Juhani Lähdevirta

The international epidemiology of disseminated Mycobacterium avium complex infection in AIDS

Objective:To determine rates of disseminated Mycobacterium avium complex (MAC) infection among AIDS patients in developed and developing countries, and to determine whether different rates reflect differences in exposure or immunity, or both. Design:Prospective cohort study. Setting:University hospitals and outpatient AIDS programs. Methods:HIV-infected subjects with CD4 counts < 200×106/l were interviewed and had CD4 lymphocyte counts, blood cultures for mycobacteria (baseline and at 6 months), and skin tests with purified protein derivative (PPD) and M. avium sensitin. Results:Among 566 study patients rates of disseminated MAC were 10.5–21.6% in New Hampshire, Boston and Finland compared to 2.4–2.6% in Trinidad and Kenya (P < 0.001). PPD skin test reactions ≥ 5 mm were present in 20% of patients from Kenya compared to 1% at other sites (P < 0.001). Among patients from the United States and Finland, multiple logistic regression indicated that occupational exposure to soil and water was associated with a decreased risk of disseminated MAC, whereas the following were associated with an increased risk of disseminated MAC: low CD4 count, swimming in an indoor pool, history of bronchoscopy, regular consumption of raw or partially cooked fish/shellfish and treatment with granulocyte colony-stimulating factor. Conclusions:Rates of disseminated MAC in AIDS are higher in developed than developing countries and are due to both differences in exposure and differences in immunity. These data provide a rationale for prevention of MAC through both active immunization and reduction in exposure to the organism.

T-cell response towards HIV in infected individuals with and without zidovudine therapy, and in HIV-exposed sexual partners.

HIV-specific T-cell response in HIV-infected individuals at different stages of the disease and during zidovudine therapy was studied using HIV and HIV-envelope derived native and recombinant proteins as antigens. Neither antibody-negative at-risk individuals nor HIV-infected individuals responded to HIV or its envelope-derived proteins, even though they responded to a recall antigen, purified protein derivative of tuberculin (PPD). However, five out of 14 antibody- and antigen-negative sexual partners of known HIV-positive men did respond to HIV, native gp 120 and recombinant envelope and core proteins. Some AIDS-related complex (ARC) and AIDS patients treated with zidovudine also showed a low T-cell response which diminished along with clinical deterioration. A synthetic peptide representing one of the major T-cell epitopes in HIV envelope, frequently recognized by immunized and infected primates, gave only marginal stimulation in man. Our findings suggest that HIV infection in man results in a T-helper cell anergy directed against viral proteins. The response observed in the antibody- and antigen-negative sexual partners and in some of the zidovudine-treated patients implies that at least some epitopes on HIV envelope are immunogenic in man.

CSF protein and cellular profiles in various stages of HIV infection related to neurological manifestations

CSF protein and cellular profiles were studied in 28 HIV-infected patients. Twenty of them had neurological complaints, but only 6 patients had objective neurological deficits such as dementia, ocular motility disorders or polyneuropathy. The serum/CSF HIV antibody ratio was on average lowest in acquired immunodeficiency syndrome (AIDS) (4 patients) and highest or almost normal in lymphadenopathy syndrome (LAS) (11) and asymptomatic seropositivity (ASX) (7), while it varied between these extremes in AIDS-related complex (ARC) (6). However, low values of the ratio were also found in the HIV-infected patients free of neurological symptoms and even in one ASX patient. The CSF IgG index was elevated in all these 4 general stages of HIV infection without any significant differences between them. The CSF/serum albumin ratio was slightly increased in patients with neurological deficits, but this ratio showed no association with any other clinical factor analysed. CSF leucocytes were increased in the early stages of the disease, but later the cellular reaction subsided. HIV was isolated from post mortem brain tissue of two AIDS patients and from the CSF of one of them. The results suggest increased intrathecal virus-specific IgG synthesis, not only in patients with neurological deficits and at advanced stages of infection, but also in neurologically symptom-free subjects and at early infection. The lack of correlation between the increased virus-specific IgG synthesis within the CNS and the presence of neurological symptoms suggests that neurologically silent areas of brain white matter are often affected in HIV infection.

