Robert E. Baughn

Effect of Human Immunodeficiency Virus (HIV) Infection on the Course of Syphilis and on the Response to Treatment

PURPOSE To evaluate evidence that concurrent infection with human immunodeficiency virus (HIV) alters both the natural history of syphilis (by increasing the frequency of early neurosyphilis) and the response to penicillin. DATA IDENTIFICATION Review of major works on syphilis in the English language and files maintained since 1971, supplemented by a systematic search using Index Medicus and MEDLARS. DATA EXTRACTION The works mentioned above were critically reviewed for information on early neurosyphilis and, where relevant, HIV infection. RESULTS OF DATA ANALYSIS The central nervous system is regularly involved in early syphilis. Standard recommended doses of benzathine penicillin provide cerebrospinal fluid levels that are probably at the borderline of efficacy, and cure relies on treatment and an adequate host immune response. Early neurosyphilis, appearing within 2 years of onset of infection with Treponema pallidum, was uncommon in the prepenicillin era and usually occurred after inadequate therapy. This complication was exceedingly rare in the first three decades of penicillin use. In contrast, in the past decade, 40 patients with HIV infection have been reported to have asymptomatic neurosyphilis, or syphilitic meningitis, cranial nerve abnormalities (predominantly in cranial nerves II and VIII), or cerebrovascular accidents, singly or together. In 40% of cases, HIV infection was first diagnosed when neurologic symptoms appeared. Of the 38 patients for whom information was available, 18 had the acquired immunodeficiency syndrome (AIDS), 7 had AIDS-related complex, and 13 had antibody to HIV. Sixteen had previously been treated for syphilis, of whom 5 (31%) had received benzathine penicillin within the previous 6 months. Preliminary data also suggest that skin lesions and VDRL (Venereal Disease Research Laboratory) antibody in HIV-infected patients with secondary syphilis respond more slowly to conventional penicillin therapy. CONCLUSION Intensive therapy and follow-up observation is indicated for early syphilis in HIV-infected subjects. Novel approaches to treatment deserve systematic evaluation.

Pneumonia and Acute Febrile Tracheobronchitis Due to Haemophilus influenzae

Of 30 patients with pneumonia due to Haemophilus influenzae, 26 had infection due to nontypable and 4 due to typable organisms. Biotype I isolates were implicated with surprising frequency. Blood cultures were positive in six patients. An additional 14 patients, all with nontypable H. influenzae infection, had febrile purulent tracheobronchitis that was clinically indistinguishable from pneumonia except for the absence of a radiographic infiltrate; none were bacteremic. Penicillin susceptibility was shown for 95% of isolates, and response to ampicillin was prompt. Patients had high serum levels of bactericidal antibody on admission but had lower levels of serum opsonizing activity against their own organism than did uninfected carriers with chronic bronchitis; 2 to 3 weeks later, levels of opsonizing antibody had risen to equal those of carriers. Deficient opsonizing activity may have contributed to susceptibility to infection. These findings identify both host and bacterial factors that may cause susceptibility to pulmonary infection from H. influenzae.

Secondary Syphilitic Lesions

SUMMARY An important theme that emerges from all early historical accounts is that in addition to the decreased virulence of Treponema pallidum, the incidence of secondary syphilis has decreased drastically over the past three centuries. Even in the early 20th century, most syphilologists were of the opinion that the disease had undergone changes in its manifestations and that they were dealing with an attenuated form of the spirochete. Such opinions were based primarily on the observations that violent cutaneous reactions and fatalities associated with the secondary stage had become extremely rare. The rate of primary and secondary syphilis in the United States increased in 2002 for the second consecutive year. After a decade-long decline that led to an all-time low in 2000, the recent trend is attributable, to a large extent, by a increase in reported syphilis cases among men, particularly homosexual and bisexual men having sex with men. The present review addresses the clinical and diagnostic criteria for the recognition of secondary syphilis, the clinical course and manifestations of the disease if allowed to proceed past the primary stage of disease in untreated individuals, and the treatment for this stage of the disease.

Hypoglycemia as a manifestation of sepsis

Hypoglycemia has rarely been described as a clinical sign of severe bacterial sepsis. We recently encountered nine patients in whom hypoglycemia (mean serum glucose of 22 mg/dl) was associated with overwhelming sepsis. Clinical disease in these patients included pneumonia and cellulitis; in three patients, no focus of infection was apparent. Altered mental status, metabolic acidosis, leukopenia, abnormal clotting studies and bacteremia were common features in these cases. In four patients, no cause for hypoglycemia other than sepsis was present. In five patients, another possible metabolic cause for hypoglycemia was present (alcoholism in four and chronic renal insufficiency in one) although none had been observed to be hypoglycemic on previous hospitalizations. Streptococcus pneumoniae (three cases) and Hemophilus influenzae, type b, (two cases) were the most common pathogens, and the over-all mortality was 67 per cent. The mechanism(s) for hypoglycemia with sepsis is not well defined. Depleted glycogen stores, impaired gluconeogenesis and increased peripheral glucose utilization may all be contributing factors. Incubation of bacteria in fresh blood at room temperature does not increase the normal rate of breakdown of glucose suggesting that the hypoglycemia occurs in vivo. Hypoglycemia is an important sign of overwhelming sepsis that may be more common than has previously been recognized.

