Immune-suppressed Patients Research Articles

Virus-Specific Nanobody-Chimeras Degrade the Human Cytomegalovirus US28 Protein in CD34+ Cells.

After primary infection, human cytomegalovirus (HCMV) establishes lifelong persistence, underpinned by latent carriage of the virus with spontaneous reactivation events. In the immune-competent, primary infection or reactivation from latency rarely causes disease. However, HCMV can cause significant disease in immune-compromised individuals such as immune-suppressed transplant patients. Latency, where the viral genome is carried in the absence of the production of infectious virions, can be established in undifferentiated cells of the myeloid lineage. A number of stimuli can cause virus reactivation from latency to occur, beginning with the induction of viral immediate-early (IE) lytic gene expression. The suppression of viral IE gene expression to establish and maintain latent infection is known to result from a balance of viral and cellular factors. One key viral factor involved in this is the G protein-coupled receptor US28. Recently, we have shown that US28 is targeted for degradation by a modified nanobody (PCTD-Vun100bv) based on the novel PACTAC (PCSK9-antibody clearance-targeting chimeras) approach for targeted protein degradation. Furthermore, we have shown that this PCTD-Vun100bv-induced degradation of US28 results in IE gene expression in experimentally latently infected CD14+ monocytes. However, HCMV also establishes latency in CD34+ bone marrow cells, the progenitors of CD14+ cells. Here, we show that PCTD-Vun100bv also causes US28 degradation in these CD34+ primary cells, again resulting in the induction of viral IE gene expression. Additionally, we show that PCTD-Vun100bv can target US28 in naturally latently infected CD14+ monocytes from an HCMV-seropositive donor, allowing these latently infected cells to be killed by HCMV-specific cytotoxic T cells from that same donor. These observations support the view that targeting US28 for degradation during natural latency could be a tractable 'shock-and-kill' strategy to target the latent HCMV reservoir in myeloid cells.

Antifungal Potential of Bioactive Metabolites Produced by Pseudomonas aeruginosa against Candida Species

Abstract: Background: The frequency of fungal infections targeting immune-suppressed patients has been prominently rising day by day. Among these infections, Candidiasis is one of the most common life-threatening systemic fungal infections in recent years. These infections are challenging to treat because of the inconvenience of effective antifungal drugs. Therefore, the insufficiency of current drug regimens coupled with constant mutations by the fungi to develop drug resistance can pose a potential problem for future anti-fungal treatments. This frequent increase in drug-resistant fungi has directed attention toward the use of alternative therapy from natural sources. Objective: This study aimed to evaluate Pseudomonas aeruginosa for its antifungal potential against Candida species. Materials and Methods: This study was conducted at the Federal Urdu University of Arts, Science and Technology, Karachi, Pakistan during 2021-2022. For the detection of the antifungal compound, a clinical isolate P. aeruginosa HS 28 (identified conventionally as well as by 16S r RNA analysis) was screened for its bioactivity against Candida species by using agar well diffusion technique. The growth kinetics as well as the effect of different physical and chemical factors were also determined in the study. The compound was also partially purified by ammonium sulfate precipitation. Result: This antifungal compound showed good inhibitory activity against Candida species such as Candida albicans, C. glabrata, C. tropicalis, C. krusei, etc. This compound retained its stability at a high range of temperatures, and varying pH. Moreover, its bioactivity was also conserved when treated with organic solvents, chloroform vapors, metal salts, and different surfactants/detergents. The growth kinetics analysis illustrated that the maximum production of antifungal compounds occurred in the log phase of growth and extended supreme until the late log phase. Furthermore, the highest saturation of this protein was achieved at the concentration of 60% ammonium sulfate. Conclusion: The overall results indicated the promising antifungal potential of the compound produced by Pseudomonas aeruginosa HS 28 against Candida species.

Chemical Peeling Therapy Using Phenol for the Cervico-Vaginal Intraepithelial Neoplasia.

