Giora Gottesman

Genotypic variation of HIV-1 reverse transcriptase and protease: comparative analysis of clade C and clade B.

Objective To compare drug-resistant variants from untreated (naive) and treated patients infected with clade B or C virus. Methods Consecutive samples (165) from patients throughout Israel were analyzed. All those in the treated group were failing highly active antiretroviral therapy. Results There were 78 clade C (20 naive) and 87 clade B (14 naive) with significant differences in the prevalence of known drug-resistance mutations between the clades: in naive patients in the protease region M36I 7% and 95% (P < 0.0001), K20R 0% and 27% (P = 0.063), A71V 18% and 0% (P = 0.063), M46I 0% and 13%, and V77I 18% and 0% (P = 0.063), respectively, and in the reverse transcriptase region A98G/S 0% and 20% (P = 0.12), respectively. Most clade C viruses also showed significant differences from clade B consensus sequence at additional protease sites: R41K 100%, H69K/Q 85%, L89M 95% and I93L 80% (P < 0.0001). There were also significant differences (P < 0.03 to < 0.0001) in treated patients in clades B and C: in the protease region L10I 40% and 12%, M36I 26% and 95%, L63P 67% and 40%, A71I 38% and 7%, G73I and V77I 18% and 0%, I84V 16% and 3%, and L90M 40% and 12%, respectively; in the reverse transcriptase M41L 41% and 17%, D67N 41% and12%, K70R 30% and 7%, T215Y 48% and 29%, K219Q 21% and 7%, and A98G/S 3% and 24%, respectively. Conclusion Significantly differences between clade B and C viruses may be associated with development of differing resistance patterns during therapy and may affect drug utility in patients infected with clade C.

Chronic granulomatous disease in Israel : Clinical, functional and molecular studies of 38 patients

Chronic granulomatous disease (CGD) is an innate immunodeficiency due to a genetic defect in one of the NADPH-oxidase components. In the course of 21 years, 38 Israeli CGD patients were diagnosed with 17 gene mutations, seven of which were new. Clinical, functional, and molecular studies were accomplished. Although X-linked recessive (XLR)-CGD is worldwide the most common genotype of the disease (~70%), in our study only 11 patients (29%) suffered from XLR-CGD. In Israel, the higher incidence of the autosomal recessive (AR) form of CGD (63%) may be related to consanguineous marriages. In three patients (8%), all four proteins of the NADPH oxidase were present. Severe clinical expression was found both in the XLR and AR forms, but in general a milder disease was evident in AR-CGD, particularly in patients with p47(phox) deficiency. Despite early and aggressive therapy, a mortality rate of 26% was noted. Given that bone-marrow transplantation was successful in five of seven patients, it is recommended to perform it as early as possible before tissue damage is irreversible.

Severe Coxsackie virus B infection in preterm newborns treated with pleconaril

Four preterm newborn infants with severe multisystem Coxsackie virus B infection were treated with an oral suspension of pleconaril (5xa0mg/kg per day). The patients had myocarditis, fulminant hepatitis, meningoencephalitis and disseminated intravascular coagulopathy. All four infants recovered, and no adverse effects of the treatment were noted. Conclusion: pleconaril needs to be comprehensively evaluated in this population.

