomly selected from patients who had been previously scanned as part of the study and who were seen in our clinics for routine visits over a 3-week period (19 November to 9 December 1999). Statistical Analysis We used the method of Clopper and Pearson (42) to calculate exact CIs for proportions. Associations of osteonecrosis with categorical variables were evaluated by using a two-sided Fisher exact test or, for variables with more than two categories, the FisherFreemanHalton test (43). Associations with continuous variables were evaluated by using a two-sided Wilcoxon rank-sum test with continuity correction. Confidence intervals for relative risks for osteonecrosis were estimated by using the likelihood score method (44). For CIs of odds ratios, we estimated variance according to the method of Robins and colleagues (45). For these calculations, we used the NCSS 2000 software package (Number Cruncher Statistical Systems, Kaysville, Utah) and the StatXact 4 software package (Cytel Software Corp., Cambridge, Mass

The Incidence and Natural History of Osteonecrosis in HIV-Infected Adults

BACKGROUND Osteonecrosis is increasingly recognized as a debilitating complication of human immunodeficiency virus (HIV) infection, but the natural history has not been well described. We previously documented a high prevalence (4.4%) of magnetic resonance imaging (MRI)-documented osteonecrosis of the hip in a cohort of 339 asymptomatic HIV-infected patients. The present study was designed to determine the incidence of newly diagnosed osteonecrosis in this cohort and to describe the natural history of osteonecrosis in HIV-infected patients. METHODS Asymptomatic HIV-infected patients with a previous hip MRI negative for osteonecrosis underwent follow-up MRI. Patients with asymptomatic or symptomatic osteonecrosis were enrolled in a natural history study, which included serial MRIs and a physiotherapy follow-up. RESULTS Two hundred thirty-nine patients underwent a second MRI a median of 23 months after the initial MRI. Osteonecrosis of the femoral head was diagnosed in 3 patients (incidence, 0.65 cases per 100 person-years). During the period of January 1999 through April 2006, symptomatic hip osteonecrosis developed in 13 clinic patients (incidence, 0.26 cases per 100 person-years). Among 22 patients enrolled with symptomatic hip osteonecrosis, 18 had bilateral involvement of the femoral heads, and 7 had osteonecrosis involving other bones. Two (11%) of 18 asymptomatic patients and 13 (59%) of 22 symptomatic patients underwent total hip replacement. The percentage of involvement of the weight-bearing surface of the femoral head and the rate of progression to total hip replacement was significantly greater (P<.001) in symptomatic patients than in asymptomatic patients. CONCLUSIONS HIV-infected patients are at approximately 100-fold greater risk of developing osteonecrosis than the general population. Disease progression is slower in asymptomatic patients than in symptomatic patients. Given the high frequency of total hip replacement in symptomatic patients, studies to assess preventive and treatment strategies are essential.

Intravenous immune globulin in hereditary inclusion body myopathy: a pilot study

BackgroundHereditary Inclusion Body Myopathy (HIBM) is an autosomal recessive, adult onset, non-inflammatory neuromuscular disorder with no effective treatment. The causative gene, GNE, codes for UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase, which catalyzes the first two reactions in the synthesis of sialic acid. Reduced sialylation of muscle glycoproteins, such as α-dystroglycan and neural cell adhesion molecule (NCAM), has been reported in HIBM.MethodsWe treated 4 HIBM patients with intravenous immune globulin (IVIG), in order to provide sialic acid, because IgG contains 8 μmol of sialic acid/g. IVIG was infused as a loading dose of 1 g/kg on two consecutive days followed by 3 doses of 400 mg/kg at weekly intervals.ResultsFor all four patients, mean quadriceps strength improved from 19.0 kg at baseline to 23.2 kg (+22%) directly after IVIG loading to 25.6 kg (+35%) at the end of the study. Mean shoulder strength improved from 4.1 kg at baseline to 5.9 kg (+44%) directly after IVIG loading to 6.0 kg (+46%) at the end of the study. The composite improvement for 8 other muscle groups was 5% after the initial loading and 19% by the end of the study. Esophageal motility and lingual strength improved in the patients with abnormal barium swallows. Objective measures of functional improvement gave variable results, but the patients experienced improvements in daily activities that they considered clinically significant. Immunohistochemical staining and immunoblotting of muscle biopsies for α-dystroglycan and NCAM did not provide consistent evidence for increased sialylation after IVIG treatment. Side effects were limited to transient headaches and vomiting.ConclusionThe mild benefits in muscle strength experienced by HIBM patients after IVIG treatment may be related to the provision of sialic acid supplied by IVIG. Other sources of sialic acid are being explored as treatment options for HIBM.

