The need for area under the curve measurements in the field of ganciclovir therapeutic drug monitoring in children: a case report

Background Ganciclovir pharmacokinetics is characterized by a high variability in drug exposure. Usually, monitoring of ganciclovir exposure is performed by measuring trough concentration. However, due to the specificity of pediatric pharmacokinetics, trough concentration measurements may not be a relevant surrogate of ganciclovir exposure. Area under the curve of concentration (AUC) may be a more appropriate biomarker. Case presentation We report the case of 3.6-year-old boy with Emberger syndrome with a cytomegalovirus reactivation occurring after allogenic hematopoietic stem cell transplantation. After a few days of treatment with intravenous ganciclovir, sub-therapeutic trough ganciclovir concentrations were measured (< 0.5 µg/mL) and viral load still increased. Ganciclovir dosage was increased by two-fold to deal with this treatment failure. Trough concentrations remained sub-therapeutic. The patient had hematologic disorder therefore it was decided to estimate ganciclovir AUC to assess more accurately drug exposure before any further dosage modification. AUC0–12 h was measured at 51 μg h/mL, which was within the therapeutic range (40–60 μg h/mL). Afterward, viral load decreased and became undetectable. Conclusions This case report highlights that monitoring ganciclovir exposure based on AUC should be performed to tailor drug dosage in order to improve treatment efficacy and safety in pediatric patients.

Ganciclovir Treatment in Symptomatic Congenital CMV Infection at Siriraj Hospital: 11 Year-Review (2008 to 2019)

Background: Congenital cytomegalovirus (CMV) infection is the most common non-genetic cause of permanent sensorineural hearing loss in infants and children. A 6-month course of intravenous ganciclovir or valganciclovir is recommended for treatment of patients with moderate to severe symptomatic congenital CMV disease. Hearing status improvement has been reported in those that received treatment within the first month of life. In Thailand, there has been no data of antiviral treatment in symptomatic congenital CMV patients. Objective: To determine the incidence of symptomatic congenital CMV infection in the past 11 years and to evaluate the hearing, neurological, and developmental outcomes of the antiviral treatment and factors associated with hearing outcomes. Materials and Methods: A retrospective observational study was performed at Siriraj Hospital, between January 2008 and December 2019. The medical records of the patients diagnosed of symptomatic congenital CMV infection (ICD10-P351) were reviewed. Results: The incidence of symptomatic congenital CMV infection was 0 to 1.01 case per 1,000 livebirths. Of the 52 patients, 18 received 6-week course of ganciclovir and five continued with oral valganciclovir for three to six months. Developmental delayed was found in 69.2% (36). No difference in hearing outcomes at 6 and 12 months of age between the patients who did or did not receive treatment. Among 24 (46.1%) children who underwent hearing test at two to three years of age, the birth characteristics, as well as antiviral treatment (attributable risk 0.007, 95% CI –0.4 to 0.4, p=0.973), had no difference in hearing outcome. Long-term disability was diagnosed in the lower proportion among the patients receiving antiviral treatment (attributable risk –0.3, 95% CI –0.5 to –0.1, p=0.030). Conclusion: Symptomatic congenital CMV infection resulted in poor hearing and developmental outcomes. Antiviral treatment reduced risk of disability but did not improve hearing outcomes. The results underscore the need for early diagnosis and initiation of antiviral treatment in infants with symptomatic congenital CMV. Keywords: Congenital infection; CMV; Hearing loss; Ganciclovir; Valganciclovir; Disability

CMV enteritis as unusual source of bleeding to GIT

Introduction: Cytomegalovirus disease affecting the gastrointestinal tract is a rare but severe disease presenting particularly in people under immunosuppression, solid organ transplant recipients and AIDS patients with CD4 count under 100/mm3. When colon or small intestine are affected, the disease may be complicated by severe bleeding. CMV therapy includes antivirals and, in case of bleeding, methods of therapeutic endoscopy or interventional radiology. Case description: We present a case of a 74-year-old woman 3 years after kidney transplantation owing to vascular nephrosclerosis, treated with belatacept, mycophenolate mophetile and prednisone. She was admitted to hospital for acute dyspnoea. During hospitalisation, she presented with intestinal bleeding, but the endoscopic intervention at the first colonoscopy was not successful. She was referred to the Department of Hepatogastroenterology of the Institute of Clinical and Experimental Medicine and subsequent colonoscopy revealed a 15 cm long part of ileum with ulcerations as the source of bleeding. The histological assessment described a severe CMV enteritis. The CMV DNA blood level established by PCR was higher than 10 000 000 U/ml. The patient was treated with intravenous ganciclovir and she underwent selective embolization of the inferior mesenteric artery with an excellent clinical effect. Conclusions: CMV enteritis may be associated with a high mortality. The approach to therapy is multidisciplinary and needs collaboration of gastroenterologist, endoscopist and interventional radiologist. Key words: CMV – GIT bleeding – immunosuppression – transplantation

