Healthcare-associated infections: the hallmark of Middle East respiratory syndrome coronavirus with review of the literature.

Middle East respiratory syndrome coronavirus (MERS-CoV) is capable of causing acute respiratory illness. Laboratory-confirmed MERS-CoV cases may be asymptomatic, have mild disease, or have a life-threatening infection with a high case fatality rate. There are three patterns of transmission: sporadic community cases from presumed non-human exposure, family clusters arising from contact with an infected family index case, and healthcare-acquired infections among patients and from patients to healthcare workers. Healthcare-acquired MERS infection has become a well-known characteristic of the disease and a leading means of spread. The main factors contributing to healthcare-associated outbreaks include delayed recognition, inadequate infection control measures, inadequate triaging and isolation of suspected MERS or other respiratory illness patients, crowding, and patients remaining in the emergency department for many days. A review of the literature suggests that effective control of hospital outbreaks was accomplished in most instances by the application of proper infection control procedures. Prompt recognition, isolation and management of suspected cases are key factors for prevention of the spread of MERS. Repeated assessments of infection control and monitoring of corrective measures contribute to changing the course of an outbreak. Limiting the number of contacts and hospital visits are also important factors to decrease the spread of infection.

Measles virus infection in rhesus macaques: altered immune responses and comparison of the virulence of six different virus strains.

Measles remains a major cause of childhood mortality, with questions about virus virulence and pathogenesis still requiring answers. Rhesus macaques were infected with 5 different culture-adapted strains of measles virus, including 2 from patients with progressive vaccine-induced disease, and a sixth nonculture-adapted strain, Bilthoven. All caused infection detectable by reverse transcriptase-polymerase chain reaction and induction of antibody. Chicago-1 and Bilthoven induced viremias detectable by leukocyte cocultivation. Bilthoven induced Koplik's spots, conjunctivitis, and rash. Lymphopenia and depressed interleukin (IL)-2 production were followed by monocytosis and eosinophilia. All monkeys, including 41 involved in a primate facility outbreak, showed suppressed responses to phytohemagglutinin. As the rash resolved production of IL-2, IL-1beta, tumor necrosis factor-alpha, IL-6, and IL-5 mRNA increased. Monkeys are useful for studies of measles immunopathogenesis, but virus strains must be carefully chosen. Increased virulence of vaccine strains isolated from immunocompromised infants with fatal infections was not evident.

Altered virulence of vaccine strains of measles virus after prolonged replication in human tissue.

To understand the molecular determinants of measles virus (MV) virulence, we have used the SCID-hu thymus/liver xenograft model (SCID-hu thy/liv) in which in vivo MV virulence phenotypes are faithfully duplicated. Stromal epithelial and monocytic cells are infected by MV in thymus implants, and virulent strains induce massive thymocyte apoptosis, although thymocytes are not infected. To determine whether passage of an avirulent vaccine strain in human tissue increases virulence, we studied a virus isolated from thymic tissue 90 days after infection with the vaccine strain Moraten (pMor-1) and a virus isolated from an immunodeficient child with progressive vaccine-induced disease (Hu2). These viruses were compared to a minimally passaged wild-type Edmonston strain (Ed-wt) and the vaccine strain Moraten. pMor-1, Hu2, and Ed-wt displayed virulent phenotypes in thymic implants, with high levels of virus being detected by 3 days after infection (10(5.2), 10(2.8), and 10(3. 4), respectively) and maximal levels being detected between 7 and 14 days after infection. In contrast, Moraten required over 14 days to grow to detectable levels. pMor-1 produced the highest levels of virus throughout infection, suggesting thymic adaptation of this strain. Similar to other virulent strains, Ed-wt, Hu2, and pMor-1 caused a decrease in the number of viable thymocytes as assessed by trypan blue exclusion and fluorescence-activated cell sorter analysis. Thymic architecture was also disrupted by these strains. Sequence analysis of the hemagglutinin (H) and matrix (M) genes showed no common changes in Hu2 and pMor-1. M sequences were identical in pMor-1 and Mor and varied in H at amino acid 469 (threonine to alanine), a position near the base of propeller 4 in the propeller blade/stem model of H structure. Further study will provide insights into the determinants of virulence.

Production of atypical measles in rhesus macaques: evidence for disease mediated by immune complex formation and eosinophils in the presence of fusion-inhibiting antibody.

The severe disease atypical measles occurred when individuals immunized with a poorly protective inactivated vaccine contracted measles, and was postulated to be due to a lack of fusion-inhibiting antibodies. Here, rhesus macaques immunized with formalin-inactivated measles vaccine developed transient neutralizing and fusion-inhibiting antibodies, but no cytotoxic T-cell response. Subsequent infection with measles virus caused an atypical rash and pneumonitis, accompanied by immune complex deposition and an increase in eosinophils. Fusion-inhibiting antibody appeared earlier in these monkeys than in non-immunized monkeys. These data indicate that atypical measles results from previous priming for a nonprotective type 2 CD4 T-cell response rather than from lack of functional antibody against the fusion protein.

