Primaquine plus clindamycin as a promising salvage therapy for Pneumocystis jirovecii pneumonia: A retrospective analysis in Japanese patients.

Treatment of intractable Pneumocystis jirovecii pneumonia (PCP) patients with primaquine (PQ) in combination with clindamycin (CLDM) was conducted by the Research Group on Chemotherapy of Tropical Diseases (RG-CTD), as a kind of compassionate use. Primaquine was not nationally licensed at the time but imported by RG-CTD for the use in a clinical research to investigate safety and efficacy in malaria treatment. Eighteen Japanese adult patients thus treated were analyzed. Prior to the treatment with PQ-CLDM, most of the patients had been treated with trimethoprim-sulfamethoxazole first, all of which being followed by pentamidine and/or atovaquone treatment. This combination regimen of PQ-CLDM was effective in 16 (89%) patients and developed adverse events (AEs) in five (28%) patients. AEs included skin lesions, methemoglobinemia, and hepatic dysfunction, though none of them were serious. As a second-line or salvage treatment for PCP, PQ-CLDM appears to be a better option than pentamidine or atovaquone. Currently in Japan, both PQ and CLDM are licensed drugs but neither of them is approved for treatment of PCP. Considering the potentially fatal nature of PCP, approval of PQ-CLDM for treating this illness should be urged.

[Kaposi's Sarcoma Herpesvirus-associated Inflammatory Cytokine Syndrome (KICS) Improved by Antiretroviral Therapy in an HIV-infected Patient].

We report a case of a 63-year-old HIV-positive Japanese male with a CD4 cell count of 127/µL who was admitted to our hospital because of suspected malignant lymphoma. Initial blood tests revealed anemia, thrombocytopenia, hypoalbuminemia, and hypergammaglobulinemia. Imaging tests revealed a lung nodule, bilateral pleural effusion, hepatosplenomegaly and generalized lymphadenopathy. No evidence of malignant lymphoma or multicentric Castleman's disease was noted on biopsy specimens; however, Kaposi sarcoma-associated herpesvirus (KSHV)-encoded latency-associated nuclear antigen-1-positive cells were observed as well as an elevated interleukin (IL)-6, IL-10 and KSHV viral load. He fulfilled the novel diagnostic criteria for KSHV-associated inflammatory cytokine syndrome (KICS). After initiating antiretroviral therapy, his symptoms and radiological abnormalities drastically improved. After 1-year follow-up, his HIV was well controlled without any relapsing symptoms.

[Ocular Syphilis Complicated with HIV Infection: A Report of 3 Cases].

We present 3 cases of ocular syphilis in patients who had been newly diagnosed as having HIV. All the patients had only complained of ophthalmologic symptoms at the time of their initial visit. Treatment with penicillin was successful, resulting in no significant sequelae. Ocular syphilis may lead to reduced visual acuity or even blindness if left untreated. However, the diagnosis may be challenging, since patients may lack symptoms that are commonly observed in cases with primary and secondary syphilis. Considering the recent increase in the number of syphilis patients, clinicians should be aware of ocular syphilis and should have a high index of suspicion for syphilis in any patient at risk so as to ensure a prompt diagnosis.

Comparison of cystatin C and creatinine to determine the incidence of composite adverse outcomes in HIV-infected individuals.

