Carlos Fritzsche

Immunization in the adult immunocompromised host

The number of patients with impaired immune response has been steadily increasing within the last years, not only with the onset of the AIDS epidemic, but also due to increasing numbers of subjects on immunosuppressive therapies. These patients are at an increased risk for infections, many of which are preventable by immunization. Inactivated vaccines are generally safe in subjects with underlying immunosuppression. However, immune response and protection may be hampered, depending on the extent of immunosuppression. In contrast, live vaccines such as yellow fever, measles, rubella, herpes zoster, and cholera may lead to severe reactions in immunocompromised patients and have been shown to deteriorate some immune-mediated diseases such as multiple sclerosis. Data on the efficacy of vaccines in biological therapies is scarce. Where necessary vaccines should be updated before immunosuppressive therapies are started. To improve the vaccination status several guidelines exist for immunosuppressed patients at risk such as those with rheumatic diseases, asplenia or solid organ and hematopoietic stem cell transplantation.

Diarrhea caused by primarily non-gastrointestinal infections

Infectious diseases that do not primarily affect the gastrointestinal tract can cause severe diarrhea. The pathogenesis of this kind of diarrhea includes cytokine action, intestinal inflammation, sequestration of red blood cells, apoptosis and increased permeability of endothelial cells in the gut microvasculature, and direct invasion of gut epithelial cells by various infectious agents. Of the travel-associated systemic infections presenting with fever, diarrhea occurs in patients with malaria, dengue fever and SARS. Diarrhea also occurs in patients with community-acquired pneumonia, when it is suggestive of legionellosis. Diarrhea can also occur in patients with systemic bacterial infections. In addition, although diarrhea is rare in patients with early Lyme borreliosis, the incidence is higher in those with other tick-borne infections, such as ehrlichiosis, tick-borne relapsing fever and Rocky Mountain spotted fever. Unfortunately, it is often not established whether diarrhea is an initial symptom or develops during the course of the disease. The real incidence of diarrhea in some infectious diseases must also be questioned because it could represent an adverse reaction to antibiotics.

High prevalence of Pneumocystis jirovecii colonization among patients with autoimmune inflammatory diseases and corticosteroid therapy

Background: Patients with autoimmune inflammatory diseases (AID) account for 13–36% of Pneumocystis pneumonia (PCP) cases in human immunodeficiency virus (HIV)-negative patients. Up to 88% of PCP cases in HIV-negative patients are associated with prior steroid treatment. Pulmonary colonization with Pneumocystis in HIV-negative patients is associated with corticosteroid therapy in up to 75% of cases. The aim of this study was to detect the prevalence and risk factors of pulmonary colonization with Pneumocystis jirovecii in patients with AID receiving corticosteroid therapy in comparison with healthy control persons. Methods: We investigated induced sputa of 102 patients with AID on current corticosteroid treatment and of 117 healthy controls for the presence of P. jirovecii using polymerase chain reaction (PCR). Results: Twenty-nine patients (28.5%) with AID were colonized with P. jirovecii compared to three healthy controls (2.6%) [p < 0.001, odds ratio (OR) 15.10, 95% confidence interval (CI) 4.43–51.38]. In patients with AID, age over 60 years was significantly associated with colonization (p = 0.015, OR 3.19, 95% CI 1.27–7.94). Multivariate analysis showed age to be independently associated with the colonization of P. jirovecii (95% CI 1.002–1.092). Neither duration nor dose of corticosteroid therapy nor immunosuppressive co-medication had a significant influence on P. jirovecii colonization. Conclusion: Patients with AID, especially those over 60 years of age, display a high prevalence of colonization with P. jirovecii. Clinicians should be aware of this and ensure that they consider the possibility of PCP when pulmonary symptoms arise in these patients.

Calculation of Direct Antiretroviral Treatment Costs and Potential Cost Savings by Using Generics in the German HIV ClinSurv Cohort.