Response of latent syphilis or neurosyphilis to ceftriaxone therapy in persons infected with human immunodeficiency virus

OBJECTIVE To evaluate the effect of ceftriaxone in treating latent syphilis or asymptomatic neurosyphilis in patients infected with the human immunodeficiency virus (HIV). DESIGN Follow-up study of patients treated at two HIV-based clinics during 16 months from 1989 to 1991. PATIENTS Patients were those in whom a clinical diagnosis of latent syphilis or asymptomatic neurosyphilis was made, who received all recommended doses of antimicrobial therapy, and who returned for follow-up visits for 6 or more months. RESULTS Forty-three patients were treated with ceftriaxone, 1 to 2 g daily for 10 to 14 days. Thirteen underwent lumbar puncture before treatment; 7 (58%) had documented neurosyphilis (pleocytosis in 5, elevated protein levels in 6, VDRL reactive in cerebrospinal fluid [CSF] in 7), and 6 had documented latent syphilis (entirely normal CSF). The remaining 30 were said to have presumed latent syphilis. There was no relation between the diagnosis and the selected dosage of ceftriaxone. Response rates were similar in those who had documented neurosyphilis and documented or presumed latent syphilis. Overall, 28 patients (65%) responded to therapy, 5 (12%) were serofast, 9 (21%) had a serologic relapse, and 1 (2%) who experienced progression to symptomatic neurosyphilis was a therapeutic failure. Thirteen patients received benzathine penicillin for presumed latent syphilis; results were similar to those observed after ceftriaxone therapy, with 8 (62%) responders, 1 (8%) serofast, 2 (15%) relapses, and 2 (15%) failures. CD4 cell counts in responders were not different from those who failed to respond. CONCLUSIONS Even in the absence of neurologic symptoms, half of the HIV-infected persons who have serologic evidence of syphilis may have neurosyphilis. Although ceftriaxone achieves high serum and CSF levels, 10 to 14 days of treatment with this drug were associated with a 23% failure rate in HIV-infected patients who had latent syphilis or asymptomatic neurosyphilis. Three doses of benzathine penicillin did not have a significantly higher relapse rate and may provide appropriate therapy, at least for documented latent syphilis in persons co-infected with HIV. Studies comparing ceftriaxone with 10 to 14 doses of procaine penicillin are needed to determine the most cost-effective treatment for asymptomatic neurosyphilis or presumed latent syphilis in this group of patients.

Protection against Bacteremic Pneumococcal Infection by Antibody to Pneumolysin

Pneumolysin is an important virulence factor of Streptococcus pneumoniae. This study examined the hypothesis that human antibody to pneumolysin provides protection against pneumococcal infection. At the time of hospital admission, patients with nonbacteremic pneumococcal pneumonia had higher levels of serum anti-pneumolysin IgG than did patients with bacteremic pneumococcal pneumonia or uninfected control subjects. IgG levels rose significantly during convalescence in patients with bacteremic pneumonia, reaching levels observed in nonbacteremic patients. Purified human anti-pneumolysin IgG protected mice against intraperitoneal challenge with S. pneumoniae types 1 or 4 in a dose-related fashion; mice that received anti-pneumolysin IgG had a greater likelihood of surviving challenge and had negative blood cultures. Pneumolysin damages epithelial cells and inhibits phagocytic function of polymorphonuclear leukocytes. One hypothesis that might explain the study results is that, early in infection, IgG to pneumolysin blocks these effects in the alveoli, thereby protecting the host against bacteremic pneumococcal disease.

Cardiolipin-protein complexes and initiation of complement activation after coronary artery occlusion.

