Benjamin J. Luft

Toxoplasmic Encephalitis in Patients with the Acquired Immunodeficiency Syndrome

BACKGROUND In patients with the acquired immunodeficiency syndrome (AIDS), toxoplasmic encephalitis is usually a presumptive diagnosis based on the clinical manifestations, a positive antitoxoplasma-antibody titer, and characteristic neuroradiologic abnormalities. A response to specific therapy helps to confirm the diagnosis, but it is unclear how rapid the response should be. We studied the course of patients treated for acute toxoplasmic encephalitis and evaluated objective clinical criteria for this empirical diagnosis. METHODS A quantifiable neurologic assessment was used prospectively to evaluate the clinical outcome of patients with AIDS and toxoplasmic encephalitis who were treated with oral clindamycin (600 mg four times a day) and pyrimethamine (75 mg every day) for six weeks. RESULTS Thirty-five of 49 patients (71 percent) responded to therapy, and 30 of these (86 percent) had improvement by day 7. Thirty-two of those with a response (91 percent) improved with respect to at least half of their base-line abnormalities by day 14. Improvement in neurologic abnormalities within 7 to 14 days after the start of therapy was strongly associated with the neurologic response at 6 weeks. The four patients in whom treatment failed and the two patients with lymphoma had progressing neurologic abnormalities or new abnormalities during the first 12 days of therapy. Nonlocalizing abnormalities (headache and seizure) improved regardless of the clinical outcome. CONCLUSIONS Oral clindamycin and pyrimethamine are an effective treatment for toxoplasmic encephalitis. Patients who have early neurologic deterioration despite treatment or who do not improve neurologically after 10 to 14 days of appropriate antitoxoplasma therapy should be considered candidates for brain biopsy.

Seronegative Lyme disease. Dissociation of specific T- and B-lymphocyte responses to Borrelia burgdorferi.

The diagnosis of Lyme disease often depends on the measurement of serum antibodies to Borrelia burgdorferi, the spirochete that causes this disorder. Although prompt treatment with antibiotics may abrogate the antibody response to the infection, symptoms persist in some patients. We studied 17 patients who had presented with acute Lyme disease and received prompt treatment with oral antibiotics, but in whom chronic Lyme disease subsequently developed. Although these patients had clinically active disease, none had diagnostic levels of antibodies to B. burgdorferi on either a standard enzyme-linked immunosorbent assay or immunofluorescence assay. On Western blot analysis, the level of immunoglobulin reactivity against B. burgdorferi in serum from these patients was no greater than that in serum from normal controls. The patients had a vigorous T-cell proliferative response to whole B. burgdorferi, with a mean ( +/- SEM) stimulation index of 17.8 +/- 3.3, similar to that (15.8 +/- 3.2) in 18 patients with chronic Lyme disease who had detectable antibodies. The T-cell response of both groups was greater than that of a control group of healthy subjects (3.1 +/- 0.5; P less than 0.001). We conclude that the presence of chronic Lyme disease cannot be excluded by the absence of antibodies against B. burgdorferi and that a specific T-cell blastogenic response to B. burgdorferi is evidence of infection in seronegative patients with clinical indications of chronic Lyme disease.

Treatment of Toxoplasmic Encephalitis in Patients with AIDS: A Randomized Trial Comparing Pyrimethamine plus Clindamycin to Pyrimethamine plus Sulfadiazine

OBJECTIVE To compare pyrimethamine plus clindamycin (PC) to pyrimethamine plus sulfadiazine (PS) as a treatment for toxoplasmic encephalitis (TE) in patients with the acquired immunodeficiency syndrome (AIDS). DESIGN Randomized, unblinded phase II, multicenter trial with provision for crossover for failure or intolerance of the assigned regimen. SETTING University hospitals. PATIENTS Eighty-four patients with presumptive TE were entered. Thirteen were excluded when they were found to have another diagnosis, and 12 were excluded because they did not meet entry criteria. The baseline characteristics in the remaining 26 patients randomized to PC and 33 randomized to PS were comparable. INTERVENTIONS Patients were treated for 6 weeks with pyrimethamine and folinic acid plus either sulfadiazine or clindamycin. Clindamycin was given intravenously during the first 3 weeks. MEASUREMENTS AND MAIN RESULTS There was a trend toward greater survival in patients randomized to PS (hazard ratio, 3.25; 95% CI, 0.63 to 16.8; P = 0.13), but most study deaths were not directly related to TE. In contrast, patients randomized to PC appeared more likely to achieve complete clinical (odds ratio, 0.67; CI, 0.2 to 1.97; P greater than 0.2) and radiologic responses (odds ratio, 0.28; CI, 0.08 to 0.96; P = 0.02). Multivariate analysis revealed drug effects to be largely independent of other variables. Similar efficacy of the treatments was also suggested by a hazard analysis of resolution of abnormal mental status, fever, and headache. Skin rash was the most common adverse event in both treatment arms. Because of toxicity, six patients randomized to PC and 11 patients randomized to PS had to switch to the alternate treatment, but only three were unable to complete therapy after crossover. CONCLUSIONS The results of several end points of efficacy, taken together, suggest that the relative efficacy of PC approximately equals that of PS. PC appears to be an acceptable alternative in patients unable to tolerate PS.