BACKGROUND: Cystatin C is an overall biomarker of pathophysiologic abnormalities that accompany chronic kidney disease (CKD). The utility of cystatin C is not fully understood in an HIV-infected population. METHODS: This prospective study investigated 661 HIV-infected individuals for 4 years to determine the incidence of adverse outcomes, including all-cause mortality, cardiovascular disease, and renal dysfunction. The risk of developing the outcomes was discriminated with a 4 color-coded classification in a 3 × 6 contingency table, that combined 3 grades of dipstick proteinuria with 6 grades of estimated glomerular filtration rate (eGFR) calculated using either serum creatinine (eGFRcr) or cystatin C (eGFRcy): green, low risk; yellow, moderately increased risk; orange, high risk; and red, very high risk. The cumulative incidence of the outcomes was assessed by the Kaplan-Meier method, and the association between color-coded risk and the time to outcome was evaluated using multivariate proportional hazards analysis. RESULTS: Compared with eGFRcr, the use of eGFRcy reduced the prevalence of risk ≥ orange by 0.8%. The adverse outcomes were significantly more likely to occur to the patients with baseline risk category ≥orange than those with ≤ yellow, independent of risk categories based on eGFRcr or eGFRcy. However, in multivariate analysis, risk category ≥orange with eGFRcy-based classification was significantly associated with adverse outcomes, but not the one with eGFRcr. CONCLUSIONS: Replacing creatinine by cystatin C in the CKD color-coded risk classification may be appropriate to discriminate HIV-infected patients at increased risk of a poor prognosis.

Pyoderma gangrenosum successfully treated with antiretroviral therapy alone in a human immunodeficiency virus-infected individual.

We report a case of a 60-year-old man infected with human immunodeficiency virus (HIV) who was transferred to our hospital for management of multiple non-healing, painful ulcers on the lower extremities. The histological findings of the biopsy specimen were compatible with the diagnosis of pyoderma gangrenosum (PG). An association between HIV infection and the development of PG was considered after a thorough investigation. Antiretroviral therapy without the use of adjunctive immunosuppressive agents resulted in clinical improvement. Our case implies that antiretroviral therapy alone could heal PG in untreated HIV-infected patients.

[Murine typhus in a Japanese traveler returning from Indonesia: a case report].

We report herein on a 20-year-old Japanese man who was referred to our hospital for fever and diarrhea after returning from Indonesia. On admission, his blood test was essentially normal, besides a slight elevation in inflammatory markers. After excluding malaria and dengue fever, empiric use of ceftriaxone was initiated for suspected enteric fever, which was unsuccessful. However, drastic clinical improvement was observed after initiation of minocycline. The polymerase chain reaction test for Rickettsia typhi was positive from serum samples on admission, confirming the diagnosis of murine typhus. Although rarely seen in Japan, clinicians should be aware of this disease when examining patients with fever coming back from murine typhus endemic areas.

[A case of spinal tuberculosis in a young Filipino man].

A 19-year-old Filipino man was admitted to our hospital because of persisting fever and back pain. He had recognized his symptoms 6 months previously, but a definite diagnosis was not made. Image testing demonstrated a compressed fracture of the thoracic vertebrae accompanied with a perivertebral abscess. A biopsy specimen revealed granuloma compatible with tuberculosis (TB). Anti-TB drugs were initiated, and his clinical symptoms steadily improved. However, he developed neuropathic symptoms due to exacerbation of the abscess two months after starting the anti-TB drugs. An immediate laminectomy was performed resulting in symptom relief; however severe kyphosis remained. Polymerase chain reaction testing of the abscess collected during the operation was positive for Mycobacterium tuberculosis, confirming the diagnosis of spinal TB. The diagnosis of spinal TB has been a challenge world-wide. Clinicians should be aware of the demographic background as well as the clinical and laboratory features of spinal tuberculosis, facilitating earlier diagnosis.

[Evaluation of HIV-infected patients suspected as having HIV-associated neurocognitive disorders].

BACKGROUND: HIV-associated neurocognitive disorders (HAND) have emerged as a problem among HIV-infected individuals in the era of antiretroviral therapy. However, there are insufficient data on HAND regarding its prevalence and clinical features in Japan. METHODS: A test battery composed of eight neuropsycological tests proposed by the Ministry of Health, Labour and Welfare (MHLW test battery) was applied to assess 30 subjects at Tokyo Metropolitan Komagome Hospital. Among them, 5 subjects were excluded due to central nervous system complications. The background of each patient along with the results of head magnetic resonance imaging (MRI), cerebrospinal fluid (CSF) analysis and neuropsychological tests were compared to each HAND category. In addition, the clinical utility of a combination of neuropsychological tests as an abbreviated test battery of HAND was evaluated. RESULTS: A total of 19 (76%) subjects were diagnosed as having a HAND. Among them, HIV-associated dementia, mild neurocognitive disorders and asymptomatic neurocognitive disorders were diagnosed in 7, 8, and 4 subjects, respectively. Neither the patient's background nor the results of the head MRI and CSF analysis showed relevance to disease severity. The conventional International HIV Dementia Scale with the Digit Symbol Substitute Test was capable of detecting 94.7% cases of HAND. CONCLUSIONS: Most HIV-infected subjects clinically suspected as having neurocognitive disorders were diagnosed as having a HAND. Neuropsychological tests of the MHLW test battery were in some part useful to diagnose HAND. However, more precise neuropsychological tests are warranted to screen and diagnose HAND, based on the current criteria.