Background/Aim of the Study The study aimed to determine the cost impacts of antiretroviral drugs by analysing a long-term follow-up of direct costs for combined antiretroviral therapy, cART,-regimens in the nationwide long-term observational multi-centre German HIV ClinSurv Cohort. The second aim was to develop potential cost saving strategies by modelling different treatment scenarios. Methods Antiretroviral regimens (ART) from 10,190 HIV-infected patients from 11 participating ClinSurv study centres have been investigated since 1996. Biannual data cART,-initiation, cART-changes, surrogate markers, clinical events and the Centre of Disease Control- (CDC)-stage of HIV disease are reported. Treatment duration was calculated on a daily basis via the documented dates for the beginning and end of each antiretroviral drug treatment. Prices were calculated for each individual regimen based on actual office sales prices of the branded pharmaceuticals distributed by the license holder including German taxes. Results During the 13-year follow-up period, 21,387,427 treatment days were covered. Cumulative direct costs for antiretroviral drugs of €812,877,356 were determined according to an average of €42.08 per day (€7.52 to € 217.70). Since cART is widely used in Germany, the costs for an entire regimen increased by 13.5%. Regimens are more expensive in the advanced stages of HIV disease. The potential for cost savings was calculated using non-nucleotide-reverse-transcriptase-inhibitor, NNRTI, more frequently instead of ritonavir-boosted protease inhibitor, PI/r, in first line therapy. This calculation revealed cumulative savings of 10.9% to 19.8% of daily treatment costs (50% and 90% substitution of PI/r, respectively). Substituting certain branded drugs by generic drugs showed potential cost savings of between 1.6% and 31.8%. Conclusions Analysis of the data of this nationwide study reflects disease-specific health services research and will give insights into the cost impacts of antiretroviral therapy, and might allow a more rational allocation of resources within the German health care system.

Hepatitis B and C: neglected diseases among health care workers in Cameroon

BACKGROUND Healthcare workers (HCW) are at risk of acquiring blood-borne viral infections, particularly hepatitis B (HBV), hepatitis C (HCV), and HIV, especially in high endemic regions such as sub-Saharan Africa. METHODS Sera from 237 hospital workers in Southwest Cameroon were tested for anti-hepatitis B core antigen (anti-HBc), hepatitis B surface antigen (HBsAg), anti-hepatitis B surface antigen (anti-HBs), anti-HCV and (on a voluntary basis) for anti-HIV. Information on pre-study testing for HBV, HCV and HIV and pre-study HBV vaccination status was collected from these individuals. RESULTS The pre-study testing rate among participating hospital staff for HBV was 23.6% (56/237), for HCV 16% (38/237), and for HIV 91.6% (217/237). The pre-study HBV vaccination rate was 12.3% (29/237). Analysis of anti-HBc revealed that 73.4% (174/237) of the hospital staff had been infected by HBV. Active HBV infection (HBsAg positivity) was detected in 15 participants. Anti-HCV was found in four of 237 participants, HIV antibodies were detected in four of 200 participants tested. CONCLUSION HBV and HCV are neglected diseases among HCW in sub-Saharan Africa. The vaccination rate against HBV was very low at 12.3%, and therefore anti-HBc testing should be mandatory to identify HCW requiring HBV vaccination. Testing for HBV and routine HBV vaccination for HBV-negative HCW should be strongly enforced in Cameroon.

Borrelia burgdorferi and Anaplasma phagocytophilum coinfection.

