Immunocompromised Subjects Research Articles

Correlation of rhinovirus load in the respiratory tract and clinical symptoms in hospitalized immunocompetent and immunocompromised patients

While human rhinoviruses (HRVs) are well accepted as a major cause of common cold syndromes (rhinitis), their role in the etiology of lower respiratory tract infections is still controversial, and their detection in asymptomatic patients is relatively common. The HRV pathogenic role in four groups of hospitalized patients (pediatric immunocompetent and immunocompromised patients, and adult immunocompetent and immunocompromised patients) was investigated by quantifying HRV load in nasopharyngeal aspirates or bronchoalveolar lavage samples by real‐time reverse transcription PCR (RT‐PCR). Real‐time RT‐PCR was performed in duplicate on all respiratory samples resulting positive by qualitative RT‐PCR. In addition, molecular typing allowed detection of all known HRV species (A, B, and C). In immunocompetent pediatric patients HRVs were mostly associated with lower respiratory tract infections (in the absence of other viral agents) and wheezing, when viral load was ≥106 RNA copies/ml. In young immunocompromised patients (stem cell transplantation recipients), an inverse correlation between HRV persistence over time and time at which the infection occurred after transplantation was observed, whereas in adult immunocompromised patients (lung transplant recipients) HRVs could be detected at a medium–low level (<105 RNA copies/ml) in bronchoalveolar lavage samples taken routinely from asymptomatic patients. In conclusion, when detected at high viral load, HRVs may cause severe upper and lower respiratory tract infections, whereas when detected at a medium–low viral load, an event more frequent in immunocompromised subjects, they may represent only bystander viruses. J. Med. Virol. 81:1498–1507, 2009. © 2009 Wiley‐Liss, Inc.

Inhaled therapeutics for prevention and treatment of pneumonia

The lungs are the most common site of serious infection owing to their large surface area exposed to the external environment and minimum barrier defense. However, this architecture makes the lungs readily available for topical therapy. Therapeutic aerosols include those directed towards improving mucociliary clearance of pathogens, stimulation of innate resistance to microbial infection, cytokine stimulation of immune function and delivery of antibiotics. In our opinion inhaled antimicrobials are underused, especially in patients with difficult-to-treat lung infections. The use of inhaled antimicrobial therapy has become an important part of the treatment of airway infection with Pseudomonas aeruginosa in cystic fibrosis and the prevention of invasive fungal infection in patients undergoing heart and lung transplantation. Cytokine inhaled therapy has also been explored in the treatment of neoplastic and infectious disease. The choice of pulmonary drug delivery systems remains critical as air-jet and ultrasonic nebulizer may deliver sub-optimum drug concentration if not used properly. In future development of this field, we recommend an emphasis on the study of the use of aerosolized hypertonic saline solution to reduce pathogen burden in the airways of subjects infected with microbes of low virulence, stimulation of innate resistance to prevent pneumonia in immunocompromised subjects using cytokines or synthetic pathogen-associated molecular pattern analogues and more opportunities for the use of inhaled antimicrobials. These therapeutics are still in their infancy but show great promise.

Humoral immunity to respiratory syncytial virus in young and elderly adults

Respiratory syncytial virus (RSV) has been demonstrated to cause substantial disease in elderly and immunocompromised subjects. The relationship of serum antibody to RSV infection and the risk of infection in elderly subjects is controversial, thus we evaluated the presence of neutralizing antibodies to RSV in healthy people of different age groups and the correlation with viral protection. Baseline blood samples from 197 subjects aged 20-80 years were analysed for the presence of anti-RSV antibodies either by indirect immunofluorescence and microneutralization test. The percentage of people who had neutralizing antibodies to RSV was significantly higher (P=0.001) in the youngest group (92.51%) compared to the frail group (36.21%). The RSV antibody level tends to wane in some older people; this factor could determine proneness to RSV re-infections in the elderly who are at a greater risk of developing severe respiratory disease.

Leishmaniose cutanée au cours de la polyarthrite rhumatoïde

Cutaneous leishmaniasis is a protozoal infection. Its prevalence is increasing, especially in immunocompromised subjects. We report four patients with rheumatoid arthritis, treated with methotrexate and prednisone who developed cutaneous leishmaniasis. Clinical outcome was favorable after institution of antimony therapy in three cases despite the continuation of methotrexate and prednisone. One patient failed to respond to therapy. The frequency of cutaneous leishmaniasis is increasing especially in immunocompromised subjects. In our patients, rheumatoid arthritis, corticosteroid therapy and methotrexate were predisposing factors of cutaneous leishmaniasis.