The World Trade Center Disaster and the Health of Workers: Five-Year Assessment of a Unique Medical Screening Program

Background Approximately 40,000 rescue and recovery workers were exposed to caustic dust and toxic pollutants following the 11 September 2001 attacks on the World Trade Center (WTC). These workers included traditional first responders, such as firefighters and police, and a diverse population of construction, utility, and public sector workers. Methods To characterize WTC-related health effects, the WTC Worker and Volunteer Medical Screening Program was established. This multicenter clinical program provides free standardized examinations to responders. Examinations include medical, mental health, and exposure assessment questionnaires; physical examinations; spirometry; and chest X rays. Results Of 9,442 responders examined between July 2002 and April 2004, 69% reported new or worsened respiratory symptoms while performing WTC work. Symptoms persisted to the time of examination in 59% of these workers. Among those who had been asymptomatic before September 11, 61% developed respiratory symptoms while performing WTC work. Twenty-eight percent had abnormal spirometry; forced vital capacity (FVC) was low in 21%; and obstruction was present in 5%. Among nonsmokers, 27% had abnormal spirometry compared with 13% in the general U.S. population. Prevalence of low FVC among nonsmokers was 5-fold greater than in the U.S. population (20% vs. 4%). Respiratory symptoms and spirometry abnormalities were significantly associated with early arrival at the site. Conclusion WTC responders had exposure-related increases in respiratory symptoms and pulmonary function test abnormalities that persisted up to 2.5 years after the attacks. Long-term medical monitoring is required to track persistence of these abnormalities and identify late effects, including possible malignancies. Lessons learned should guide future responses to civil disasters.

Azithromycin compared with amoxicillin in the treatment of erythema migrans : A double-blind, randomized, controlled trial

