Genetical analysis of all Danish patients diagnosed with chronic granulomatous disease.

Chronic granulomatous disease (CGD) is a rare inherited disorder of the innate immune system caused by a defect in NADPH oxidase, leaving the granulocytes unable to kill invading microorganisms. CGD is caused by mutation in one of the five components gp91phox, p22phox, p47phox, p67phox and p40phox, encoded by the X-linked CYBB gene and the autosomal CYBA, NCF1, NCF2 and NCF4 genes respectively. We have collected samples from all Danish patients with known CGD followed in the clinic or newly diagnosed during a 5-year period, a cohort of 27 patients, and characterized them genetically. The cohort includes 10 male patients with X-linked CGD and one female with extremely lyonized expression of a defective CYBB allele. Six patients had mutation in CYBA. Seven of 10 patients with a defect in NCF1 were homozygous for the common GT deletion, one was compound heterozygous for the GT deletion and a splice-site mutation, and two patients were homozygous for a nonsense mutation in exon 7. Three novel mutations were detected, a deletion of exon 6 in CYBA, a duplication of exon 8-13 in CYBB and a splice site mutation in intron 7 of NCF1.

Low thymic size in preterm infants in the neonatal intensive care unit, a possible marker of infection? A prospective study from birth to 1 year of age.

AIM: To study the growth of the thymus in preterm infants. METHODS: Ultrasonographic thymic size (Ti) was studied in 80 preterm infants (gestational age 24-36 weeks) from birth to discharge from the neonatal intensive care unit (NICU). Thirty-three of these infants were followed to 1 year of age. RESULTS: At birth, the median Ti was 5.2 compared with 11.8 in term infants. At discharge, the median Ti was 10.0 and not significantly different from Ti in term infants at birth (p = 0.22). The size of the thymus was significantly associated with postmenstrual age and weight (both p < 0.01). Infections during admission were negatively associated with the size of the thymus (p < 0.01). During the first 3 months after discharge, preterm infants had a significantly higher frequency of infections than did term infants (p = 0.002); hereafter, the preterm infants had significantly fewer infections than term infants (p = 0.002). The median Ti in preterm infants and term infants at 1 year of age was 21.1 and 17.3, respectively. This difference was not statistically significant (p = 0.41). CONCLUSIONS: Growth of thymus was not compromised by preterm birth. Ti is negatively associated with the frequency of infections in preterm neonates submitted to NICU.

Prevention of mother-to-child transmission of HIV in Denmark, 1994-2008.

OBJECTIVES: The aim of this study was to describe trends in the management of pregnancies in HIV-infected women and their outcomes over a 14-year period in Denmark on a national basis. METHODS: The study was a retrospective cohort study of all HIV-infected women in Denmark giving birth to one or more children between 1 June 1994 and 30 June 2008. RESULTS: We identified 210 HIV-infected women with 255 pregnancies, ranging from 7 per year in 1995 to 39 per year in 2006. Thirty per cent of the women were Caucasian and 51% were Black African. Knowledge of HIV status before pregnancy increased from 8% (four of 49) in 1994-1999 to 80% (164 of 206) in 2000-2008. Only 29% (53 of 183) of the women chose to consult an infectious disease specialist when planning pregnancy, while 14% (27 of 199) received assistance with fertility. The proportion of women on antiretroviral therapy (ART) increased from 76% (37 of 49) in 1994-1999 to 98% (201 of 206) in 2000-2008. Vaginal deliveries ranged from 0 in 2003 to 35% of pregnancies in 2007. Mother-to-child transmission (MTCT) of HIV decreased from 10.4% in 1994-1999 to 0.5% in 2000-2008. All women giving birth to an HIV-positive child were diagnosed with HIV during or after delivery and did not receive prophylactic ART. CONCLUSIONS: The annual number of HIV pregnancies increased fivefold during this 14-year period and substantial changes in pregnancy management were seen. No woman treated according to the national guidelines, i.e. ART before week 22, intravenous zidovudine (ZDV) during labour, neonatal ZDV for 4 to 6 weeks and no breastfeeding, transmitted HIV to her child.

Problems in identification of Francisella philomiragia associated with fatal bacteremia in a patient with chronic granulomatous disease.

Francisella philomiragia is a rare gram-negative, halophilic coccobacillus with bizarre spherical forms on primary isolation. A case of F. philomiragia bacteremia in a 24-year-old patient with chronic granulomatous disease is reported. Identification of F. philomiragia was problematic with conventional tests but was done correctly and rapidly by kit 16S ribosomal DNA sequencing.

Thymic size in preterm neonates: a sonographic study.