Sequential changes in the non-coding control region sequences of JC polyomaviruses from the cerebrospinal fluid of patients with progressive multifocal leukoencephalopathy.

Progressive multifocal leukoencephalopathy (PML) is caused by JC polyomavirus (JCV) infection in the brain. JCV isolates from PML patients have variable mutations in the non-coding control region (NCCR) of the genome. This study was conducted to examine sequential changes in NCCR patterns of JCV isolates obtained from the cerebrospinal fluid (CSF) of PML patients. CSF specimens were collected from PML patients at different time points, the NCCR sequences were determined, and their compositions were assessed by computer-based analysis. In patients showing a marked increase in JCV load, the most frequent NCCR sequences in the follow-up specimens were different from those in the initial samples. In contrast, the dominant NCCRs in the CSF remained unaltered during the follow-up of individuals in whom the viral load decreased after therapeutic intervention. These data demonstrate that the majority of JCV variants emerge with the progression of PML and that these changes are suppressed when the viral load is decreased.

[Medical study of cases diagnosed as rubella in adults].

BACKGROUND: In 2012, the number of rubella cases sharply increased in Japan. It continued to rise in 2013. Between October 2012 and May 2013, 10 cases of congenital rubella syndrome (CRS) were reported nationwide. This current rubella outbreak comprised mainly males who were between 20 to 39 years of age, and had not received the rubella vaccine. Data have been lacking on the clinical characteristics of adults infected with the rubella virus. METHODS: Using medical charts, we collected data from 27 patients who were diagnosed with clinically or laboratory-confirmed rubella infection at Tokyo Metropolitan Komagome Hospital from January 2012 to April 2013. RESULTS: Of the 27 patients studied, their median age was 34.5 years and 70.4% were male between 21-56 years of age. For the 11 cases with known vaccination status, 9 (81.8%) occurred in persons who had not received a rubella vaccine. A total of 33.3% of the patients were hospitalized, due to persistent fever, poor oral intake, or dehydration. Major clinical symptoms were fever (96.3% of cases), lymphadenopathy (92.6%), rash (85.2%), conjunctivitis (77.8%), and headache (63.0%). The mean duration of fever was 5 days (range, 3-9). The exanthema consisted of punctate, pink maculopapules; however, the rash became confluent in 37.0%, and pigmented in 18.5% of the patients. Initial laboratory data were as follows:white cells, 3,800/microL (range: 2,000-8,300); platelets, 129,000/microL (range, 63,000 - 230,000); aspartate aminotransferase, 27IU/L (range, 16 - 49); lactase dehydrogenase, 279IU/L (range, 168-440) [all described in medians]. Rubella-specific immunoglobulin M antibodies from the serum sample obtained at the initial visit were detected in 17 cases (65.4%). Likewise, measles-specific immunoglobulin M antibodies were detected in 7 cases (26.9%), all of which were false-positive. CONCLUSIONS: The clinical characteristics of rubella in adults resembled measles in some part, which may cause difficulty for physicians to differentiate between the two diseases. Vaccinating rubella-susceptible individuals now is critical to interrupt rubella virus transmission, and to prevent further CRS cases.

[Sick sinus syndrome possibly due to lopinavir-ritonavir: report of two cases].