Cytomegalovirus skin disease in a kidney transplant patient

A 44-year-old man with a history of renal transplantation presented with right lower abdominal wall swelling, redness and pain. A bacterial abscess was drained, and he was discharged home with oral antibiotics. After failing to improve, he returned to the hospital, where he was briefly treated with intravenous antibiotics and discharged home again. The patient returned 5 days later, reporting worsening right groin swelling that extended into the ipsilateral scrotum. Imaging revealed a persistent fluid collection in the region, and he was taken for surgical debridement. Tissue immunochemistry and histopathological evaluation identified cytomegalovirus infection. Plasma quantitative PCR for cytomegalovirus demonstrated high viraemia. The patient was successfully treated with intravenous ganciclovir, followed by oral valganciclovir, with resolution of the skin changes. Persistent hydrocele with epididymitis on imaging suggests that this process may have been the source of the cutaneous cytomegalovirus infection.

Unilateral frosted branch angiitis in an human immunodeficiency virus-infected patient with concurrent COVID-19 infection: a case report

Background Frosted branch angiitis (FBA) is an uncommon ocular sign with multiple causes. With the recent outbreak of coronavirus disease 2019 (COVID-19), many cases of ocular manifestation in association with this disease have been reported. However, as yet we have no complete understanding of this condition. We report here the first case of FBA in a human immunodeficiency virus-infected patient with coexisting cytomegalovirus (CMV) and COVID-19 infection. Case presentation A 33-year-old Malay man with underlying acquired immunodeficiency syndrome receiving highly active antiretroviral therapy was referred to the Opthalmology Department with complaints of blurry vision for the past 2 months. He had tested positive for and been diagnosed with COVID-19 1 month previously. Clinical examination of the fundus revealed extensive perivascular sheathing of both the artery and vein suggestive of FBA in the right eye. Laboratory testing of nasal swabs for COVID-19 polymerase chain reaction (PCR) and serum CMV antibody were positive. The patient was then admitted to the COVID-19 ward and treated with intravenous ganciclovir. Conclusion Clinicians should be aware of and take the necessary standard precautions for possible coexistence of COVID-19 in an immunocompromised patient presenting with blurred vision, eye redness, dry eye and foreign body sensation despite the absence of clinical features suggestive of COVID-19. Whether FBA is one of the ocular signs of co-infection of COVID-19 and CMV remains unknown. Further studies are needed to provide more information on ocular signs presented in patients with concurrent COVID-19 and CMV infections.

CMV pneumonitis in a patient with Crohn’s disease taking azathioprine

This case report discusses the rare presentation of cytomegalovirus (CMV) pneumonitis in a young patient with moderately severe Crohn’s disease managed with low dose azathioprine. CMV pneumonitis was initially suspected on CT chest images and confirmed by PCR for CMV. She was treated with intravenous ganciclovir and later stepped down to oral valganciclovir. Although this patient had a prolonged and complicated hospital admission, a good clinical outcome was achieved. CMV infection was raised as an early differential and antiviral treatment was started without delay. This case study, therefore, makes the case for increased awareness of the possibility of, and recognition of CMV pneumonitis among healthcare professionals as a way of preventing significant morbidity and mortality. It also raises awareness of checking for slow metabolisers of azathioprine before initiation to look for individuals who may be at increased risk of azathioprine’s adverse effects.