A case of fatal vascular invasive rhinocerebral mucormycosis after dental extraction in a patient with type 2 diabetes mellitus

Mucormycosis is a rare life-threatening fungal infection that occurs in immunocompromised subjects, including patients with poorly controlled diabetes Mellitus (DM) There have been even rarer case reports that describe the development of rhinocerebral mucormycosis in diabetic patients after dental extraction. Here, we describe a 57-year-old female patient with type 2 DM who developed a fatal vascular invasive rhinocerebral mucormycosis after dental extraction.

Epidermal growth factor receptor modulates the tumorigenic potential of melanoma

Potential contribution of the Epidermal Growth Factor Receptor (EGFR) in melanoma immunobiology remains unclear, in part due to a lack of experimental models. We demonstrated previously that B16F10 melanoma transfected with the full length cDNA of the human EGFR increases the tumor cell proliferation in vitro. To further study its contribution in vivo, EGFR-transfected B16F10 cells were inoculated in syngenic C57BL/6 mice and its tumorigenic capacity was compared with the parental melanoma. Contrary to the observed in vitro effect, EGFR-transfected B16F10 cells displayed a delayed tumor growth rate in vivo, correlating inversely to the transgene expression. Interestingly, resulting tumors showed a downregulation of the EGFR transgene expression. Contrastingly, parental and EGFR-transfected B16F10 cells exhibited a similar tumorigenic potential in immunocompromised subjects, persisting the EGFR transgene expression. These results document the adaptability of melanoma to growth in immunocompetent individuals. Moreover, the potential EGFR expression during the melanoma outgrowth that would be downregulated by interacting with the host immune system during the tumor evolution is not excluded and which may be dissected in this model.

Genetic Identification of Intestinal Microsporidia Species in Immunocompromised Patients in Tunisia

Stool samples from 86 immunocompromised patients (51 human immunodeficiency virus (HIV)-infected patients and 35 patients with haematologic malignancies) were systematically screened for intestinal microspordiosis by microscopic examination and polymerase chain reaction (PCR) using universal primer V1/PMP2. Nine samples (10.5%) showed amplification with the predictive size of fragment (6 from HIV-infected patients and 3 from patients with myeloma). Only 5 out of them (all HIV-infected patients) were revealed positive by microscopy. By means of amplicons fragment size, species-specific primers (V1/EB450, V1/IS500) and sequencing, 3 microsporidia species were for the first time identified in Tunisia: Enterocytozoon bieneusi (3 isolates), Encephelitozoon intestinalis (2 isolates), and Encephalitozoon hellem (1 isolate). Systematic use of such sensitive and discriminative molecular tools will contribute to determining the true prevalence of microsporidiosis in Tunisia and to better management of infected immunocompromised subjects.

An unusual cause of chest pain: atraumatic clostridial myonecrosis

Atraumatic clostridial myonecrosis is a rare but potentially life-threatening infective condition which is thought to occur in elderly and immunocompromised subjects via bacterial translocation through the gut wall and distant...

JC virus VP1 loop-specific polymorphisms are associated with favorable prognosis for progressive multifocal leukoencephalopathy

JC virus (JCV) is a human polyomavirus that causes progressive multifocal leukoencephalopathy (PML), a fatal demyelinating disease that mainly affects immunocompromised subjects. Since its discovery, PML has been considered a rapidly progressing fatal disease; however, amino acid substitutions in the capsid viral protein have recently been tentatively associated with changes in PML clinical course. In order to provide more insight to PML pathogenesis and identify potential prognostic markers, seven cerebrospinal fluid (CSF) samples and four brain autopsy samples were collected from patients afflicted with PML with different clinical courses (fast- and slow-progressing), and the JCV VP1 coding region was amplified, cloned, and sequenced. In addition, urine samples were collected and analyzed from nine patients with PML or other neurological diseases (ONDs) as a control group. Sequencing analysis of the genomic region encoding the VP1 outer loops revealed polymorphic residues restricted to four positions (74, 75, 117, and 128) in patients with slow PML progression, whereas no significant mutation was found in JCV isolated from urine. Collectively, these data show that JCV VP1 loop mutations are associated with a favorable prognosis for PML. It is therefore possible that slower progression of PML may be related to the emergence of a less virulent JCV strain with a lower replication rate.