Recombinant measles viruses with mutations in the C, V, or F gene have altered growth phenotypes in vivo.

An understanding of the determinants of measles virus (MV) virulence has been hampered by the lack of an experimental model of infection. We have previously demonstrated that virulence phenotypes in human infections are faithfully reproduced by infection of human thymus/liver (thy/liv) implants engrafted into SCID mice, where the virus grows primarily in stromal cells but induces thymocyte apoptosis (P. G. Auwaerter et al., J. Virol. 70:3734-3740, 1996). To begin to elucidate the roles of the C protein, V protein, and the 5' untranslated region of the F gene (F 5'UTR) in MV infection in vivo, the replication of strains bearing mutations of these genes was compared to that of the parent sequence-tagged Edmonston strain (EdTag). Growth curves show that mutants fall into two phenotypic classes. One class of mutants demonstrated kinetics of growth similar to that of EdTag, with decreased peak titers. The second class of mutants manifested peak titers similar to that of EdTag but had different replication kinetics. Abrogation of V expression led to delayed and markedly prolonged replication. Additionally, thymocyte survival was prolonged and implant architecture was preserved throughout the course of infection. In contrast, massive bystander thymocyte death occurred after infection with EdTag and all other mutants. A mutant which overexpressed V in Vero cells (V+) had the opposite phenotype of the A mutant not expressing V (V-). V+ grew more rapidly than EdTag with 100-fold-greater levels of virus production 3 days after infection. These results suggest that C, V, and the F 5'UTR are accessory factors required for efficient virus replication in vivo. In addition, thymocyte survival after V- infection suggests this protein may play multiple roles in pathogenesis of MV infection of thymus. Since these recombinant mutant viruses grew identically to the parent virus in Vero cells, the data show that thy/liv implants are an excellent model for investigating the determinants of MV virulence.

Implications for macrolide treatment in community-acquired pneumonia. Hopkins CAP Team.

STUDY OBJECTIVES: To identify associated clinical parameters, concurrent respiratory tract infections, and the association between macrolide-based therapy and mortality in patients with community-acquired pneumonia ascribed to atypical. DESIGN: Secondary analysis of prospective, cross-sectional study. SETTING: Tertiary care hospital. PATIENTS: Three hundred eighty-five consecutive patients who were admitted to the Johns Hopkins Hospital from November 11, 1990, through November 10, 1991, and treated for community-acquired pneumonia. RESULTS: An atypical pathogen was identified in 29 of 385 adults (7.5%). A second pathogen was detected in 16 of 29 patients (55.2%) in whom an atypical pathogen was detected, compared with 13 of 137 patients (9.5%) in whom conventional bacterial pathogens were detected (odds ratio, 10.22; 95% confidence interval, 3.7 to 28.8; p<0.0001). During hospitalization, only four patients (13.8%) with detection of an atypical pathogen received at least 7 days of either a macrolide or tetracycline. No patient identified to have an atypical pathogen died. For patients who either provided paired sera or who died, 24 of 197 (12.2%) had atypical pathogens detected. CONCLUSIONS: Despite vigorous study methods, atypical pathogens were uncommon in our hospitalized population. A second concurrent respiratory pathogen was identified for most patients with atypical pneumonia. Although macrolide use was rare in this patient population, mortality was zero for patients in whom an atypical pathogen was detected, affirming that macrolide-based therapy need not be routine in the therapeutic management of community-acquired pneumonia.

Measles virus infection of thymic epithelium in the SCID-hu mouse leads to thymocyte apoptosis.

Mortality from measles is caused mostly by secondary infections associated with the depression of cellular immunity. The mechanism of immune suppression and the role of virus strain differences on the immune system are incompletely understood. SCID-hu mice were used to determine the effects of virulent, wild-type (Chicago-1) and avirulent, vaccine (Moraten) strains of measles virus (MV) on the human thymus in vivo. Chicago-1 replicated rapidly, with a 100-fold decrease in numbers of thymocytes, whereas Moraten replicated slowly, without significant thymocyte death. Productive MV infection occurred not in thymocytes but in thymic epithelial and myelomonocytic cells. Wild-type MV infection of thymic stromata leads to induction of thymocyte apoptosis and may contribute to a long-term alteration of immune responses. The extent of thymic disruption reflects the virulence of the virus, and therefore the SCID-hu mouse may serve as the first small animal model for the study of MV pathogenesis.

Changes within T cell receptor V beta subsets in infants following measles vaccination.

Measles produces immune suppression which contributes to an increased susceptibility to other infections. Recently, high titered measles vaccines have been linked to increased long-term mortality among some female recipients. Because the mechanisms by which wild-type or attenuated live-vaccine strains of measles virus alter subsequent immune responses are not fully understood, this prompted an examination of the changes within the peripheral blood T cell receptor V beta repertoire following measles immunization. Twenty-four 6- and 9-month-old infants were studied at 2 weeks and 3 months following immunization by semiquantitative reverse transcription-polymerase chain reaction. There was a significant increase in V beta 2 expression (P less than 0.05), and a decrease in the V beta 4 subset (P less than 0.03) 2 weeks following vaccination with subsequent return to baselines at 3 months in vaccine recipients who seroconverted. These data suggest that measles virus may affect immune responses in part by altering the T cell receptor repertoire.