To the Editor: In central Europe, Anaplasma phagocytophilum and Borrelia burgdorferi are transmitted by the hard tick Ixodes ricinus (1). Acute human granulocytic ehrlichiosis (HGE) caused by A. phagocytophilum has rarely been documented in Europe (2). Typical symptoms include fever, headache, myalgia, leukopenia, thrombocytopenia, and abnormal liver function test results. The serologic prevalence ranges from 1.9% to 14% in Germany (1), while clinically apparent infections of HGE have not been reported. Acute Lyme borreliosis in Europe is associated with erythema migrans (3), recognized in up to 90% of patients (4). Erythema migrans may be accompanied by systemic symptoms such as fever, fatigue, myalgia, arthralgia, headache, or stiff neck (3,4). In southern Germany, an incidence of 111 per 100,000 inhabitants has been reported (4). A 60-year-old woman from northern Germany was admitted with temperature of <40°C, headache, myalgia, and generalized weakness that had begun 6 days earlier. She had noticed an erythema migrans on her right thigh 4 days before she sought treatment. At admission, a tender, 5 × 8 cm rash and a central papule were seen, but without central clearing. The clinical examination was otherwise normal. Three weeks earlier she had been on a trekking tour in Austria and Slovenia but had not been aware of any tick bites. The leukocyte count was 3,030/μL (normal 4,000–9,000), with 65% neutrophils, 24% lymphocytes, 10% monocytes, and 1% lymphoid cells. The following results were observed: platelets 127,000/μL (normal 150,000–450,000), aspartate aminotransferase 108 U/L (normal <31), alanine aminotransferase 154 U/L (normal <34), gamma-glutamyl transferase 98 U/L (normal <38), lactate dehydrogenase 317 U/L (normal <247), alkaline phosphatase 314 U/L (normal <237), direct bilirubin 4.7 μmol/L (normal <3.4), C-reactive protein 132 mg/L (normal <5), and neopterin 30 nmol/L (normal <10). All other routine laboratory parameters were normal. May-Grunwald-Giemsa (Fluke, Neu Ulm, Germany)–stained whole-blood smears did not show Anaplasma initially and during follow-up. On admission serum antibody tests were negative for A. phagocytophilum, B. burgdorferi, hepatitis A, B, and C, human herpes virus 6, herpes simplex virus 1 and 2, Epstein-Barr virus, cytomegalovirus, and tickborne encephalitis virus. Because Lyme borreliosis and possible HGE were suspected, the patient was treated with oral doxycycline 200 mg once daily for 3 weeks. Within 4 days after initiation of treatment, the patient recovered completely; thrombocytes and leukocytes had normalized. Liver enzyme levels were still elevated but had normalized at a follow-up examination 28 days later. Four days after the initial examination, results for Borrelia-specific immunoglobulin M (IgM) antibodies were positive, while results for IgG antibodies remained negative (Table). Four weeks after the onset of symptoms, a test for A. phagocytophilum–specific IgM antibodies was positive and IgG was negative thereafter (Table). An initial EDTA blood sample that was stored frozen and examined retrospectively as well as follow-up EDTA blood samples were negative for A. phagocytophilum in a polymerase chain reaction (PCR) assay. Table Results of serologic tests at diagnosis and during follow-up* One year after initial examination, results for Borrelia-specific IgM antibodies were positive and results for A. phagocytophilum-specific antibodies were negative (Table). Although HGE has not been reported in Germany, a coinfection with B. burgdorferi and A. phagocytophilum should be considered in patients with erythema migrans and atypical changes for Lyme borreliosis such as fever, leukopenia, thrombocytopenia, and elevated liver function test results. The patient had traveled to an area where both tickborne pathogens, A. phagocytophilum and B. burgdorferi, were endemic. Erythema migrans and antibody follow up suggested Lyme borreliosis. High fever, leukopenia, thrombocytopenia, and elevated liver enzyme levels indicated HGE. Anaplasma PCR was negative, possibly because blood samples were tested retrospectively after 3 months of storage at –20°C. However, a commercially available indirect fluorescent antibody assay was able to demonstrate seroconversion of HGE-specific IgM antibodies 1 month after the initial onset of symptoms. According to manufacturers information, specificity ranged from 97.5% to 100%; sensitivity was 71.4% at 60 days after A. phagocytophilum infection. A. phagocytophilum IgG antibodies were not detected during follow-up, likely because of prompt treatment with doxycycline. Wormser et al. (5) suggested that Borrelia-specific antibodies might indicate false-positive results in patients with HGE infection. Our case, however, meets criteria of a newly acquired infection with B. burgdorferi sensu lato, with an erythema migrans and seroconversion of Borrelia-specific IgM antibodies.

Safety and immunogenicity of a trivalent single dose seasonal influenza vaccine containing pandemic A(H1N1) antigen in younger and elderly subjects: a phase III open-label single-arm study.

BACKGROUND During the pandemic of the 2009 A(H1N1) influenza virus strain, 20-40% of the population in some areas were infected. Infection with A(H1N1) may be mild, with an average case fatality rate below 0.25%, but severe disease is not limited to patients with underlying medical conditions. Since A(H1N1) is expected to continue to circulate it is included in the seasonal influenza vaccines for the 2010-2011 winter season. We investigated the immunogenicity and safety of a preservative-free non-adjuvanted seasonal trivalent influenza vaccine. METHODS We conducted a single center single-arm study involving 142 subjects (77 adults of 18-60 years and 65 subjects 61 years and above) to test the immunogenicity, safety, and tolerability of a trivalent split influenza vaccine. The vaccine contained 15μg of hemagglutinin of each of the virus strains recommended for the 2010-2011 northern hemisphere winter season (A/California/7/2009 (H1N1)-like strain; A/Perth/16/2009 (H3N2)-like strain; B/Brisbane/60/2008-like strain) in a non-adjuvanted preservative-free formulation. Antibody response to each antigen was measured by hemagglutination inhibition (HI) 21 days after immunization. Subject diary cards and additional telephone interviews were used to assess the safety profile. RESULTS By day 21 after the vaccination, seroconversion, or a 4-fold antibody increase in HI antibody titers, was detectable against A(H1N1) in 84% and 75% of younger and older adults, against A(H3N2) in 80% and 57%, and against the B influenza strain in 61% and 33%. HI antibody titers of 40 or more were observed against A(H1N1) in 99% and 90% of younger and older adults, against A(H3N2) in 100% and 90%, and against the B influenza strain in 91% and 78%. Pre-vaccination antibody titers were protective against A(H1N1), A(H3N2), and B in 26%, 44% and 33%, respectively of the adults below 61 years and in 27%, 54% and 44% of the subjects of 61 years and above. Local and systemic reactions were more common in younger than in older subjects and the most frequently reported reactions were pain at the injection site (36%), myalgia (24%), and fatigue (15%). Five percent elderly subjects and 1% of younger subjects had mild or moderate unsolicited adverse events such as prolonged ecchymosis or night sweats that resolved within 7 days after vaccination. CONCLUSIONS This single dose trivalent seasonal influenza vaccine generated protective antibodies to all three viral strains and had an acceptable safety profile in both younger and older adults (ClinicalTrials.gov identifier: NCT01147081).