Interaction of human papillomaviruses with the host immune system: A well evolved relationship

Human papillomavirus (HPV) infections are generally long lasting, and a host immune response to infection is hard to detect. Nevertheless immunocompromised subjects control HPV infection less well than those with intact immunity. Immune responses are best documented for the papillomavirus groups that cause evident human disease, particularly those responsible for anogenital cancers and genital warts. Humoral immunity to the viral capsid has been shown sufficient for protection against infection, while innate and adaptive cell mediated immunity appears important for eventual elimination of HPV infection. However, molecular and cellular mechanisms responsible for protection from and clearance of HPV infection are not completely established.

BCGite disséminée révélant un déficit immunitaire combiné sévère lié à l’X

Live attenuated Bacillus Calmette-Guérin (BCG) vaccine is rarely responsible for disseminated infection. We report a case of X-linked severe combined immunodeficiency (SCID) revealed by a disseminated skin infection. A 4-month-old baby was hospitalized for prolonged gastroenteritis. He was in poor general condition, with prolonged fever, oral and gluteal candidiasis and purple nodules associated with ulceration of the BCG scar. The absence of a thymus, T-cells and NK-cells, and the presence of nonfunctional B-lymphocytes led to a diagnosis of SCID. Biopsies of nodules revealed a dermal infiltrate without necrosis. A Ziehl-Neelson stain was highly positive and the culture grew Mycobacterium bovis. Treatment consisted of a four-drug antibiotic regimen directed against M. bovis combined with gamma interferon, immunoglobulins and antibiotic prophylaxis by cotrimoxazole and was followed by a haploid-identical bone marrow transplant without rejection at six months. The early death of the child's maternal uncle from sepsis suggested X-linked transmission, which was subsequently confirmed by genetic analysis. BCG vaccination can cause serious infections in immunocompromised subjects. Skin involvement is extremely rare but may be the first sign of SCID, of which the X-linked form is the most common and corresponds to a variety of mutations in the gene coding for the gamma chain common to several interleukin receptors. Genetic counselling is essential to identify female carriers and allow early antenatal diagnosis. Bone marrow transplantation is the only treatment.

Susceptibility profile of yeast-like organisms isolated from HIV/AIDS patients; using NCCLs macrodiltion method compared with agar diffusion technique.

Yeast like opportunistic fungal infection has been reported globally amongst HIV/AIDS patients, particularly as the etiologic agent of oral thrush. Fluconazole antibiotic has been most popularly employed in treating cases of oral thrush in HIV/AIDS patients. Recent reports have recorded antifungal drug resistance amongst immunocompromised subjects. This constitutes a big problem in the management of opportunistic candidiasis. The NCCLS micro/macrodilusion sensitivity testing procedure is expensive, cumbersome and requires a level of sophistication. This study was designed to compare NCCLS M-27-A macrodilution method (expensive) with agar diffusion technique (cheap and simple), to provide a reliable rapid alternative to the new pressing need for antifungal routine sensitivity testing. Sputum specimens from 213(108 females and 105 males) HIV positive patients were plated onto SDA. The isolates were identified by morphotyping, microscopy and speciated using germ tube test, and battery of biochemical sugar fermentation; and assimilation tests. Fluconazole agar diffusion susceptibility testing was carried out on each isolate, compared with the NCCLS macrodilution sensitivity assay standard. Of the 74 isolates tested for fluconazole sensitivity, 59(79.7%) were sensitive (zone diameter > 19mm, mean diameter 28mm), 6(8.1%) were Sensitive Dose Dependent (S-DD) (zone diameter 13-18mm, mean diameter 16mm), while 9(12.2%) were resistant (zone diameter 64μg/ml profile, using the NCCLS macrodilution assay. The differences between the test method (Agar diffusion) and the control standard method (NCCLS-M 27-A broth Macrodilution MICS) were not statistically significant using t-test (two tail) (t = 4.302656, P=1.0). Among the C. albicans isolates, 26(86.7%) were sensitive to fluconazole. The rank of susceptibility was C. albicans > C. tropicalis > C. krusei. It is concluded that broncho-oro-pharyngeal Candida and other yeast-like species existed in about one third of the HIV and AIDS patients studied; in which C. albicans was the most prevalent, while about ten percent of all the Candida isolates were resistant to fluconazole. The reliability of germ tube production as a confirmatory test for Candida albicans in HIV infection was as high as 96.7% and is therefore, recommended for continued use. Agar diffusion compared favourably with the NCCLS macrodilution technique, hence it is recommended for routine antifungal sensitivity test on all isolates of yeast-like cells from HIV and AIDS subjects. Keywords : HIV/AIDS, oral thrush, yeast-like cells, fluconazole resistance, NCCLS vs agar diffusion technique. African Journal of Clinical and Experimental Microbiology Vol. 9 (2) 2008 pp. 88-96