Hantavirus serologies in patients hospitalized with community-acquired pneumonia.

In many patients, the etiology of community-acquired pneumonia is not known but may be caused by previously undescribed pathogens in some cases. The recently identified hantavirus Sin Nombre (SN) causes hantavirus pulmonary syndrome. Because sporadic cases have occurred outside the range of its reservoir (the deer mouse Peromyscus maniculatus), an investigation sought to determine whether hantaviruses contributed to cases of community-acquired pneumonia in a large Baltimore hospital. Acute-phase sera from 385 hospitalized patients with pneumonia were examined using an IgG ELISA technique with antigens prepared from several hantaviruses: prototype Hantaan (HTN), Seoul (SEO), Puumala (PUU), Convict Creek (HN107), and SN. Of 385 sera, 8 (2.1%) showed some reactivity with one or more HTN, SEO, or PUU antigens but none had detectable specific IgM antibodies. No sera were reactive with SN or HN107 antigens. Thus, hantaviruses are an uncommon cause of community-acquired pneumonia in the Baltimore area.

Immunodeficiency and elevated CD4 T lymphocyte counts in two patients coinfected with human immunodeficiency virus and human lymphotropic virus type I.

We describe two patients who were coinfected with human immunodeficiency virus (HIV) and human T-cell lymphotropic virus (HTLV) type I. They had clinical evidence of immunodeficiency (anergy, oral candidiasis, and disseminated herpes zoster) despite having elevated CD4 T lymphocyte counts (range, 2,450-5,292/mm3). We conclude that CD4 lymphocyte counts may not be reliable markers of immunologic competence in patients coinfected with HIV and HTLV-I.

Community-acquired pneumonia: impact of immune status.

This cross-sectional and prospective one year study evaluated adults admitted to an inner city hospital with community-acquired pneumonia. The study used extensive diagnostic methods to evaluate the etiologies of community-acquired pneumonia in hospitalized patients with differing immunologic status. Of 385 study patients, concurrent problems associated with immunosuppression were noted in 221 (57%) patients, 180 of whom were human immunodeficiency virus (HIV)-infected. The five most common causes of community-acquired pneumonia were: Streptococcus pneumoniae, Pneumocystis carinii, aspiration, Hemophilus influenzae, and gram-negative bacilli. Only 8.3% of patients had either Legionella, Chlamydia pneumoniae or Mycoplasma pneumoniae. Despite use of state-of-the-art diagnostic techniques, no diagnosis was made in 46 of 180 (25.6%) HIV-infected patients, 56 of 164 (34.1%) immunocompetent patients, and 20 of 41 (48.8%) non-HIV-infected immunosuppressed patients. The diagnostic yield of pre-antibiotic sputum culture for conventional bacteria was 99/155 (63.9%) compared to 52 of 169 patients (32.7%) with adequate post-antibiotic sputum culture (p < 0.0001). Although S. pneumonia continues to be the most commonly identified etiologic agent of community-acquired pneumonia, it is surpassed by P. carinii in the HIV-infected patient population. The apparent decline in the frequency of S. pneumoniae in our series presumably reflects administration of antibiotics prior to procurement of sputum culture. The paucity of atypical agents in this study support the current American Thoracic Society guidelines for selective use of macrolide therapy in immunocompetent adults hospitalized with community-acquired pneumonia.(ABSTRACT TRUNCATED AT 250 WORDS)

Diagnosis of Chlamydia pneumoniae infection in patients with community-acquired pneumonia by polymerase chain reaction enzyme immunoassay.

We conducted a prospective study of 385 patients who had community-acquired pneumonia with use of a modified polymerase chain reaction (PCR) assay that detects amplified DNA by enzyme immunoassay (EIA). We used PCR-EIA to improve detection of Chlamydia pneumoniae infection and to differentiate C. pneumoniae infection from other chlamydial infections. Cultures of throat swab specimens from four patients yielded Chlamydia species (C. pneumoniae, one patient; Chlamydia species, two patients; and C. psittaci, one patient). C. pneumoniae was repeatedly detected by PCR-EIA for thirteen (3.4%) of these 385 patients. Six of these 13 patients were infected with the human immunodeficiency virus. Ten (76.9%) of the patients who were positive by PCR-EIA had IgG titers of > or = 1:16, and two (15.4%) of the 13 patients had IgG titers of < 1:16; no sera was available in one case. Other pathogens were recovered in eight (61.5%) of the 13 cases in which C. pneumoniae was detected by PCR-EIA. In addition, for 46 (11.9%) of the 385 patients the titers of antibody were considered diagnostic of C. pneumoniae infection; however, as 36 of the 46 patients were infected with the human immunodeficiency virus (which may have affected their serological response to C. pneumoniae), interpretation of these titers was problematic. As PCR-EIA was more sensitive than was culture for detecting C. pneumoniae infection in this study, this method may be a valuable tool for the prompt diagnosis of this infection.