Objective: This study aimed to validate the use of liquid phenol-based chemical peeling therapy for cervical and vaginal intraepithelial neoplasia (CIN and VaIN, respectively), with the goal of circumventing obstetric complications associated with surgical treatment and to determine the factors associated with treatment resistance. Methods: A total of 483 eligible women diagnosed with CIN, VaIN, or both, participated in this study. Participants underwent phenol-based chemical peeling therapy every 4 weeks until disease clearance. Disease clearance was determined by negative Pap tests for four consecutive weeks or by colposcopy. HPV genotyping was conducted at the onset of the study and after disease clearance in select cases. Our preliminary analysis compared the recurrence and persistence rates between 294 individuals who received phenol-based chemical peeling therapy and 189 untreated patients. Results: At 2 years following diagnosis, persistent disease was observed in 18%, 60%, and 88% of untreated patients with CIN1-3, respectively, and <2% of patients with CIN who received phenol-based chemical peeling therapy. Among 483 participants, 10 immune-suppressed patients required multiple treatments to achieve disease clearance, and 7 were diagnosed with cervical cancer. Of the 466 participants, except those with cancer or immune suppression, the number of treatment sessions until CIN/VaIN clearance ranged from 2 to 42 (average: 9.2 sessions). In total, 43 participants (9.2%) underwent surgical treatment. Six patients (1.3%) experienced recurrence of CIN2 or worse, suggesting that treatment failed in 46 patients (9.9%). No obstetrical complications were noted among the 98 pregnancies following this therapy. Factors associated with resistance to this therapy include immune suppression, ages 35-39 years, higher-grade lesions, and multiple HPV-type infections. Conclusions: Phenol-based therapy is safe and effective for CINs and VaINs. Women aged < 35 years and with persistent CIN1 or CIN2 with a single HPV-type infection are suitable candidates for phenol-based chemical peeling therapy. However, this therapy requires multiple lengthy sessions.

Enhanced monitoring of healthcare shower water in augmented and non-augmented care wards showing persistence of Pseudomonas aeruginosa despite remediation work.

Introduction. Pseudomonas aeruginosa in healthcare shower waters presents a high risk of infection to immune-suppressed patients; identifying the colonization-status of water outlets is essential in preventing acquisition.Hypothesis/Gap Statement. Testing frequencies may be insufficient to capture presence/absence of contamination in healthcare waters between sampling and remediation activities. Standardization of outlets may facilitate the management and control of P. aeruginosa.Aim. This study aims to monitor shower waters and drains for P. aeruginosa in augmented and non-augmented healthcare settings every 2 weeks for a period of 7 months during remedial actions.Methodology. All shower facilities were standardized to include antimicrobial silver-impregnated showerhead/hose units, hose-length fixed to 0.8 m and replaced every 3 months. Standard hospital manual decontamination/disinfection occurred daily. Thermostatic-mixer-valves (TMVs) were replaced and disinfected if standard remediation unsuccessful.Results. Of 560 shower and drain samples collected over 14 time-points covering 7 months, P. aeruginosa colonized 40 %(4/10; non-augmented) and 80 %(8/10; augmented-care) showers in the first week. For each week elapsed, new outlets became contaminated with P. aeruginosa by 18-19 % (P<0.001) in shower waters (OR=1.19; CI=1.09-1.31) and drains (OR=1.18; CI=1.09-1.30). P. aeruginosa occurrence in shower water was associated with subsequent colonization of the corresponding drain and vice versa (chi-square; P<0.001) with simultaneous contamination present in 31 %(87/280) of areas. TMV replacement was ineffective in eradicating colonisation in ~83 % of a subset (6/20; three per ward) of contaminated showers.Conclusions. We demonstrate the difficulties in eradicating P. aeruginosa from hospital plumbing, particularly when contamination is no longer sporadic. Non-augmented care settings are reservoirs of P. aeruginosa and should not be overlooked in outbreak investigations. Antimicrobial-impregnated materials may be ineffective once colonization with P. aeruginosa is established beyond the hose and head. Reducing hose-length insufficient to prevent cross-contamination from shower drains. P. aeruginosa colonization can be transient in both drain and shower hose/head. Frequent microbiological monitoring suggests testing frequencies following HTM04-01 guidelines are insufficient to capture the colonization-status of healthcare waters between samples. Disinfection/decontamination is recommended to minimize bioburden and the effect of remediation should be verified with microbiological monitoring. Where standard remediation did not remove P. aeruginosa contamination, intensive monitoring supported justifying replacement of showers and contiguous plumbing.

Post-COVID Pulmonary Aspergillosis with Pulmonary Thromboembolism and Pulmonary Artery Hypertension Unmasking Prediabetes: A Case Report

Multiple complications during and following COVID-19 infection are being reported worldwide. The most serious and life-threatening are thromboembolism and invasive fungal diseases. We report a post-COVID-19 case with complications of fungal infection of the lungs and pulmonary thromboembolism with pulmonary hypertension and unmasking prediabetes. A 53-year-old male patient presented with complaints of cough, fever, exertional breathlessness for 15 days, chest pain and hoarseness of voice for 7 days. He had a prior history of COVID 10 months earlier and no comorbidities. On further investigation by computed pulmonary tomography angiography, bronchoscopy and other investigations, the patient was found to have pulmonary thromboembolism, pulmonary aspergillosis and pulmonary artery hypertension. He was treated with amphotericin B for 21 days and anticoagulants for 6 months. He had significant clinical and radiological improvement with the resolution of the embolism. The crucial factors for successful care in post-COVID-19 immune-suppressed patients include a high index of suspicion, early use of adequate diagnostic tests helped by antifungal medications, anticoagulants and control of risk factors such as hyperglycaemia.