We describe herein two cases of sick sinus syndrome possibly due to lopinavir-ritonavir in HIV-infected individuals. The heart rate dropped to 30 to 40 beats per minute in both cases, but patients remained asymptomatic and recovered promptly after discontinuation of lopinavir-ritonavir. The time until onset varied; one patient developed bradyarrhythmia 9 days after the initial dose, and another 4 hours after. Since lopinavir-ritonavir is a frequently used antiretroviral agent, clinicians must be aware of this potentially lethal adverse effect.

[Necrotizing fasciitis after a cat bite: a case report].

We report on a previously healthy 56-year-old woman who was referred to our hospital with fever and progressive left foot pain. She had been bitten by a cat 7 days previously, and cephalosporins had been prescribed for treatment. However, her clinical symptoms deteriorated, and physical examination on admission was compatible with necrotizing fasciitis. Treatment with ampicillin-sulbactam and clindamycin was initiated. In addition, immediate surgical debridement was performed, resulting in therapeutic success. Culture of the necrotizing tissue grew multiple organisms, including Pasteurella multocida and Bacteroides caccae. Administration of appropriate antibiotics after a cat bite is essential for the prevention of potentially fatal complications.

[Prevalence of chronic kidney disease among HIV-infected individuals in Japan--a report from two tertiary hospitals].

BACKGROUND: The improved survival of subjects with human immunodeficiency virus (HIV) has been accompanied by an increased prevalence of chronic kidney disease (CKD). Epidemic of CKD among those with HIV has not yet been evaluated in multiple tertiary hospitals in Japan. METHODS: A cross-sectional study was conducted in 2011 at Tokyo Metropolitan Komagome Hospital (TMKH) and Tokyo Medical University Hospital (TMUH). A total of 1482 HIV-infected subjects (1384 men, 98 female, mean age: 44.2 +/- 11.4 years old) were consecutively enrolled in the study. Random urine and blood samples were collected to study prevalence of CKD. CKD was diagnosed as a decrease in glomerular function and/or proteinuria and classified into 5 stages based on National Kidney Foundation guidelines. The estimated glomerular filtration rate based on serum creatinine was calculated using the 3-variable equation, constructed by the Japanese Society of Nephrology. Proteinuria was defined as > or = 1+ on urine dipstick examination. All electronic medical charts were reviewed to determine comorbidities, including hypertension and diabetes mellitus (DM). The proportion of subjects receiving tenofovir disoproxil fumarate (TDF) was investigated. Risk factors for CKD were determined using multivariate logistic regression analysis. RESULTS: The mean CD4 cell count was 487 +/- 216/microL and 80.5% had undetectable HIV-RNA level in the combined cohort. Of the 90.2% of subjects taking antiretroviral agents, 61.5% was using TDF. The prevalence of overall CKD and CKD > or = stage 3 was 12.9% and 6.7%, respectively, both of which were nearly 3-fold higher in the TMKH cohort (p < .0001). Mean age and proportional prevalent hypertension and DM were significantly higher in the TKMH cohort than in the TMUH cohort. Multivariate analysis showed significant CKD to be associated with age > or =50 years (odds ratio [OR], 2.81), hypertension (OR, 3.04), and DM (OR, 2.05). CONCLUSIONS: CKD prevalence was 12.9% among combined cohorts, but differed significantly between them. Differences in age distribution and the proportion of comorbidities, including hypertension and DM, are likely involved.

Immunogenicity of intradermal vaccination of Japanese rabies vaccine for preexposure immunization following WHO recommendation.

In the present study, we evaluated the immunogenicity of intradermal vaccination of Japanese purified chick embryo cell rabies vaccine (PCEC-K) for preexposure immunization (PEI). A total of 39 healthy subjects were administered a single 0.1-ml dose of PCEC-K intradermally at the antebrachial region on days 0, 7, and 28. To assess immunogenicity, rabies neutralizing antibody (NA) titers were measured on days 7, 28, and 42 post vaccination. By day 42, all subjects developed NA titers ≥0.5 IU/ml (geometric mean titer, 2.7 IU/ml), a level that is considered protective. The vaccine was well tolerated; vaccinated subjects displayed minimal redness and pruritus. Although a 1.0-ml dose of PCEC-K administered subcutaneously is considered the standard method, the intradermal regimen using a 0.1-ml dose of PCEC-K is immunogenic, safe, and highly recommended for situations of vaccine shortage.