CHILDHOOD BRUCELLOSIS IN ISRAEL

BACKGROUNDnBrucellosis has become a major medical problem in Israel particularly in the Muslim Arab population.nnnMETHODSnEighty-eight children with acute brucellosis are described. Sixty-seven were studied retrospectively during 1987 through 1988, and 21 children were studied prospectively during 1989 through 1992. Epidemiologic, clinical and laboratory features were evaluated, and the outcome of 4 antimicrobial regimens are compared.nnnRESULTSnAlthough the clinical manifestation varied, the classical triad of fever (91%), arthralgia or arthritis (83%) and hepato- and/or splenomegaly (63%) characterized most patients. Sixty-one percent of the children had elevated liver enzymes. Brucella melitensis was isolated from 61% of blood cultures. The relapse rate in patients who were treated with monotherapy (doxycycline) was 43% compared with 14% with regimens of combined therapy with rifampin and doxycycline, streptomycin and doxycycline or rifampin and trimethoprim-sulfamethoxazole (P < 0.049). Eleven children (33%) who were treated for 3 weeks had relapse compared with 1 patient (3.5%) treated for 4 weeks or longer. The total relapse or reinfection rate was 20%. All patients with relapse recovered after a second course of antibiotic therapy. During the 2 years of follow-up one child progressed to chronic osteomyelitis.nnnCONCLUSIONSnCombination therapy and extending treatment for 4 weeks or longer gave significantly better results than monotherapy or shorter courses of therapy and resulted in fewer relapses.

The Clinical Spectrum of Zika Virus in Returning Travelers

INTRODUCTIONnThe clinical spectrum of Zika virus had, to date, been described in small series from endemic/epidemic countries and is not well established.nnnMETHODSnWe describe the clinical manifestations of laboratory-proven Zika virus infection in Israeli travelers during December 2015-February 2016, and review all published cases of travel-related Zika virus.nnnRESULTSnDuring the study period, 8 returning Israeli travelers were diagnosed with Zika virus infection. In addition, 41 published cases were included, mostly from Latin America to Europe and North America. Overall, 65.3% were diagnosed by polymerase chain reaction. Rash was the most frequent symptom, present in 95.7% of cases, followed by fever and arthralgia. Conjunctivitis was present in 53.1%; however, only 40.3% presented with a triad of conjunctivitis, fever, and rash. Less frequent symptoms included dysgeusia and nightmares, which, together with arthralgia, persisted for several weeks in some travelers.nnnCONCLUSIONSnZika virus clinical picture in travelers is diverse. Prolonged symptoms may occur.

Zika Virus Disease in Traveler Returning from Vietnam to Israel.

To the Editor: On February 1, 2016, the World Health Organization designated the Zika virus disease outbreak in Latin America as a Public Health Emergency of International Concern (1). Genetic and epidemiological data suggest that Zika virus had been present in Southeast Asia since the 1940s (2); however, the disease burden and geographic extent of Zika virus disease in Asia are not clear. Occasional cases in some Asian countries, mostly in returning travelers, have recently been documented (3–5); however, as of February 2016, none were in Vietnam.

Enteric Gram-Negative Sepsis Complicating Rotavirus Gastroenteritis in Previously Healthy Infants:

Rotavirus is the most common cause of diarrhea in infants and young children worldwide, accounting for approximately one third of cases of severe diarrhea requiring hospitalization.1 In developing countries, rotavirus infections are responsible for 800,000 deaths per year from diarrhea.1 Although an association between enteric gram-negative rods (EGNR) bacteremia and gastrointestinal pathologies (including gastroenteritis) in children has been described,2,3 we could not find in the English literature a description of EGNR bacteremia as a complication of rotavirus infection. In this article we describe 3 cases of previously healthy infants who developed EGNR sepsis during rotavirus gastroenteritis. The pathogenesis and the clinical features are discussed.

Diminished selection for thymidine-analog mutations associated with the presence of M184V in Ethiopian children infected with HIV subtype C receiving lamivudine-containing therapy.