Variant enterovirus A71 found in immune-suppressed patient binds to heparan sulfate and exhibits neurotropism in B-cell-depleted mice

Enterovirus A71 (EV-A71) causes hand, foot, and mouth disease outbreaks with neurological complications and deaths. We previously isolated an EV-A71 variant in the stool, cerebrospinal fluid, and blood of an immunocompromised patient who had a leucine-to-arginine substitution on the VP1 capsid protein, resulting in increased heparin sulfate binding. We show here that this mutation increases the virus's pathogenicity in orally infected mice with depleted B cells, which mimics the patient's immune status, and increases susceptibility to neutralizing antibodies. However, a double mutant with even greater heparin sulfate affinity is not pathogenic, suggesting that increased heparin sulfate affinity may trap virions in peripheral tissues and reduce neurovirulence. This research sheds light on the increased pathogenicity of variant with heparin sulfate (HS)-binding ability in individuals with decreased B cell immunity.

Natural killer cells suppress human cutaneous squamous cell carcinoma cancer cell survival and tumor growth.

Cutaneous squamous cell carcinoma (CSCC), which develops in response to ultraviolet irradiation exposure, is among the most common cancers. CSCC lesions can be removed by surgical excision, but 4.5% of these cancers reappear as aggressive and therapy-resistant tumors. CSCC tumors display a high mutation burden, and tumor frequency is dramatically increased in immune-suppressed patients, indicating a vital role for the immune system in controlling cancer development. Natural killer cells (NK cells) play a key role in cancer immune surveillance, and recent studies suggest that NK cells from healthy donors can be expanded from peripheral blood for use in therapy. In the present study, we test the ability of ex vivo expanded human NK cells to suppress the CSCC cell cancer phenotype and reduce tumor growth. We expanded human NK cells from multiple healthy donors, in the presence of IL-2, and tested their ability to suppress the CSCC cell cancer phenotype. NK cell treatment produced a dose-dependent reduction in SCC-13 and HaCaT cell spheroid growth and matrigel invasion and induced SCC-13 and HaCaT cell apoptosis as evidenced by increased procaspase 9, procaspase 3, and PARP cleavage. Moreover, two important CSCC cell pro-cancer signaling pathways, YAP1/TAZ/TEAD and MEK1/2-ERK1/2, were markedly reduced. Furthermore, tail-vein injection of NK cells markedly suppressed the growth of SCC-13 xenograft tumors in NSG mice, which was also associated with a reduction in YAP1 and MEK1/2-P levels and enhanced apoptosis. These findings show that NK cell treatment suppresses CSCC cell spheroid formation, invasion, viability, and tumor growth, suggesting NK cell treatment may be a candidate therapy for CSCC.

“50 shades of groin pain” in an unusual case of osteomyelitis pubis following surgery

Osteomyelitis pubis (OP) is a rare type of infection involving the pubic bones that often poses diagnostic and consecutive therapeutic problems. The infection can be mono or polymicrobial, bacterial, mycotic or bacillary with Staphylococcus aureus being the most common infectious agent involved. OP is generally seen in immune-suppressed patients of oncologic and diabetic population or in pediatric and geriatric subjects. The main symptom is represented by local pain with radiation to thighs which in later stages is accompanied by general non-specific symptoms such as malaise, fever and loss of appetite. The specificity-lacking initial presentation often leads to diagnostic delays which furthermore decrease the effectiveness of drug therapy, leading to higher chances of bone and joint destruction. Initial therapy consists of empirical antibiotherapy that should cover Staph. aureus; depending on culture results, the scheme should be changed accordingly. Moreover, symptomatic treatment of pain and inflammation consisting of NSAIDs, small dose glucocorticoids and minor opioids should be considered. Selected cases may benefit from surgical intervention when improvement or remission is considered improbable under drug therapy or when severe bony destructions are present.

Withania somnifera (L.) Dunal (Ashwagandha) for the possible therapeutics and clinical management of SARS-CoV-2 infection: Plant-based drug discovery and targeted therapy.