Four Fatal Cases of nephropathia epidemica

Four serologically confirmed fatal cases of nephropathia epidemica (NE), the mild form of hemorrhagic fever with renal syndrome (HFRS) are described. All the patients had disseminated intravascular coagulation. Autopsies revealed hemorrhage and necrotic areas of their pituitary glands, myocarditis, venous congestion and hemorrhage of the kidneys as well as pulmonary edema and hemorrhage of the lungs in all patients. This report provides new evidence that NE can be a fatal disease.

Mild brain atrophy in early HIV infection: the lack of association with cognitive deficits and HIV-specific intrathecal immune response

Brain MRI and/or CT were performed on 72 HIV-infected patients at various stages of the disease, and on 34 controls. The neuroradiological findings were related to duration of the infection, neurological symptoms, and cognitive abnormalities as well as to immunological findings in the CSF and blood. All types of brain atrophy were more severe and more frequent in HIV-infected subjects than in controls. Patients with neurological symptoms, those with advanced HIV infection, and patients with a duration of HIV infection of more than 4 years showed the most severe and most frequent neuroradiological abnormalities, including central and cortical atrophy, brain stem atrophy, and cerebellar atrophy. Subjects with cognitive defects exhibited more severe central atrophy than cognitively intact patients. However, slight brain atrophy and/or parenchymal lesions were found in 57% of cognitively intact HIV-seropositive individuals. Patients with brain atrophy and those with radiologically normal brain, both showed increased intrathecal synthesis of total IgG, and intrathecal HIV-antibody synthesis. However, a declined general immune response and a lowered CSF leukocyte count were seen predominantly in patients with brain atrophy. The results suggest that subcortical, neurologically silent areas of brain white matter are an early target of HIV infection.

Cognitive changes as early signs of HIV infection

ABSTRACT‐ Neuropsychological examination was performed on 13 patients and 10 matched controls to assess the brain involvement of patients with human immunodeficiency virus (HIV) infection. HIV‐infected patients showed a significant decline in visuomotor, visuoconstructive and practical abilities as well as in motorfree visuospatial performance and repeating a long sentence. These findings could not be explained by the concomitant mental depression of these patients. Neither were they associated with any particular stage of HIV infection. The results suggest that mild cognitive changes may be detected even in the early stages of HIV infection, when examined by appropriate neuropsychological methods.

DIVERSITY OF CLINICAL SPECTRUM OF HTLV-III INFECTION

In a prospective follow-up volunteer study lasting 4 to 16 months, 17 of 200 homosexual men living in Finland had antibodies to human T-lymphotrophic virus type III (HTLV-III). 1 man who initially had a low titre of HTLV-III antibodies became seronegative within 6 months without any symptoms developing, and a seronegative man became seropositive. 14 men had high titres of HTLV-III antibodies when they first joined the study and during the study titres rose in all other HTLV-III-positive men except those with AIDS. Initially 9 men were symptom-free, 3 had lymphadenopathy syndrome (LAS), 3 had AIDS-related complex (ARC), and 2 had AIDS. During follow-up LAS developed in 3 symptom-free HTLV-III positive men but none of those with LAS or ARC progressed to AIDS. Most HTLV-III-positive men, including those who were otherwise symptom-free, had mucocutaneous lesions generally associated with immune deficiency. Regardless of the symptoms, those with increasing HTLV-III antibody titres showed lowered T helper/T suppressor ratios, decreased numbers of T helper cells, and/or diminished responses to tuberculin antigen (PPD). These results suggest that the clinical spectrum of HTLV-III infection ranges from transient infection through chronic provirus state, asymptomatic virus producer state, LAS or ARC, and rarely full-blown AIDS. Cofactors probably determine the final outcome of infection in the individual.