Pneumocystis jirovecii colonization among renal transplant recipients

Renal transplant recipients are at risk of developing Pneumocystis pneumonia (PcP), especially in the first 2 years after transplantation, with a mortality rate of up to 50%. No data are available on pulmonary colonization with Pneumocystis jirovecii in renal transplant recipients. The aim of this study was to determine the prevalence of pulmonary colonization with Pneumocystis jirovecii in renal transplant recipients and to find related risk factors.

Clinical Trial to Evaluate the Safety and Immunogenicity of a Trivalent Surface Antigen Seasonal Influenza Vaccine Produced in Mammalian Cell Culture and Administered to Young and Elderly Adults with and without A(H1N1) Pre-Vaccination

Vaccination against influenza is an important means of reducing morbidity and mortality in subjects at risk. The prevalent viral strains responsible for seasonal epidemics usually change annually, but the WHO recommendations for the 2011/2012-season in the Northern hemisphere included the same antigens as for the previous season. We conducted a single-center, single-arm study involving 62 younger (18–60 years) and 64 older (>60 years) adults to test the immunogenicity, safety and tolerability of a trivalent surface antigen, inactivated influenza vaccine produced in mammalian cell-culture. The vaccine contained 15 µg hemagglutinin of each of the virus strains recommended for the 2011–2012 Northern hemisphere winter season (A/California/7/09 (H1N1)-; A/Perth/16/09 (H3N2)-; B/Brisbane/60/08-like strain) in a non-adjuvanted preservative-free formulation. Antibody response was measured by hemagglutination inhibition 21 days after immunization. Adverse events and safety were assessed using subject diary cards and telephone interviews. Seroconversion or a 4-fold antibody increase in antibody titers was detectable against A(H1N1) in 68% of both younger and older adults, against A(H3N2) in 53% and 27%, and against the B influenza strain in 35% and 17%. Antibody titers of 40 or more were observed against A(H1N1) in 87% and 90% of younger and older adults, against A(H3N2) in 98% and 98%, and against the B influenza strain in 93% and 90%. Pre-vaccination antibody titers were protective against A(H1N1), A(H3N2) and B in 38%, 58% and 58%, respectively, of younger and in 43%, 88% and 70% of older adults. Among subjects with previous A(H1N1) vaccination only 48% of younger and 47% of older adults had protective A(H1N1) antibodies at inclusion. Adverse reactions were generally mild. The most frequently reported reactions were pain at the injection site, myalgia and fatigue. The vaccine generated protective antibodies against all three viral strains and had an acceptable safety profile in both younger and older adults. Trial Registration ClinicalTrials.gov NCT01422512

Pneumocystis jiroveci Dihydropteroate Synthase Gene Mutations at Codon 171 but Not at Codons 55 or 57 Detected in Germany

NOTE. PR, present report; TMP-SMZ, trimethoprim-sulfamethoxazole. in Missouri and other areas where the disease is not endemic needs review. The national Lyme disease surveillance case definition was developed nearly 10 years ago [3], and a great amount of relevant new scientific evidence regarding Lyme disease and southern tick–associated rash illness has accumulated since that time. The findings of Wormser et al. [6, 9] argue in favor of establishing more rigorous inclusion criteria for patients who present with erythema migrans–like lesions in areas where Lyme disease is not endemic.