AIM: To assess the variation in size of the thymus in vivo in preterm neonates and to identify relations between thymic size and gestational age (GA), birthweight, occurrence of postnatal infections and maternal alcohol and tobacco intake during pregnancy. METHODS: Eighty preterm neonates with a GA between 24 and 36 wk, and a birthweight between 490 and 4110 g were examined between days 0 and 19 after birth. The thymic size was assessed by sonography as a volume estimate, the so-called thymic index (Ti). The median Ti was 5.2 (1.2-17.9). Ti was positively correlated with birthweight and GA and negatively correlated with occurrence of postnatal infection (p < 0.01, p = 0.03, p = 0.05, R2 = 0.68). A correlation between thymic size and maternal alcohol and tobacco intake was not demonstrated. CONCLUSION: It is possible to assess the size of the thymus by sonography in very low-birthweight and preterm neonates. A normal range for Ti in preterm neonates has been established. The sonographic method is a safe and effective technique for measuring the size of the thymus in preterm infants.

Thymic size in uninfected infants born to HIV-positive mothers and fed with pasteurized human milk.

AIM: To examine the size of the thymus in uninfected infants born to HIV-positive mothers and to study the effects of feeding by human donor milk on the size of the thymus in these infants. METHODS: The absolute and relative thymic size was assessed by sonography as thymic index (Ti), and the Ti/weight-ratio (Ti/w) at birth and at 4 mo of age in 12 healthy uninfected infants born to HlV-infected mothers. All infants were exclusively fed pasteurized donor milk. The results were compared with those obtained from a previous cohort of exclusively breastfed, partially breastfed and exclusively formula-fed infants. RESULTS: At birth the Ti was reduced in infants born to HIV-infected mothers in comparison with that in control infants but this difference disappeared when their birthweights were taken into consideration (Ti/w-ratio). At 4 mo of age the geometric mean Ti of infants fed donor milk was 23.8 and the mean Ti/w-ratio was 4.2. Compared with those of exclusively breastfed infants, the Ti and Ti/w-ratio of infants fed donor milk were significantly reduced (p < 0.01). The Ti/w-ratio increased in donor-milk-fed infants compared with that in the formula-fed infants (p = 0.02). CONCLUSION: At birth the size of the thymus was smaller in uninfected infants of HIV-positive mothers compared with infants of HIV-negative mothers but when birthweight was taken into account this difference disappeared. Feeding by human donor milk seemed to result in an increased size of the thymus at 4 mo of age compared with thymic size in infants that were exclusively formula fed.

Impaired progenitor cell function in HIV-negative infants of HIV-positive mothers results in decreased thymic output and low CD4 counts.

Hematologic and immunologic functions were examined in 19 HIV-negative infants of HIV-positive mothers and 19 control infants of HIV-negative mothers. Control infants were selected to match for gestational age, weight, and mode of delivery. Cord blood was obtained from all infants and used for flow cytometric determination of lymphocyte subsets, including the naive CD4 count. Furthermore, to determine thymic output, cord blood mononuclear cells were used for determination of T-cell receptor excision circles (TRECs). Evaluation of progenitor cell function was done by means of colony-forming cell assay and fetal thymic organ cultures (FTOCs). Lower naive CD4 counts (459.3 +/- 68.9 vs 1128.9 +/- 146.8 cells/microL, P <.001) and reduced thymic output in infants of HIV-positive mothers were found (frequency of CD4(+) cells with TRECs was 3.6% +/- 0.7% compared with 14.3% +/- 2.2% in controls, P <.001). In combination with lower red blood cell counts in infants of HIV-positive mothers, this finding suggested impairment of progenitor cell function. Indeed, progenitors from infants of HIV-positive mothers had decreased cloning efficiency (15.7% +/- 2.6% vs 55.8% +/- 15.9%, P =.009) and seemed to generate fewer T cells in FTOCs. In conclusion, lower numbers of naive CD4(+) cells and reduced thymic output in HIV-negative infants of HIV-positive mothers may be due to impaired progenitor cell function.

Regression of HIV-associated progressive encephalopathy of childhood during HAART.

HIV-associated progressive encephalopathy of childhood is characterized by impaired brain growth, decline in cognitive and neurobehavioral performances, and progressive motoric dysfunction The diagnosis is based on neurological examination, neuropsychological assessment and cerebral CT or MR imaging. While the importance of early use of antiretroviral combination therapy has been emphasized, limited data exist as to the effect of protease inhibitors in children with HIV-associated encephalopathy. We describe the effect of 3-drug antiretroviral combination therapy, including the protease inhibitor nelfinavir, in a 7-y-old girl with vertically acquired HIV infection and late onset progressive encephalopathy.

Tuberculous cellulitis in a child demonstrated by magnetic resonance imaging.