Clinical characteristics of Japanese lung cancer patients with human immunodeficiency virus infection.

BACKGROUND: Lung cancer has emerged as a crucial problem among human immunodeficiency virus (HIV)-infected patients, contributing to significant mortality in Western countries. Japan has an increasing number of newly infected HIV patients, but clinical characteristics of lung cancer have not been well investigated in Asian populations with HIV. PATIENTS AND METHODS: We retrospectively analyzed patients diagnosed with HIV and lung cancer simultaneously in our institution between 1985 and 2010. Data regarding HIV status, characteristics, treatment, and prognosis of lung cancer were evaluated. RESULTS: We identified 13 consecutive patients (all men; mean age, 59.0 ± 10.2 years) since 1985, 7 of whom had been diagnosed since 2008. Mean CD4 cell count was 332 ± 159 cells/µL, and HIV viral loads were undetectable in 8 patients (61.5%) at the time of lung cancer diagnosis. The mean latency from HIV diagnosis to detection of lung cancer was 4.0 years. Histological examination demonstrated adenocarcinoma in 9 patients (69.2%), followed by squamous cell carcinoma (23.1%), and small cell carcinoma (7.7%). Among the 7 patients available for examination, 2 patients (28.6%) harbored EGFR mutation. Six patients had stage IA-IIIA, and 7 patients had stage IIIB/IV. Among 6 patients treated with chemotherapy for unresectable stages, 5 (83.3%) achieved a partial response. Median overall survival was 17 months for all stages and 14 months for advanced stages. Toxicities for treatment modalities were largely acceptable. CONCLUSIONS: Clinical characteristics of Japanese HIV-infected patients with lung cancer resemble those of Western populations. The prognosis for patients in the metastatic stage was better than previously reported.

[Syphilis proctitis complicated with HIV infection: a case report].

We report on a 26-year-old Japanese man who was referred to our hospital because of anal pain and hematochezia. On admission, in addition to his gastrointestinal symptoms, a generalized maculopapular rash was observed, involving the palms of his hands and soles of his feet. His history and physical examination were compatible with syphilis, confirmed by a high syphilis titer on blood examination. Further tests revealed the presence of HIV infection, with a CD4 cell count of 227/microL. Colonoscopy demonstrated a deep ulcer in the lower rectum, although biopsy specimens did not reveal any syphilis spirochetes, or any other specific microorganisms. Intravenous penicillin G was initiated, resulting in a dramatic improvement of the ulcers along with the skin lesions confirming the diagnosis of syphilis proctitis. A rapid plasma reagin titer test performed 3 months after treatment demonstrated significant decrease, indicating successful treatment.

[Refractory AIDS-associated Kaposi's sarcoma treated successfully with paclitaxel: a case report].

We report a case of a 45-year-old Japanese man with AIDS-associated Kaposi's sarcoma (KS) involving skin, liver, and lungs. Antiretroviral therapy was started in conjunction with pegylated liposomal doxorubicin (PLD). A clinical response was observed initially, but symptoms recurred following cessation of medication. The chemotherapeutic agent was changed to paclitaxel (PTX), since the therapeutic response to PLD was reduced and the total dose reached the maximum dose of 500 mg/m2. The patient had a good response to PTX and tolerated the medication well. Symptoms did not recur after completing 8 courses of chemotherapy. PTX should be considered as an alternative agent in treating KS when there are problems with the use of PLD.

Clinical characteristics of kidney disease in Japanese HIV-infected patients.