Lyme borreliosis is the most common vectorborne disease in the United States and Europe [1]. Infection begins as a local process after Borrelia burgdorferi is inoculated into the skin by a feeding tick. In most persons, the initial sign of infection is the development of erythema migrans, which is characterized by an annular erythematous skin lesion. Amoxicillin and doxycycline have been advocated as the treatments of choice, primarily on the basis of small, often unblinded, randomized trials and retrospective analyses [2-4]. Azithromycin, an azalide (a new subclass of macrolide antibiotics), has been shown to have excellent in vitro and in vivo activity against B. burgdorferi in the laboratory [5, 6]. In a small, randomized, open study on the treatment of erythema migrans, a 5-day course of azithromycin was reported to be as effective as a 10-to 20-day course of doxycycline or amoxicillin with probenecid [7]. To more thoroughly assess the efficacy of azithromycin and further define the treatment of erythema migrans, we conducted this large, multicenter, double-blind, randomized trial. Amoxicillin rather than doxycycline was chosen as the comparative agent to circumvent the problems associated with sun-related hypersensitivity reactions. During the study, we clarified important clinical questions about the natural history of this disease, its manifestations, and the usefulness of enzyme-linked immunosorbent assay (ELISA) for serologic testing. Methods Patients Adult patients who had had erythema migrans diagnosed by a physician were recruited between June 1990 and October 1991 from 12 centers in eight states: New York (83 patients), Connecticut (85 patients), Missouri (35 patients), Wisconsin (23 patients), New Jersey (10 patients), Minnesota (6 patients), California (2 patients), and Rhode Island (2 patients). To be eligible for the study, patients had to be at least 12 years of age and had to weigh at least 45 kg. Erythema migrans lesions at least 5 cm in diameter were photographed for documentation. Pregnant or nursing women were not enrolled. Exclusion criteria included frank arthritis or objective evidence of central nervous system or cardiac (second- or third-degree block) involvement at time of presentation; evidence of meningismus or Bell palsy with pleocytosis [more than 7 cells/mm3]; and history of 1) nervous system, cardiac, rheumatic, or collagen vascular disease, 2) an immediate hypersensitivity reaction to -lactam antibiotics or macrolides, 3) any antibiotic therapy within 72 hours before enrollment or use of any antibiotic during the study other than those supplied, or 4) antibiotic treatment for Lyme disease during the preceding 12 months. The study protocol was approved by the Institutional Review Board of each study center, and all participants gave written informed consent. Clinical Diagnostic Evaluations Patients were evaluated by a physician at baseline and 8, 20, 30, 90, and 180 days after initiation of therapy. Subjective symptom scores for 11 key symptoms (fatigue, joint pain, headache, muscle pain, anorexia, stiff neck, fevers, paresthesias, dizziness, cough, and nausea and vomiting) were recorded on a visual analog scale at each evaluation. Blood samples were obtained for B. burgdorferi serologic testing (IgG and IgM), hepatitis B serologic tests, and liver function tests. Electrocardiography was done. All tests except for the hepatitis B serologic test were repeated on days 8, 20, and 30. In addition, blood samples for B. burgdorferi serologic testing and electrocardiograms were obtained at the 90- and 180-day evaluations. All ELISAs for Lyme disease were done at the University of Minnesota as previously described [8]. Patients were seen at unscheduled visits if indicated by their clinical condition. Treatment and Study Design Patients were stratified by the presence of flu-like constitutional symptoms (such as fever, chills, headache, malaise, fatigue, arthralgias, and myalgias) and then randomly assigned to one of the two treatment arms. Each center was given a randomization schedule for two types of presenting symptoms: erythema migrans alone and erythema migrans with flu-like symptoms. These randomization schedules consisted of sequential numbers to which the following study drug regimens were allocated: 500 mg of azithromycin once daily and placebo doses twice daily (to match the three-times-daily dosing regimen of amoxicillin); or amoxicillin, 500 mg three times daily. The drugs were provided by Pfizer Central Research in a double-matching (dummy) form so that all pills for both groups of patients were identical. All patients received the oral (active or placebo) medication for 20 days, but those in the azithromycin group received active drug for only 7 days. Both the clinical investigator and the patient were blinded to treatment assignments. Efficacy was evaluated in the patients who returned for an examination on day 20 and had taken at least one half of their medication. Patients who withdrew from the study because of adverse events and who took less than one half of their medication were considered nonevaluable for efficacy analysis. Response was assessed by clearance or persistence of erythema migrans and presenting objective signs and by relief of symptoms (assessed using the visual analog scale), and was then graded according to the following criteria. 1. Complete response: complete clearance of erythema migrans and all objective signs and greater than 75% relief of presenting symptoms. 2. Partial response: 1) complete clearance of erythema migrans with persistent signs and 50% to 75% relief of symptoms or 2) persistent erythema migrans with complete clearance of signs and greater than 75% relief of symptoms. 3. Treatment failure: 1) persistent erythema migrans, persistent signs, and less than 50% relief of symptoms or 2) development of new signs and symptoms of disease before the examination on day 20. Symptom relief was calculated as a percent reduction from baseline in the sum of the symptom scores on the visual analog scale. On subsequent examinations up to 180 days, patients were evaluated for relapse, which was defined as any objective evidence of arthritis, evanescent skin lesions, facial palsies, atrioventricular heart block, or peripheral or central nervous system disease, including meningitis. Toleration of treatment was determined from treatment-related adverse events and laboratory abnormalities. Statistical Analysis To compare responses to therapy, we used chisquare analysis or the Fisher exact test (two-tailed) for ordinal data and the t-test (two-tailed) for interval data. Confidence intervals on percentages were calculated using a normal approximation with are sine transformation. Results Study Population The baseline demographic and clinical characteristics of the patients are shown in Table 1. The mean diameter of the largest erythema migrans lesion, the distribution of single and multiple erythema migrans lesions, the presence of concomitant flu-like illness, and the seropositivity rate did not differ significantly between the treatment groups. The baseline characteristics were similar, except that the azithromycin group had more patients with multiple erythema migrans lesions. Table 1. Baseline Demographic and Clinical Characteristics of Evaluable Patients On physical examination at study entry, the most common signs of disease included lymphadenopathy (18%; lymphadenopathy was regional in 40 patients and generalized in 3), pain on neck flexion (13%), muscle tenderness (12%), and joint tenderness (11%) (Table 2). Of the 11 self-reported symptoms, the most frequent were fatigue (52%), joint pain (34%), headache (29%), muscle pain (26%), anorexia (24%), fever (22%), and stiff neck (21%) (Table 2). Electrocardiographic abnormalities (first-degree block) attributed to Lyme disease were present in four patients (2%); none had cardiac abnormalities by day 20. Although one patient, who had first-degree heart block, had a relapse (joint pain) at 180 days, his electrocardiogram continued to be normal. Mild liver function abnormalities were noted in more than 20% of patients; increases in aminotransferase levels occurred most frequently. Table 2. Clinical Manifestations of Erythema Migrans in Evaluable Patients Of the 246 patients enrolled, 217 (88%) were evaluable for efficacy at day 20. Seven patients (2 receiving azithromycin and 5 receiving amoxicillin) were excluded because they had received less than 50% of their study medication as a result of adverse events; 17 patients (8 receiving azithromycin and 9 receiving amoxicillin) did not return for the follow-up examination at day 20; 2 patients (both receiving amoxicillin) were noncompliant; and 3 patients (all receiving azithromycin) did not meet entry criteria. The baseline signs of disease in the nonevaluable patients were regional lymphadenopathy (9 patients [31%]), muscle tenderness (1 patient [3%]), neck pain (2 patients [7%]), pharyngitis (4 patients [14%]), evanescent erythema migrans (3 patients [10%]), right upper quadrant tenderness (1 patients [3%]), and first-degree atrioventricular block (1 patient [3%]). The baseline symptoms of these patients were fatigue (13 patients [45%]), joint pain (8 patients [28%]), headache (7 patients [24%]), muscle pain (7 patients [24%]), anorexia (5 patients [17%]), stiff neck (11 patients [38%]), fever (4 patients [14%]), paresthesia (4 patients [14%]), dizziness (3 patients [10%]), and cough (2 patients [7%]). Response to Therapy Twenty days after the initiation of therapy, 93 of 106 patients treated with amoxicillin (88% [95% CI, 80% to 93%]) had had a complete response to therapy compared with 84 of 111 patients treated with azithromycin (76% [CI, 67% to 83%]) (P = 0.024) (Table 3). Furthermore, 3 patients treated with azithromycin had not responded or had worsened within the first 20 days (for example, they had persistent erythema migrans, joint tenderness,