Cognitive performance in HIV‐1 infection: relationship to severity of disease and brain atrophy

We examined cognitive performance in 72 HIV‐1 infected patients and 34 controls. None of the patients had opportunistic infections or unusual neoplasms of the central nervous system (CNS). Factors other than HIV‐1 known to cause cognitive decline were excluded from both groups. Cognitive functioning analysed with special emphasis on the severity of HIV infection was related to neuroradiological and immunological findings. In patients with AIDS‐related complex (CDC IVa) or AIDS (CDC IVc,d), a deterioration of memory as well as cognitive speed and flexibility was detected. Furthermore, memory deficits were associated with central cerebral and infratentorial atrophy in those patients, while no association was found between cognitive deficits and immunological abnormalities. Patients at CDC stages II or III showed slight association between altered cognitive speed and flexibility and elevated leukocyte count, suggesting a subclinical CNS disease already at early stages of HIV infection.

The risks and benefits of childhood bacille Calmette-Guerin immunization among adults with AIDS

Objective:To define the risks of disseminated bacille Calmette-Guérin (BCG) or disseminated Mycobacterium tuberculosis in adults with AIDS who were immunized with BCG in childhood. Design:HIV-infected patients with CD4 < 200 × 106/l were enrolled from five study sites (New Hampshire, Boston, Finland, Trinidad and Kenya). Prior BCG immunization was determined and blood cultures for mycobacteria were obtained at study entry and at 6 months. Acid-fast bacilli were identified as Mycobacterium tuberculosis complex (MTBC) using DNA probes. MTBC isolates were then typed by both IS6110 restriction fragment length polymorphism and polymerase chain reaction/restriction enzyme analysis. Setting:Most patients in New Hampshire and Finland were outpatients; most patients in Trinidad were inpatients with terminal illness; and most patients in Kenya were outpatients, although 44 were inpatients with terminal illness. Participants:A total of 566 patients were enrolled, including 155 with childhood BCG immunization; 318 patients had a single study visit and culture, and 248 patients had two study visits and cultures. Main outcome measures:Isolation and identification of mycobacteria from blood cultures. Results:Blood cultures were positive for MTBC in 21 patients; none were positive for M. bovis BCG, and 21 were M. tuberculosis-positive. In Trinidad, seven (87%) out of eight isolates of M. tuberculosis were indistinguishable by IS6110 typing; BCG immunization was associated with a decreased risk of bacteremic infection with M. tuberculosis (P = 0.05). Conclusions:The risk of disseminated BCG among adult AIDS patients with childhood BCG immunization is very low. Childhood BCG immunization is associated with protection against bacteremia with M. tuberculosis among adults with advanced AIDS in Trinidad.

Acute Schistosomiasis Mansoni in Finnish Hunters Visiting Africa: Need for Appropriate Diagnostic Serology

Three symptomatic and 3 asymptomatic patients with acute schistosomiasis mansoni are described. The index case presented with fever and eosinophilia 4-6 weeks after swimming in the Pipi River of the Central African Republic, suggesting acute schistosomiasis (Katayama fever). A fortunate early diagnosis led to early treatment of these schistosomiasis patients. Diagnosis was obtained based on the finding of one Schistosoma mansoni egg in the index case and positive serology in all cases. A commercially available passive haemagglutination test for serum bilharzia antibodies was negative in all cases prior to, and 2 weeks after treatment. However, antibodies against gut-associated antigens (GAA) of adult S. mansoni worms could be demonstrated using the indirect immunofluorescence technique. These cases illustrate the importance of using appropriate diagnostic assays for the early demonstration of infection by schistosomes in previously unexposed nonimmune patients with atypical symptoms and in asymptomatic individuals at risk even after brief exposure to schistosome-containing water in endemic countries. Careful (and repeated) stool examination and appropriate serological tests are the keys to prompt diagnosis of S. mansoni infection.