The increasing prevalence of extrapulmonary tuberculosis means that it is important for clinicians to review their knowledge of unusual presentations of mycobacterial infections. Involvement of subcutaneous tissue and skeletal muscle is rare in tuberculosis. Occasionally, infection of soft tissue may be the sole manifestation of tuberculosis. Apart from cases of tuberculous lymphadenitis, the diagnosis of extrapulmonary tuberculosis may be difficult. Modern imaging techniques, such as magnetic resonance imaging, may be helpful in making a differential diagnosis. We present here a case of tuberculous cellulitis in an immunocompetent child and discuss the contribution of MRI in diagnosis.

[Acute transverse myelitis caused by enterovirus]. / Akut transversel myelitis forårsaget af enterovirus.

Enteroviruses comprise a group of commonly encountered small RNA viruses with genetic similarities. We report a case of transverse myelitis associated with an enterovirus infection. By use of PCR, enterovirus-specific RNA sequences were detected in the cerebrospinal fluid and in swabs from the throat and the rectum at the time of admission. Routine cultures and serology gave no other explanation for the clinical condition. The patient was treated with intravenous immunoglobulin and steroids and improved gradually. She was fully recovered 18 months after onset of disease.

[Tuberculous meningitis in children]. / Tuberkuløs meningitis hos børn.

Medical records of six children with tuberculous meningitis were reviewed. The patients were admitted to the paediatric departments in the city and country of Copenhagen between 1983 and 1997. Interpretation of cerebrospinal fluid findings, and difficulties in early recognition of tuberculous meningitis are discussed.

[Occurrence of tuberculosis among children in the area of Copenhagen 1984-1993]. / Tuberkuloseforekomst blandt børn i Københavnsområdet 1984-1993.

This study was undertaken to describe the epidemiology, clinical manifestations and prognosis of childhood tuberculosis in Copenhagen, with special attention to differences between Danish children and children of foreign origin. Medical records for all children with tuberculosis cared for in the hospitals of the Copenhagen area 1984-1993 were reviewed. Sixty-six patients were identified. Sixteen of 20 Danish patients (80%) and 67% of foreign children had respiratory tuberculosis. Tuberculosis located in cervical lymph nodes was found only in children of foreign origin. Five patients had meningitis. The high incidence among foreign children reflects the incidence in their home countries, but poorer living conditions among ethnic minorities in Denmark may facilitate transmission of tuberculosis. Severe manifestations of tuberculosis still occur, even in a low incidence country.

Childhood tuberculosis in a Scandinavian metropolitan area 1984-93.

This study was undertaken to describe the epidemiology, clinical manifestations and prognosis of childhood tuberculosis in Copenhagen, with special attention to differences between Danish children and children of foreign origin. From 1984-93, 66 children, aged 0-14 years, in the Copenhagen area were notified for tuberculosis. More than two-thirds of the children of foreign origin, including 5 patients from Greenland, who were transferred to Denmark for treatment. A close adult contact with contagious tuberculosis was identified in only a few patients born to foreign parents, but more than one-third had travelled to their homeland within 1 y prior to diagnosis. 48 patients (73%) were reported to have only respiratory tuberculosis. Tuberculosis located in cervical lymph glands was the most frequent nonrespiratory manifestation, but was found only in children of foreign origin. Five patients had meningitis. The high incidence among foreign children reflects the incidence in their home countries, but poorer and more crowded living conditions among ethnic minorities in Denmark may also facilitate transmission of tuberculosis. Severe manifestations of tuberculosis still occur, even in a low incidence country.

Treatment of enteritis in chronic granulomatous disease with granulocyte colony stimulating factor.

BACKGROUND: In several diseases there is a relation between deficiency of neutrophil granulocytes and granulomatous lesions. Recently, in glycogen storage disease type Ib, this relation has been supported by the beneficial effect of treatment of enteritis with granulocyte-macrophage colony stimulating factor. AIM: To investigate whether chronic granulomatous disease could be treated according to the same principle. PATIENTS AND METHODS: Inflammatory lesions were monitored in two brothers with chronic granulomatous disease demonstrated by very low superoxide production in neutrophil granulocytes. The two patients were treated with recombinant human granulocyte colony stimulating factor on three occasions when the disease was active. RESULTS: In one patient, remission of an inflamed stenosis of the colon sigmoideum was shown by granulocyte scintigraphy after one month of treatment with granulocyte colony stimulating factor. In the other patient, remission of colon disease of later of a non-malignant tumor in the right lung hilum was shown by colonoscopy and computed tomography scans respectively. CONCLUSION: Remission of inflammatory lesions in two brothers with chronic granulomatous disease was induced by granulocyte colony stimulating factor on three occasions. The mechanism for this effect is now known. The result is similar to the response found in patients with leucocyte deficiency due to glycogen storage disease type Ib.

Secretory IgM and IgA antibodies to respiratory syncytial virus in nasopharyngeal aspirates: a diagnostic supplement to antigen detection.