CEFTRIAXONE COMPARED WITH DOXYCYCLINE FOR THE TREATMENT OF ACUTE DISSEMINATED LYME DISEASE

BACKGROUND Localized Lyme disease, manifested by erythema migrans, is usually treated with oral doxycycline or amoxicillin. Whether acute disseminated Borrelia burgdorferi infection should be treated differently from localized infection is unknown. METHODS We conducted a prospective, open-label, randomized, multicenter study comparing parenteral ceftriaxone (2 g once daily for 14 days) with oral doxycycline (100 mg twice daily for 21 days) in patients with acute disseminated B. burgdorferi infection but without meningitis. The erythema migrans skin lesion was required for study entry, and disseminated disease had to be indicated by either multiple erythema migrans lesions or objective evidence of organ involvement. RESULTS Of 140 patients enrolled, 133 had multiple erythema migrans lesions. Both treatments were highly effective. Rates of clinical cure at the last evaluation were similar among the patients treated with ceftriaxone (85 percent) and those treated with doxycycline (88 percent); treatment was considered to have failed in only one patient in each group. Among patients whose infections were cured, 18 of 67 patients in the ceftriaxone group (27 percent) reported one or more residual symptoms at the last follow-up visit, as did 10 of 71 patients in the doxycycline group (14 percent, P > or = 0.05). Mild arthralgia was the most common persistent symptom. Both regimens were well tolerated; only four patients (6 percent) in each group withdrew because of adverse events. CONCLUSIONS In patients with acute disseminated Lyme disease but without meningitis, oral doxycycline and parenterally administered ceftriaxone were equally effective in preventing the late manifestations of disease.

Enduring Mental Health Morbidity and Social Function Impairment in World Trade Center Rescue, Recovery, and Cleanup Workers: The Psychological Dimension of an Environmental Health Disaster