Background: We retrospectively studied the effect of the lamivudine-induced reverse transcription mutation M184V on selection of thymidine analog mutations (TAMs) in HIV subtype C-infected children and on clinical outcome. Methods: We genotyped 135 blood samples from 55 children. TAMs accumulation, viral load and clinical outcome were compared in children maintained on zidovudine/stavudine + lamivudine + protease inhibitor/nonnucleoside reverse transcriptase inhibitor (PI/NNRTI) despite loss of viral suppression and in children treated with, or switched to, other nucleoside reverse transcriptase inhibitors (NRTIs). Drug susceptibility and replication capacity of selected samples were measured. Results: M184V developed in 18 of 22 of children who had received only zidovudine/stavudine + lamivudine + PI/NNRTI during a mean of 23.2 ± 3.2 months versus in 3 of 14 children treated with other drugs and/or having multiple regimen changes (P = 0.001). TAMs appeared, respectively, in 2 of 22 versus 12 of 14 (P < 0.0001). The 2 groups did not differ significantly in baseline HIV-RNA or CD4 count, sampling time, and follow-up period. In M184V-containing samples, we found large reductions in susceptibility to lamivudine and emtricitabine but not to other NRTIs. When T215Y was present without M184V, susceptibility to zidovudine was reduced 8-fold. When both M184V + T215Y occurred, susceptibility to zidovudine was substantially increased. Average inhibition concentration 50 values were similar to those documented in the Stanford database for subtype B HIV with these mutation patterns. Conclusions: Maintaining a thymidine analog + lamivudine-based regimen reduced accumulation of TAMs and increased zidovudine susceptibility. This is likely the result of an increased susceptibility to thymidine analog (zidovudine) in the context of M184V documented here for the first time in subtype C-infected children. This retrospective study supports the strategy of maintaining lamivudine-containing therapy in subtype C-infected children. This strategy may be beneficially applied in the treatment of children in Africa, where thymidine analog + lamivudine-based regimen became available recently but further options are limited.

Differential impact of pneumococcal conjugate vaccines on bacteremic pneumonia versus other invasive pneumococcal disease.

Background: Bacteremic pneumonia (BP) accounts for ~35% of invasive pneumococcal disease (IPD) in young children. Our aims were to compare age, seasonal and serotype distribution of BP versus non-BP IPD and to determine whether the impact of the sequential 7/13-valent pneumococcal conjugate vaccine (PCV7/PCV13) introduction on disease incidence differed between BP and non-BP IPD in children <5 years of age. Methods: A nationwide, prospective, population-based, active surveillance (July 2004–June 2013) was conducted. All IPD episodes were included. PCV7 was introduced to the Israeli National Immunization Plan in July 2009 and has been replaced by PCV13 since November 2010. Results: In all, 983 (36.8%) BP and 1687 (63.2%) non-BP IPD episodes were recorded. A higher proportion of BP than that of non-BP IPD episodes (42.0% vs. 20.7%; P < 0.001) occurred in children >24 months old. Seasonality differed between BP and non-BP IPD, with yearly earlier peaks of non-BP IPD. The proportion of the 5 additional PCV13 serotypes (1, 3, 5, 7F and 19A) was higher in children with BP versus non-BP IPD (39.6% vs. 23.6%; P < 0.01). Shortly after PCV7 introduction, non-BP IPD rate was significantly reduced but that of BP was not. However, PCV13 introduction resulted in rapid reduction of BP rate, with a further reduction of non-BP IPD. Conclusion: The differences in age distribution, seasonality and serotype distribution between BP and non-BP IPD suggest that the pathogenesis of these 2 entities is not identical and resulted in different impact rate dynamics after PCV7 and PCV13 introduction.

Actinobacillus actinomycetemcomitans endocarditis in a 1.5 year old toddler

The authors report a 1.5-year-old girl who developed Actinobacillus actinomycetemcomitans (AA) endocarditis involving the pulmonic valve. She had a congenital cardiac abnormality, but no history of dental manipulation. The case illustrates an uncomplicated course with three unique features; the youngest reported infant with endocarditis caused by AA with vegetation on the pulmonic valve. She underwent a benign course with complete recovery. The authors report a 1.5-year-old girl who developed AA endocarditis involving the pulmonic valve. She had a congenital cardiac abnormality, but no history of dental manipulation. The case illustrates an uncomplicated course with three unique features; the youngest reported infant with endocarditis caused by AA with vegetation on the pulmonic valve. She underwent a benign course with complete recovery.