Specific rabbit anti-cardiolipin (anti-CL) antibodies were used to investigate the hypothesis that cardiolipin, associated with mitochondrial membrane proteins, binds C1 and facilitates activation of the complement cascade following reperfusion of ischemic myocardium. By immunoelectron microscopy, anti-CL localized to subsarcolemmal mitochondria, emerging through breaks in membranes of damaged cardiac myocytes. Anti-CL reacted with > 15 mitochondrial constituents, most of which comigrated with the proteins that bind C1q in transblots of subsarcolemmal mitochondria, fractionated by polyacrylamide gel electrophoresis under reducing conditions in the presence of sodium dodecyl sulfate. A subset of the C1q-binding proteins > 24 to 37 kDa served as stable sites for assembly of C3, C5, and C9. Cardiac lymph, collected during the first hour after reperfusion of ischemic myocardium, contained proteins of diverse size that reacted with both anti-CL and C1q. Cardiac lymph, collected before occlusion and 4 to 5 hours after reperfusion, in comparison, had few if any C1q or anti-CL reactive proteins. Treatment with phospholipase suppressed the C1q-binding activity and anti-CL reactivity of the proteins in reperfusion lymph and those with similar properties in mitochondrial extracts. Our data suggest that during ischemia, mitochondria, extruded through breaks in the sarcolemma, unfold and release membrane fragments in which cardiolipin and protein are intimately associated. By binding C1 and supplying sites for the assembly of later-acting complement components, these fragments provide the means to disseminate the complement-mediated inflammatory response to ischemic injury.

Antibody to capsular polysaccharide of Streptococcus pneumoniae at the time of hospital admission for pneumococcal pneumonia

IgG to capsular polysaccharide (CPS) of Streptococcus pneumoniae is thought to provide the greatest degree of protection against pneumococcal disease. Serum obtained at hospital admission from 14 (27%) of 51 patients with bacteremic pneumococcal pneumonia and 11 (37%) of 30 with nonbacteremic pneumococcal pneumonia contained IgG to CPS of the infecting serotype; these percentages are similar to the prevalence of IgG to CPS in a control population. However, when compared with antibody from healthy adults, this IgG had far less capacity to opsonize the infecting pneumococcal serotype for phagocytosis in vitro by normal human polymorphonuclear leukocytes or to protect mice against experimental challenge. Failure to opsonize correlated closely with failure to protect mice, and each of these parameters correlated well with poor avidity for CPS. Future vaccine studies may need to examine the functional capacity of antibodies as a surrogate for infection, in addition to measuring their concentration in serum.

Nonspecificity of Assaying for IgG Antibody to Pneumolysin in Circulating Immune Complexes as a Means to Diagnose Pneumococcal Pneumonia

Detection of immunoglobulin G (IgG) antibody to pneumolysin (PLY) in precipitated circulating immune complexes (CICs) has been used to diagnose pneumococcal pneumonia. With care to include appropriate controls, we precipitated and dissociated CICs and then assayed for IgG antibody to PLY. We detected IgG antibody to PLY in CICs that were precipitated from serum samples that were obtained at the time of admission to the hospital from 5 (23%) of 22 healthy adults, 7 (44%) of 16 subjects with stable chronic obstructive pulmonary disease, 10 (63%) of 16 subjects colonized with Streptococcus pneumoniae, and 9 (60%) of 15 patients with nonbacteremic pneumococcal pneumonia. Of the 16 patients with bacteremic pneumococcal pneumonia, 4 (25%) had IgG antibody to PLY at the time of admission, and 8 (50%) had IgG antibody to PLY in convalescence. Levels of IgG antibody in CICs closely correlated with serum levels of IgG antibody to PLY, implicating precipitation of free serum antibody in tests with false-positive results. Detection of IgG antibody to PLY in precipitated CICs is not a reliable method for diagnosing pneumococcal pneumonia.

Fibronectin fragments modulate monocyte VLA-5 expression and monocyte migration

To identify the mechanisms that cause monocyte localization in infarcted myocardium, we studied the impact of ischemia-reperfusion injury on the surface expression and function of the monocyte fibronectin (FN) receptor VLA-5 (alpha(5)beta(1) integrin, CD49e/CD29). Myocardial infarction was associated with the release of FN fragments into cardiac extracellular fluids. Incubating monocytes with postreperfusion cardiac lymph that contained these FN fragments selectively reduced expression of VLA-5, an effect suppressed by specific immunoadsorption of the fragments. Treating monocytes with purified, 120-kDa cell-binding FN fragments (FN120) likewise decreased VLA-5 expression, and did so by inducing a serine proteinase-dependent proteolysis of this beta(1) integrin. We postulated that changes in VLA-5 expression, which were induced by interactions with cell-binding FN fragments, may alter monocyte migration into tissue FN, a prominent component of the cardiac extracellular matrix. Support for this hypothesis came from experiments showing that FN120 treatment significantly reduced both spontaneous and MCP-1-induced monocyte migration on an FN-impregnated collagen matrix. In vivo, it is likely that contact with cell-binding FN fragments also modulates VLA-5/FN adhesive interactions, and this causes monocytes to accumulate at sites where the fragment concentration is sufficient to ensure proteolytic degradation of VLA-5.