BACKGROUND: RSV-shedding during an RSV-infection declines dramatically after the first week of infection. It could be of interest to be able to diagnose RSV-infection for a longer period of time by detection of specific RSV-IgM and RSV-IgA in nasopharyngeal aspirates (NPA) in order to minimize unnecessary antibiotics. OBJECTIVES: To evaluate an ELISA to detect specific RSV-IgM and RSV-IgA in NPA as a supplement to RSV-antigen detection. STUDY DESIGN: A total of 104 NPA from 101 children (median age 9 months) with acute respiratory disease (group 1) admitted to hospital and consecutive NPA (collected on day 0, 7, 14, 30 and 60) from 11 children (median age 3 months) with a proven RSV infection (group 2) were collected. All NPA from group 1 were analysed for RSV-antigen, RSV-IgM and RSV-IgA. NPA from group 2 were analysed for RSV-IgM and RSV-IgA. RESULTS: Thirty-five NPA in group 1 were positive for RSV-antigen and 64 were positive for RSV-antigen test alone found 44% and the RSV-IgM test alone found 80%. In group 2 8/11 (73%) has an excellent RSV-IgM response day 7, the rest responded later. Only 5/11 (46%) had a less pronounced RSV-IgA response on day 7, three cases responded later and three did not respond at all. RSV-IgM disappeared in 8/11 (73%) and RSV-IgA in 7/8 (88%) between day 30-60. CONCLUSIONS: Specific RSV-IgM is a valuable supplement to RSV-antigen detection for the diagnosis of acute and recent RSV infection.

Disseminated infection with Bacillus Calmette-Guerin in a child with advanced HIV disease.

An 8-month-old boy with vertically acquired HIV-infection who developed a disseminated BCG infection is described. The patient had been immunized at birth with BCG. In spite of a normal CD-4 lymphocyte count, he suffered from fever, anaemia and failure to thrive. BCG was isolated by culture from CSF, bone marrow and peripheral blood. Anti-tuberculous treatment initially seemed successful, but shortly after, the patient died from Pneumocystis carinii pneumonia. In symptomatic HIV-infected children originating from countries with BCG immunization programs, disseminated BCG infection should be considered.

[Idiopathic pulmonary hemosiderosis. A cause of severe iron deficiency anemia in childhood]. / Idiopatisk pulmonal haemosiderose. En årsag til svoer jernmangelanoemi i barnealderen.

The most common cause of anaemia in childhood is iron deficiency. Anaemia due to poor dietary iron is seen most often between 9-24 months of age in infants being fed with large amounts of milk during periods of high growth rate. After the age of two years one must look for other causes of iron deficiency, particularly blood loss. In the description of three cases of idiopathic pulmonary haemosiderosis, the problems of severe chronic anaemia in childhood are discussed. Idiopathic pulmonary haemosiderosis is a rare disease in children, characterized by iron deficiency, anaemia and pulmonary symptoms. It has a high mortality, mostly due to acute pulmonary haemorrhage. However, early diagnosis is important, as some therapeutical regimens have succeeded in delaying the pulmonary haemorrhages and a few patients have possibly gained complete remission.

The role of Mycobacteria Other Than Tuberculosis (MOTT) in patients with cystic fibrosis.

The purpose of this study was to estimate the frequency of and evaluate the clinical impact of pulmonary mycobacterial infections among cystic fibrosis (CF) patients. 185 CF patients aged 2.2-38.5 years were screened by sputum samples and by intracutaneous skin tests against tuberculin and sensitins produced from Mycobacterium chelonae subsp. abscessus, M. avium, M. intracellulare and M. scrofulaceum (the MAIS complex). The skin tests towards the sensitins in BCG-vaccinated patients (n = 60) were significantly influenced by the vaccination. 26 of the remaining 125 non-vaccinated patients had > or = 1 positive skin test (95% confidence limits 15-29%). The majority reacted against the MAIS complex. However, the reactions were similar to those of healthy siblings and an age-matched control group. Moreover, the lung function, growth and HbA1c were similar among skin test positive and negative patients. Three patients had repeated positive sputum cultures, the point prevalence being 1.6% (M. intracellulare, n = 2 and M. chelonae subsp. abscessus, n = 1). During the subsequent 4 years, 4 additional patients with M. chelonae subsp. abscessus were identified. Based on clinical observations, 5 of the infected patients were considered asymptomatic, while 2 might have been symptomatic. In 1 patient, M. chelonae subsp. abscessus disappeared spontaneously. Despite intensive treatment with new antibiotics against Mycobacteria Other Than Tuberculosis (MOTT) in 4 patients, the mycobacteria were not eradicated. In conclusion, MOTT infection was rare and the clinical impact difficult to prove. Treatment should focus on clinical improvement in the individual patient suspected of suffering from significant symptomatic infection. Eradication of the bacteria should not be expected.