Strongyloides hyperinfection syndrome, Cytomegalovirus enteritis with viremia and recurrent gram-negative sepsis in a patient with recurrent thymoma: a case report

Strongyloides stercoralis is an intestinal nematode which is endemic in tropical and subtropical countries. It may cause asymptomatic infections, mild eosinophilia or hyperinfection syndrome in the most severe form. We are reporting a case of Strongyloides hyperinfection syndrome in an immunosuppressed patient with recurrent thymoma and myasthenic crisis. This patient is a 51-year-old man with myasthenia gravis on long term pyridostigmine and prednisolone and mycophenolate. He presented with copious diarrhoea and was in septic shock. His blood and urine cultures grew Klebsiella pneumoniae and Pseudomonas aeruginosa. Oesophago-gastro-duodenoscopy (OGD scopy) and biopsy showed severe active duodenitis with strongyloidiasis and moderate active antral gastritis with strongyloidiasis. He was diagnosed to have Strongyloides hyperinfection and was treated with oral Ivermectin. He recovered well. He was subsequently diagnosed to have CMV enteritis with viraemia and was treated with intravenous Ganciclovir. Our case emphasizes the association of Strongyloides hyperinfection with superimposed CMV infection and gram-negative sepsis due to prolonged immunosuppression and autoimmunity in Thymoma patients. Recurrent thymoma and high-grade infiltrative thymoma often poses difficulty in the management of myasthenia patients. A high index of suspicion and aggressive treatment is paramount in approaching a patient with multiple risk factors of hyperinfection syndrome and autoimmunity. This case is reported in view of its rarity and significance regarding the multidisciplinary approach in decreasing morbidity and mortality in hyperinfection syndrome with an autoimmune background.

Preemptive ganciclovir for mechanically ventilated patients with cytomegalovirus reactivation

Background The effect of cytomegalovirus (CMV) reactivation on the length of mechanical ventilation and mortality in immunocompetent ICU patients requiring invasive mechanical ventilation remains controversial. The main objective of this study was to determine whether preemptive intravenous ganciclovir increases the number of ventilator-free days in patients with CMV blood reactivation. Methods This double-blind, placebo-controlled, randomized clinical trial involved 19 ICUs in France. Seventy-six adults ≥ 18 years old who had been mechanically ventilated for at least 96 h, expected to remain on mechanical ventilation for ≥ 48 h, and exhibited reactivation of CMV in blood were enrolled between February 5th, 2014, and January 23rd, 2019. Participants were randomized to receive ganciclovir 5 mg/kg bid for 14 days (n = 39) or a matching placebo (n = 37). Results The primary endpoint was ventilator-free days from randomization to day 60. Prespecified secondary outcomes included day 60 mortality. The trial was stopped for futility based on the results of an interim analysis by the DSMB. The subdistribution hazard ratio for being alive and weaned from mechanical ventilation at day 60 for patients receiving ganciclovir (N = 39) compared with control patients (N = 37) was 1.14 (95% CI from 0.63 to 2.06; P = 0.66). The median [IQR] numbers of ventilator-free days for ganciclovir-treated patients and controls were 10 [0–51] and 0 [0–43] days, respectively (P = 0.46). Mortality at day 60 was 41% in patients in the ganciclovir group and 43% in the placebo group (P = .845). Creatinine levels and blood cells counts did not differ significantly between the two groups. Conclusions In patients mechanically ventilated for ≥ 96 h with CMV reactivation in blood, preemptive ganciclovir did not improve the outcome.

Unilateral Frosted Branch Angiitis in An Immunocompromised Patient With Concurrent Coronavirus Disease 2019 Infection

Background Frosted branch angiitis is an uncommon ocular sign with multiple causes. With the advent of coronavirus disease 2019 (COVID-19) pandemic, more and more cases of ocular manifestation with COVID-19 has been reported. These poses great challenges to clinicians when handling COVID-19 patients with ocular signs and symptoms. The challenges are even greater when dealing with uncommon disease that co-exists with COVID-19 as both diseases are not well understood. Finding We report the first case of frosted branch angiitis in a patient with coexisting cytomegalovirus and COVID-19 infection. A 33- year-old gentleman with underlying acquired immunodeficiency syndrome who was newly started on highly active antiretroviral therapy, complained of gradual blurring of vision one month after he was diagnosed positive for COVID-19. Upon clinical examination, fundus findings demonstrated extensive perivascular sheathing of both artery and vein, suggestive of frosted branch angiitis of the right eye. Laboratory investigations revealed both nasal swab for COVID-19 polymerase chain reaction and serum cytomegalovirus antibody was positive. The patient was then admitted to COVID-19 ward and treated with intravenous ganciclovir. Conclusion The challenges remain when handling Covid-19 patients with FBA. However, clinicians need to be aware of the possible coexistence of COVID-19 in an immunocompromised patient with frosted branch angiitis.