Therapy of environmental mycobacterial infections

Environmental mycobacteria are the causative factors of an increasing number of infections worldwide. Cutaneous infections as a result of environmental mycobacteria are often misdiagnosed, and their treatment is difficult because these agents can show in vivo and in vitro multidrug resistance. The most common environmental mycobacteria that can cause cutaneous infections are Mycobacterium fortuitum and Mycobacterium marinum. All mycobacteria are characterized by low pathogenicity and they can contaminate affected or traumatized skin only in immunocompetent subjects (mainly in fishermen, swimming-pool attendants, and aquarium owners) whereas medical and esthetic procedures are at risk for the infections because of the quick-growing mycobacteria. Immunocompromised subjects can instead easily develop environmental mycobacterial infections of differing degrees of severity.

Epidemiological Profile of Cryptococcal Meningitis Patients in Rio Grande do Sul, Brazil

Cryptococcosis is a major opportunistic mycosis which has meningitis as its most frequent clinical presentation and can be fatal in the absence of antifungal therapy. The aetiological agents are Cryptococcus neoformans, which affects mainly immunocompromised subjects, and C. gattii, the aetiologic agent for cryptococcosis in healthy individuals. A recent outbreak of cryptococcosis on Vancouver Island, Canada, raised the level of concern about the epidemiology of this disease. In Brazil, between 1980 and 2002, six per cent of AIDS patients had cryptococcosis in course at the time of diagnosis. To identify the profile of cryptococcal meningitis patients in Rio Grande do Sul (RS), Brazil, a retroactive study was realized using data from patients registered at Laboratório Central de Saúde Pública IPB-LACEN/RS from 2000 to 2005. Most of the patients were men (77.12%), Caucasian (83.5%), median age between thirty and thirty-nine years old (46.24%) and HIV positive (95%).

Stimulation of Lung Innate Immunity Protects against Lethal Pneumococcal Pneumonia in Mice

The lungs are a common site of serious infection in both healthy and immunocompromised subjects, and the most likely route of delivery of a bioterror agent. Since the airway epithelium shows great structural plasticity in response to inflammatory stimuli, we hypothesized it might also show functional plasticity. To test the inducibility of lung defenses against bacterial challenge. Mice were treated with an aerosolized lysate of ultraviolet-killed nontypeable (unencapsulated) Haemophilus influenzae (NTHi), then challenged with a lethal dose of live Streptococcus pneumoniae (Spn) delivered by aerosol. Treatment with the NTHi lysate induced complete protection against challenge with a lethal dose of Spn if treatment preceded challenge by 4 to 24 hours. Lesser levels of protection occurred at shorter (83% at 2 h) and longer (83% at 48-72 h) intervals between treatment and challenge. There was also some protection when treatment was given 2 hours after challenge (survival increased from 14 to 57%), but not 24 hours after challenge. Protection did not depend on recruited neutrophils or resident mast cells and alveolar macrophages. Protection was specific to the airway route of infection, correlated in magnitude and time with rapid bacterial killing within the lungs, and was associated with increases of multiple antimicrobial polypeptides in lung lining fluid. We infer that protection derives from stimulation of local innate immune mechanisms, and that activated lung epithelium is the most likely cellular effector of this response. Augmentation of innate antimicrobial defenses of the lungs might have therapeutic value.

Latent tuberculosis: which test in which situation?

Detection of latent tuberculosis infection (LTBI) is a cost-effective procedure in patients at high risk of developing tuberculosis later and who could benefit from preventive treatment. The commonest situation where screening is indicated is the search for infected contacts of an index case with pulmonary tuberculosis. As a screening procedure the current tendency is to replace the time-honoured tuberculin skin test by one of the new blood tests measuring the release of interferon gamma by sensitised T lymphocytes after stimulation by specific peptides from M. tuberculosis. The main advantage of the new tests is the absence of interference with BCG and non-tuberculous mycobacteria, which confers high specificity on the test. This allows a more selective choice of persons for whom preventive treatment is indicated. Some controversial issues remain, such as sensitivity in children and immunocompromised subjects, the predictive value of the blood test and interpretation of possible changes in test results over time. The technical aspects required for performance of the tests must be considered.

Latent tuberculosis: which test in which situation?