BACKGROUND: Kidney disease has become an important cause of morbidity and mortality in HIV-infected patients in Western countries. Japan is a country with an increasing number of newly infected HIV patients. However, only a few studies have investigated kidney disease in Asian populations infected with HIV. METHODS: We studied the prevalence of kidney disease by reviewing the clinical data of 732 HIV-infected Japanese patients. Risk factors for proteinuria, albuminuria, and renal dysfunction were determined using multivariate logistic regression analysis. RESULTS: Microalbuminuria, macroalbuminuria and proteinuria were present in 13.2, 4.55 and 9.52% of patients, respectively. The prevalence of chronic kidney disease of any stage and CKD ≥ stage 3 was 15.4 and 9.70%, respectively. Multivariate analysis showed significant associations between increasing levels of serum creatinine and cholesterol, and the coexistence of diabetes, hypertension and hepatitis C coinfection with either proteinuria or albuminuria, which was significantly related to the presence of renal dysfunction. Lower CD4 cell count was associated with the presence of renal dysfunction, but higher HIV-RNA level was not. CONCLUSIONS: Our study has shown the international dimension of the burden of kidney disease in HIV-infected patients. Either proteinuria or albuminuria is likely the most significant factor for renal dysfunction in these patients.

Pre-exposure immunization against rabies using Japanese rabies vaccine following the WHO recommended schedule.

We examined the efficacy and safety of the Japanese purified chick embryo cell rabies vaccine (PCEC-K) when administered on days 0, 7, and 28, as recommended by the WHO. Post-vaccination serum samples were obtained from 53 human subjects, and rabies antibody titers were determined by a combination of enzyme-linked immunosorbent assay (ELISA) and neutralizing antibody (NA) assay. By day 42 of the experiment, which was 2 weeks after the third dose, all subjects had developed NA titers of 0.5 IU/ml or higher. The geometric mean titers of ELISA antibody and NA were 3.8 EU/ml and 5.7 IU/ml, respectively. Overall, the vaccine was well tolerated by all subjects. These results suggest that PCEC-K used for pre-exposure immunization according to the WHO schedule is as immunogenic and effective as the current pre-exposure immunization regimen in Japan, which consists of vaccines administered on days 0, 28, and 180. An accelerated schedule would be of great advantage to Japanese travelers, who could complete the required three doses for primary immunization in 1 month.

[Prevalence of kidney disease in HIV-infected patients in Japan--A single center study].

BACKGROUND: Kidney disease is a significant cause of morbidity and mortality among persons infected with the human immunodeficiency virus (HIV). However, epidemiologic and clinical variables regarding kidney disease have not been determined among HIV-infected patients in Japan. PATIENTS AND METHODS: A cross-sectional study of 788 HIV-infected outpatients including 706 men was conducted in 2009. The patient's mean age and CD4+ T cell count were 46.2 +/-11.8 years and 418 +/- 202/microL, respectively. Of them, 677 patients (86%) had an undetectable HIV-RNA level (<50 copies/mL). Random urine and blood samples were collected to study the coexistence of chronic kidney disease (CKD). In addition, serum cystatin C was measured since it is considered to be an alternative marker of early kidney dysfunction in the HIV population. The estimated glomerular filtration rate (eGFR) based on serum creatinine was calculated using the 3-variable equation, proposed by the Japanese Society of Nephrology [eGFR (mL/ min/1.73m2) = 194 x Serum creatinine (-1.094) x Age (-0.287 x 0.739 (if female)]. CKD stages were classified based on the National Kidney Foundation guidelines. RESULTS: The prevalence of CKD and that of CKD > or = stage 3 was 14.9% and 9.4%, respectively. The pro-portion of each stage was as follows: stage 1, 15 patients (1.9%); stage 2, 28 patients (3.6%); stage 3, 66 patients (8.4%); stage 4, 1 patient (0.1%); stage 5, 1 patient (0.1%); and stage 5D, 6 patients (0.8%). Elevation of serum cystatin C (> or = 0.9 mg/L) was found in 23.3%. Comorbidities such as hypertension and diabetes were found in 55.4% and 27.0% in patients with CKD > or = stage 3, respectively. Urinalysis showed 71 patients (9.1%) with proteinuria and 44 patients (5.6%) with hematuria. CONCLUSION: CKD has become an important comorbidity for HIV-infected patients in Japan, a point that should be given more emphasis from public health perspective.