A randomized controlled trial of exercise in spinal and bulbar muscular atrophy

To determine the safety and efficacy of a home‐based functional exercise program in spinal and bulbar muscular atrophy (SBMA).

Assessing Function and Endurance in Adults with Spinal and Bulbar Muscular Atrophy: Validity of the Adult Myopathy Assessment Tool

Purpose. The adult myopathy assessment tool (AMAT) is a performance-based battery comprised of functional and endurance subscales that can be completed in approximately 30 minutes without the use of specialized equipment. The purpose of this study was to determine the construct validity and internal consistency of the AMAT with a sample of adults with spinal and bulbar muscular atrophy (SBMA). Methods. AMAT validity was assessed in 56-male participants with genetically confirmed SBMA (mean age, 53 ± 10 years). The participants completed the AMAT and assessments for disease status, strength, and functional status. Results. Lower AMAT scores were associated with longer disease duration (r = −0.29; P < 0.03) and lower serum androgen levels (r = 0.49–0.59; P < 0.001). The AMAT was significantly correlated with strength and functional status (r = 0.82–0.88; P < 0.001). The domains of the AMAT exhibited good internal consistency (Cronbachs α = 0.77–0.89; P < 0.001). Conclusions. The AMAT is a standardized, performance-based tool that may be used to assess functional limitations and muscle endurance. The AMAT has good internal consistency, and the construct validity of the AMAT is supported by its significant associations with hormonal, strength, and functional characteristics of adults with SBMA. This trial is registered with Clinicaltrials.gov identifier NCT00303446.

Malnutrition in patients with chronic GVHD.

Malnutrition is a known complication of chronic GVHD (cGVHD), but has not been well described in the context of organ-specific manifestations and the recent National Institutes of Health (NIH) criteria. Here, 210 cGVHD patients were analyzed, in a cross-sectional study design, for demographics, transplant-related history, clinical assessments, symptoms, function, quality-of-life, laboratory values and survival in order to determine their associations with nutritional status. Most patients had long-standing, moderate or severe cGVHD and had failed many lines of therapy. Twenty-nine percent (60/210) of subjects were malnourished, using the subjective Patient-Generated Subjective Global Assessment (PG-SGA) questionnaire and evaluation. No demographic or transplant characteristics were associated with malnutrition; cGVHD of the lungs, gastrointestinal (GI) tract and mouth, NIH global score, cGVHD symptoms, worse functioning, low albumin, poorer survival and low BMI were associated with malnutrition. A predictive model was developed from all variables of significance: cGVHD of the lungs, GI tract, mouth and BMI accurately predicted 84.2% of malnourished patients as well as 87.2% of well-nourished patients. The PG-SGA questionnaire may be a useful tool in diagnosing nutritional deficits in cGVHD patients undergoing one-time evaluations. Longitudinal prospective studies should assess the utility of nutritional support interventions in cGVHD.

NIH response criteria measures are associated with important parameters of disease severity in patients with chronic GVHD

Lack of standardized criteria measuring therapeutic response remains an obstacle to the development of better treatments for chronic GVHD (cGVHD). This cross-sectional prospective study examined the concurrent and predictive validity of 18 clinician-reported (‘Form A’) and 8 patient-reported (‘Form B’) response measures proposed by NIH criteria. Concurrent parameters of interest were NIH global score, cGVHD activity, Lee symptom score and SF36 PCS. Patient cohort included 193 adults with moderate-to-severe cGVHD. Measures associated with the highest number of outcomes were lung function score (LFS), 2-min walk, grip strength, 4-point health-care provider (HCP) and patient global scores, 11-point clinician- and patient-reported global symptom severity scores, and Karnofsky performance score (KPS). Measures associated with survival in univariate analyses led to a Cox model containing skin erythema, LFS, KPS, eosinophil count and interval from cGVHD diagnosis to enrollment as jointly associated with survival. In conclusion, 4-point HCP and patient global scores and 11-point clinician- and patient-reported global symptom severity scores are associated with the majority of concurrent outcomes. Skin erythema is a potentially reversible sign of cGVHD that is associated with survival. These results define a subset of measures that should be prioritized for evaluation in future studies.