Background The World Trade Center (WTC) attacks exposed thousands of workers to hazardous environmental conditions and psychological trauma. In 2002, to assess the health of these workers, Congress directed the National Institute for Occupational Safety and Health to establish the WTC Medical Monitoring and Treatment Program. This program has established a large cohort of WTC rescue, recovery, and cleanup workers. We previously documented extensive pulmonary dysfunction in this cohort related to toxic environmental exposures. Objectives Our objective in this study was to describe mental health outcomes, social function impairment, and psychiatric comorbidity in the WTC worker cohort, as well as perceived symptomatology in workers’ children. Methods Ten to 61 months after the WTC attack, 10,132 WTC workers completed a self-administered mental health questionnaire. Results Of the workers who completd the questionnaire, 11.1% met criteria for probable post-traumatic stress disorder (PTSD), 8.8% met criteria for probable depression, 5.0% met criteria for probable panic disorder, and 62% met criteria for substantial stress reaction. PTSD prevalence was comparable to that seen in returning Afghanistan war veterans and was much higher than in the U.S. general population. Point prevalence declined from 13.5% to 9.7% over the 5 years of observation. Comorbidity was extensive and included extremely high risks for impairment of social function. PTSD was significantly associated with loss of family members and friends, disruption of family, work, and social life, and higher rates of behavioral symptoms in children of workers. Conclusions Working in 9/11 recovery operations is associated with chronic impairment of mental health and social functioning. Psychological distress and psychopathology in WTC workers greatly exceed population norms. Surveillance and treatment programs continue to be needed.

Primary and Reactivated Toxoplasma Infection in Patients with Cardiac Transplants: Clinical Spectrum and Problems in Diagnosis in a Defined Population

We have attempted to define the serologic criteria for diagnosis of toxoplasmosis in heart transplant recipients. Of 31 patients who were seronegative before transplantation, 4 received a heart from a seropositive donor, and 3 of these 4 had seroconversion and developed life-threatening toxoplasmosis; the remaining 27 did not have seroconversion or develop clinical toxoplasmosis. Of 19 patients who had antibodies to Toxoplasma before transplantation, 10 developed significant increases in test titers of the dye test or double-sandwich IgM enzyme-linked immunosorbent assay but did not develop a clinical illness that could be attributed to toxoplasma infection. Significant serologic changes occurred more often in patients who received azathioprine, corticosteroids, and antithymocyte globulin than in those who received cyclosporine, corticosteroids, and antithymocyte globulin (p less than 0.05). These data show the wide clinical spectrum and differences in kinetics of antibody response of patients who develop toxoplasma infection after transplantation, and suggest that clinical disease occurs in those who have seroconversion but is rare in patients with preexisting antibody who have serologic evidence of recrudescence.

Inhibition of cytoplasmic and organellar protein synthesis in Toxoplasma gondii: Implications for the target of macrolide antibiotics

We investigated potential targets for the activity of protein synthesis inhibitors against the protozoan parasite Toxoplasma gondii. Although nanomolar concentrations of azithromycin and clindamycin prevent replication of T. gondii in both cell culture and in vivo assays, no inhibition of protein labeling was observed in either extracellular or intracellular parasites treated with up to 100 microM drug for up to 24 h. Quantitative analysis of > 300 individual spots on two-dimensional gels revealed no proteins selectively depleted by 100 microM azithromycin. In contrast, cycloheximide inhibited protein synthesis in a dose-dependent manner. Nucleotide sequence analysis of the peptidyl transferase region from genes encoding the large subunit of the parasites ribosomal RNA predict that the cytoplasmic ribosomes of T. gondii, like other eukaryotic ribosomes, should be resistant to macrolide antibiotics. Combining cycloheximide treatment with two-dimensional gel analysis revealed a small subset of parasite proteins likely to be synthesized on mitochondrial ribosomes. Synthesis of these proteins was inhibited by 100 microM tetracycline, but not by 100 microM azithromycin or clindamycin. Ribosomal DNA sequences believed to be derived from the T. gondii mitochondrial genome predict macrolide/lincosamide resistance. PCR amplification of total T. gondii DNA identified an additional class of prokaryotic-type ribosomal genes, similar to the plastid-like ribosomal genes of the Plasmodium falciparum. Ribosomes encoded by these genes are predicted to be sensitive to the lincosamide/macrolide class of antibiotics, and may serve as the functional target for azithromycin, clindamycin, and other protein synthesis inhibitors in Toxoplasma and related parasites.

Crystal structure of outer surface protein C (OspC) from the Lyme disease spirochete, Borrelia burgdorferi

Outer surface protein C (OspC) is a major antigen on the surface of the Lyme disease spirochete, Borrelia burgdorferi, when it is being transmitted to humans. Crystal structures of OspC have been determined for strains HB19 and B31 to 1.8 and 2.5 Å resolution, respectively. The three‐dimensional structure is predominantly helical. This is in contrast to the structure of OspA, a major surface protein mainly present when spirochetes are residing in the midgut of unfed ticks, which is mostly β‐sheet. The surface of OspC that would project away from the spirochetes membrane has a region of strong negative electrostatic potential which may be involved in binding to positively charged host ligands. This feature is present only on OspCs from strains known to cause invasive human disease.