Detection of latent tuberculosis infection (LTBI) is a cost-effective procedure in patients at high risk of developing tuberculosis later and who could benefit from preventive treatment. The commonest situation where screening is indicated is the search for infected contacts of an index case with pulmonary tuberculosis. As a screening procedure the current tendency is to replace the time-honoured tuberculin skin test by one of the new blood tests measuring the release of interferon gamma by sensitised T lymphocytes after stimulation by specific peptides from M. tuberculosis. The main advantage of the new tests is the absence of interference with BCG and non-tuberculous mycobacteria, which confers high specificity on the test. This allows a more selective choice of persons for whom preventive treatment is indicated. Some controversial issues remain, such as sensitivity in children and immunocompromised subjects, the predictive value of the blood test and interpretation of possible changes in test results over time. The technical aspects required for performance of the tests must be considered.

Mathematical modeling of pathogenicity of Cryptococcus neoformans

Cryptococcus neoformans (Cn) is the most common cause of fungal meningitis worldwide. In infected patients, growth of the fungus can occur within the phagolysosome of phagocytic cells, especially in non-activated macrophages of immunocompromised subjects. Since this environment is characteristically acidic, Cn must adapt to low pH to survive and efficiently cause disease. In the present work, we designed, tested, and experimentally validated a theoretical model of the sphingolipid biochemical pathway in Cn under acidic conditions. Simulations of metabolic fluxes and enzyme deletions or downregulation led to predictions that show good agreement with experimental results generated post hoc and reconcile intuitively puzzling results. This study demonstrates how biochemical modeling can yield testable predictions and aid our understanding of fungal pathogenesis through the design and computational simulation of hypothetical experiments.

Severe brain co-infection with Cryptococcus neoformans and Mycobacterium tuberculosis in a young, otherwise healthy student recently immigrated from China

While the incidence of pulmonary and extrapulmonary tuberculosis is growing in patients of advanced age, immunocompromised subjects, and immigrants coming in from developing countries [Keller A, Delavelle J, Howarth N, Bianchi S, Garcia J. Spinal and neurotuberculosis in an Asian immigrant. JBR-BTR 2002;85:136-7; Sabbatani S, Manfredi R, Legnani G. Chiodo F. Tuberculosis in a metropolitan area of northern Italy: epidemiological trends and public health concerns. Eur J Epidemiol 2004;19:501-3], the concomitant occurrence of cerebral cryptococcosis plus brain and respiratory tuberculosis in a young and otherwise healthy patient, without an evident cause of immunodeficiency and without an obvious exposure, is exceedingly rare [Silber E, Sonnenberg P, Koornhof HJ, Morris L, Saffer D. Dual infective pathology in patients with cryptococcal meningitis. Neurology 1998;51:1213-5.]. An exceptionally rare case of concurrent central nervous system infection with Cryptococcus neoformans and Mycobacterium tuberculosis in a 25-year-old otherwise healthy Chinese student, who had very recently joined an Italian post-doctoral course, is described. Also described are the diagnostic and therapeutic difficulties encountered in a five-month hospitalization period, when only transient and/or negligible immune system impairments were detected. This episode of very infrequent concurrent infections should emphasize the need to maintain an elevated clinical suspicion for opportunistic infections and tuberculosis, even in the absence of an obvious immunodeficiency and related epidemiological clues.

Recurring Candida albicans esophagitis in a HIV-infected patient undergoing long-Term antiretroviral therapy, and with absent-negligible immunodeficiency

A patient with HIV infection developed the first episode of AIDS-defining opportunism (severe Candida albicans esophagitis) with an underlying CD4+ lymphocyte count of 1,025 cells/microL. After treatment with a highly active antiretroviral therapy (HAART), taken with insufficient compliance and leaving a residual viral load, our patient suffered from two relapses of esophageal candidiasis, which occurred three months and seven years later, when his CD4+ lymphocyte count was 930 and 439 cells/microL, respectively, and a viral load slightly above 10(4) copies/mL was still present. Also in the HAART era, Candida esophagitis remains one of the most common AIDS-defining diseases, but a presentation with a concurrent CD4+ count above 1,000 cells/microL remains a rare exception, as well as the two isolated, subsequent relapses, occurred with a CD4+ count ranging from 439 to 930 cells/microL, and a residual HIV viremia due to insufficient adherence to the prescribed HAART regimens. Our case report represents the opportunity to revisit the epidemiology and, especially, the pathogenesis of this opportunistic fungal complication in HIV-infected patients and in other subjects at risk, on the ground of an extensive literature review, and to explore possible alternative supporting factors other than the crude absolute CD4+ lymphocyte count, with emphasis on the possible role of a persisting HIV viremia, and other potential contributing factors. Clinicians engaged with immunocompromised patients and subjects with HIV disease, should be aware that a Candida esophagitis may occur and relapse also when the cell-mediated immunity, as measured by a simple CD4+ cell count, do not show relevant abnormalities.