Acquired haemophilia A after stem cell transplant for sickle cell disease: treatment with recombinant porcine factor VIII (OBI‐1) and tolerance induction with rituximab/prednisone

J. N. LOZIER,* K. NGHIEM,* M. LEE,† B. HODSDON,‡ G. JOE,‡ R. P. WEITZEL,§ J . F. TISDALE§ and M. HSIEH§ *Department of Laboratory Medicine, National Institutes of Health Clinical Center, Bethesda, MD; †UCLA School of Public Health, Los Angeles, CA; ‡Rehabilitation Medicine Department, National Institutes of Health Clinical Center; and §Molecular and Clinical Hematology Branch, NHLBI, NIH, Bethesda, MD, USA

Are Repeated Single-Limb Heel Raises and Manual Muscle Testing Associated With Peak Plantar-Flexor Force in People With Inclusion Body Myositis?

Background Repeated heel raises have been proposed as a method of ankle plantar-flexor strength testing that circumvents the limitations of manual muscle testing (MMT). Objective The study objective was to examine the relationships among ankle plantar-flexion isometric maximum voluntary contraction (MVC), repeated single-limb heel raises (SLHRs), and MMT in people with myositis. Design This was a cross-sectional study with a between-group design. The ability to complete 1 SLHR determined group assignment (SLHR group, n=24; no-SLHR group, n=19). Methods Forty-three participants with myositis (13 women; median age=64.9 years) participated. Outcome measures included MVC, predicted MVC, Kendall MMT, and Daniels-Worthingham MMT. Results The Kendall MMT was unable to detect significant ankle plantar-flexor weakness established by quantitative methods and was unable to discriminate between participants who could and those who could not perform the SLHR task. Ankle plantar-flexion MVC was not associated with the number of heel-raise repetitions in the SLHR group (pseudo R2=.13). No significant relationship was observed between MVC values and MMT grades in the SLHR and no-SLHR groups. However, a moderate relationship between MVC values and MMT grades was evident in a combined-group analysis (ρ=.50–.67). Limitations The lower half of both MMT grading scales was not represented in the study despite the profound weakness of the participants. Conclusions Both Kendall MMT and Daniels-Worthingham MMT had limited utility in the assessment of ankle plantar-flexor strength. Repeated SLHRs should not be used as a proxy measure of ankle plantar-flexion MVC in people with myositis.

Diagnosis of avascular necrosis of the hip in asymptomatic HIV-infected patients: Clinical correlation of physical examination with magnetic resonance imaging

OBJECTIVE To determine if physical examination can identify avascular necrosis of the hip (AVN) in asymptomatic HIV-infected patients. DESIGN Prospective, blinded population studyResults: Ten of the 176 patients were positive for AVN by MRI. Four subjects had unilateral disease and six had bilateral disease. Five hips (1.4%) in four patients were indeterminate. We evaluated physical examination maneuvers both singly and in combination. Tests done singly generally provided a higher degree of specificity (67-92%) but sensitivities were lower (0-50%) with all p-values ≥0.08. Positive predictive values based on physical exam, were <17% and negative predictive values were >90% for any single test. Combining all tests gave a high sensitivity (88%) and negative predictive value (98%), but low specificity (34%) and positive predictive value (6%) with p = 0.10. Only two of 16 hips with positive MRI findings showed no abnormalities when all tests were combinedConclusions: This study establishes the limited usefulness of a detailed physical examination of the hip early in the course of AVN. Patients who test negative on physical exam are unlikely to have AVN positive by MRI. Positive findings on physical examination of the hip may help identify patients who need further evaluation by MRI based on overall clinical suspicion.