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.

Interleukin-6-dependent growth in a newly established plasmablastic lymphoma cell line and its therapeutic targets.

Plasmablastic lymphoma (PBL) is a rare, highly aggressive subtype of non-Hodgkin lymphoma with plasma-cell differentiation occurring typically in immune-suppressed patients such as those with AIDS. This study reports the establishment and characterization of a new cell line, PBL-1, derived from a patient with AIDS-associated PBL. Morphological assessment of PBL-1 indicated plasma-cell differentiation with a CD20(-) CD38(+) CD138(+) immunophenotype and IgH/c-myc translocation. The cell line harbours Epstein-Barr virus, but a 52.7-kbp length defect was identified in its genome, resulting in no expression of viral microRNAs encoded in the BamHI-A Rightward Transcript region. Importantly, supplementation of culture medium with >5 ng/mL of interleukin-6 (IL-6) was required for PBL-1 growth. Starvation of IL-6 or addition of tocilizumab, an inhibitory antibody for the IL-6 receptor, induced apoptosis of PBL-1. Transduction of IL-6 into PBL-1 by lentivirus vector induced autologous growth without IL-6 supplementation of culture medium. These data indicate the IL-6 dependency of PBL-1 for proliferation and survival. mTOR inhibitors induced cell death effectively, suggesting mTOR in the IL-6 signalling pathway is a potential therapeutic target for PBL. This established PBL cell line will be a useful tool to further understand the pathophysiology of PBL and aid the future development of PBL treatment.

Severe Thrombocytopenia and Acute Cytomegalovirus Colitis during Primary Human Immunodeficiency Virus Infection.

We herein report the case of a 25-year-old man who was referred to our hospital due to acute cytomegalovirus (CMV) colitis. The initial blood tests showed that the patient had concurrent primary human immunodeficiency virus (HIV) infection and severe thrombocytopenia. Raltegravir-based antiretroviral therapy (ART) was initiated without the use of ganciclovir or corticosteroids and resulted in a rapid clinical improvement. Platelet transfusions were only necessary for a short period, and subsequent colonoscopy revealed a completely healed ulcer. This case implies that ART alone could be effective for treating severe thrombocytopenia during primary HIV and CMV coinfection.

[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.

CD8 Encephalitis Caused by Persistently Detectable Drug-resistant HIV.

We herein report a 52-year-old man infected with human immunodeficiency virus (HIV) who was referred to our hospital due to the development of severe neurocognitive disorders and bilateral leukoencephalopathy. He has been treated with antiretroviral agents for 17 years, but low-level viremia has been detected consistently prior to admission. Drug resistant testing of the serum and the cerebrospinal fluid (CSF) both demonstrated a M184V mutation. A brain biopsy revealed perivascular CD8(+) T-lymphocyte infiltration, leading to the diagnosis of CD8 encephalitis. The clinical symptoms improved drastically after changing to a nucleoside reverse transcriptase inhibitor sparing regimen, which subsequently decreased the HIV viral load to an undetectable level in both the serum and CSF.

Laryngeal Kaposi's Sarcoma Complicated by the Immune Reconstitution Inflammatory Syndrome in an HIV-infected Patient.

We herein report a case of laryngeal Kaposi's sarcoma (KS) complicated by immune reconstitution inflammatory syndrome in a human immunodeficiency virus (HIV)-infected patient. The patient initially presented with KS involving the larynx, which was successfully treated with pegylated liposomal doxorubicin (PLD) and antiretroviral therapy (ART). PLD was discontinued after 2 courses because of a marked clinical improvement; however, the patient experienced progressive odynophagia and dyspnea 2 months after the initiation of ART. Laryngoscopy revealed a severely swollen, inflamed epiglottis. The readministration of PLD was successful, and the patient was thereafter discharged without any subsequent complications.

[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.

Atazanavir nephrotoxicity.

Atazanavir is commonly used as one of the key drugs in combination antiretroviral therapy for human immunodeficiency virus (HIV). However, atazanavir has the potential to yield its crystalline precipitation in urine and renal interstitial tissues, leading to crystalluria, urolithiasis, acute kidney injury (AKI) or chronic kidney disease (CKD). In epidemiological studies, atazanavir/ritonavir alone or in combination with tenofovir has been associated with increased risk of progression to CKD. However, renal biopsies were not provided in these studies. Case reports showing an association between atazanavir use and tubulointerstitial nephritis among HIV-infected individuals provide clues as to the potential causes of atazanavir nephrotoxicity. We now review atazanavir-related kidney disease including urolithiasis, renal dysfunction and interstitial nephritis and illustrate the review with a further case of atazanavir-associated kidney injury with sequential renal biopsies. There are two forms of atazanavir-associated tubulointerstitial nephritis: acute tubulointerstitial nephritis that may develop AKI rapidly (in weeks) after initiation of atazanavir, and chronic tubulointerstitial nephritis that may develop progressive CKD slowly (in years) with granuloma and intrarenal precipitation of atazanavir crystals as well as crystalluria. Caution should be exercised when prescribing atazanavir to patients at high risk of CKD, and therapy should be reevaluated if renal function deteriorates, especially associated with crystalluria and hematuria.

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.

Clinical presentation and diagnosis of toxoplasmic encephalitis in Japan.

Distinguishing life-threatening toxoplasmic encephalitis (TE) from brain lymphoma in patients with acquired immunodeficiency syndrome (AIDS) may be difficult. Empiric anti-toxoplasmosis treatment is often initiated because of the reluctance in performing brain biopsies, which may delay the diagnosis and treatment of brain lymphoma in Japan. In this study, we retrospectively examined the clinical characteristics of 13 AIDS patients with TE in Japan, including magnetic resonance imaging and thallium 201 (201TI) single photon emission computed tomography (SPECT) findings, cerebral spinal fluid analysis, serology, and polymerase chain reaction (PCR) results. All patients improved on anti-toxoplasmosis treatment. Of the 11 patients who underwent serological testing, 6 (55%) had a positive serological result. Of the 7 patients who underwent PCR testing, 3 (42.9%) had a positive PCR result. Nine of 11 patients with TE (81.8%) had multiple lesions. Analysis of the sites of TE lesions did not reveal a difference in site predilection between TE and brain lymphoma. Uptake was negative in all 9 patients who underwent 201Tl SPECT. The study findings suggest that toxoplasma serostatus and PCR may be used to discriminate TE from brain lymphoma. No focal accumulation of 201TI is strongly suggestive of TE in patients with AIDS in Japan.

[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.

[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.

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.

[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.

[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.

Bilateral emphysematous pyelonephritis with a splenic abscess.

The case of a 66-year-old woman with untreated diabetes mellitus who was admitted to our hospital with a fever, hypotension and an altered mental status is herein reported. Computed tomography revealed bilateral emphysematous pyelonephritis along with a splenic abscess. Blood and urine cultures grew Escherichia coli. Treatment with systemic antibiotics combined with the insertion of percutaneous and renoureteral catheters was successful. The patient was discharged and completed treatment without developing any subsequent complications.