Coronavirus disease 2019 (COVID-19) pandemic has killed huge populations throughout the world and acts as a high-risk factor for elderly and young immune-suppressed patients. There is a critical need to build up secure, reliable, and efficient drugs against to the infection of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus. Bioactive compounds of Ashwagandha [Withania somnifera (L.) Dunal] may implicate as herbal medicine for the management and treatment of patients infected by SARS-CoV-2 infection. The aim of the current work is to update the knowledge of SARS-CoV-2 infection and information about the implication of various compounds of medicinal plant Withania somnifera with minimum side effects on the patients’ organs. The herbal medicine Withania somnifera has an excellent antiviral activity that could be implicated in the management and treatment of flu and flu-like diseases connected with SARS-CoV-2. The analysis was performed by systematically re-evaluating the published articles related to the infection of SARS-CoV-2 and the herbal medicine Withania somnifera. In the current review, we have provided the important information and data of various bioactive compounds of Withania somnifera such as Withanoside V, Withanone, Somniferine, and some other compounds, which can possibly help in the management and treatment of SARS-CoV-2 infection. Withania somnifera has proved its potential for maintaining immune homeostasis of the body, inflammation regulation, pro-inflammatory cytokines suppression, protection of multiple organs, anti-viral, anti-stress, and anti-hypertensive properties. Withanoside V has the potential to inhibit the main proteases (Mpro) of SARS-CoV-2. At present, synthetic adjuvant vaccines are used against COVID-19. Available information showed the antiviral activity in Withanoside V of Withania somnifera, which may explore as herbal medicine against to SARS-CoV-2 infection after standardization of parameters of drug development and formulation in near future.

Complexities of JC Polyomavirus Receptor-Dependent and -Independent Mechanisms of Infection.

JC polyomavirus (JCPyV) is a small non-enveloped virus that establishes lifelong, persistent infection in most of the adult population. Immune-competent patients are generally asymptomatic, but immune-compromised and immune-suppressed patients are at risk for the neurodegenerative disease progressive multifocal leukoencephalopathy (PML). Studies with purified JCPyV found it undergoes receptor-dependent infectious entry requiring both lactoseries tetrasaccharide C (LSTc) attachment and 5-hydroxytryptamine type 2 entry receptors. Subsequent work discovered the major targets of JCPyV infection in the central nervous system (oligodendrocytes and astrocytes) do not express the required attachment receptor at detectable levels, virus could not bind these cells in tissue sections, and viral quasi-species harboring recurrent mutations in the binding pocket for attachment. While several research groups found evidence JCPyV can use novel receptors for infection, it was also discovered that extracellular vesicles (EVs) can mediate receptor independent JCPyV infection. Recent work also found JCPyV associated EVs include both exosomes and secretory autophagosomes. EVs effectively present a means of immune evasion and increased tissue tropism that complicates viral studies and anti-viral therapeutics. This review focuses on JCPyV infection mechanisms and EV associated and outlines key areas of study necessary to understand the interplay between virus and extracellular vesicles.

Kavernöse nichttuberkulöse Mykobakteriose der Lunge durch M. heckeshornense bei einem HIV-infizierten Patienten

Since we first described Mycobacterium heckeshornense, a rare species of mycobacteria in 2000, only 21 cases of infection with this mycobacterium have been described in humans. We relate the diagnosis and therapy of another case of this uncommon nontuberculous mycobacterium in an immune-suppressed patient.

GRP78: A possible relationship of COVID-19 and the mucormycosis; in silico perspective

Mucormycosis is a severe fungal infection reported in many cancer survivors, diabetic and immune-suppressed patients during organ transplants. A vast spark in the reported COVID-19 cases is noticed in India during the second wave in May 2021, when Mucormycosis is declared an epidemic. Despite being a rare disease, the mortality rate associated with Mucormycosis is more than 40%. Spore coat proteins (CotH) are essential proteins in many pathogenic bacteria and fungi. CotH3 was reported as the vital protein required for fungal virulence in Mucormycosis. We previously reported the involvement of the host cell-surface receptor GRP78 in SARS-CoV-2 spike recognition. Additionally, GRP78 is known to be the virulence factor during Mucormycosis. Using state-of-the-art structural bioinformatics and molecular modeling tools, we predicted the GRP78 binding site to the Rhizopus delemar CotH3 protein. Our findings pave the way toward rationally designing small molecule inhibitors targeting the GRP78 and its counter proteins in both pathogenic viral (SARS-CoV-2 spike) and fungal (R. delemar CotH3) diseases.

Herpes simplex encephalitis in patients receiving chemotherapy and whole-brain radiation therapy.

Herpes simplex encephalitis (HSE) is a very severe infection of the central nervous system (CNS) caused mainly by herpes simplex virus type 1 (HSV-1) and occasionally by herpes simplex virus type 2 (HSV-2). After relapse or drug-resistant to chemotherapy, whole-brain radiation therapy (WBRT) is a mainstay of treatment in patients with both identifiable brain metastases and CNS lymphoma. Although HSV-1 encephalitis predominantly affects immunocompetent host, HSV encephalitis may be more common in immune-suppressed patients than is currently recognized. Disease presentation may be atypical including lack of pleocytosis in cerebrospinal fluid (CSF). We report four patients diagnosed with HSE following chemotherapy and WBRT. The occurrence of HSE in patients with cancer seems not to be increased compared to the general population, but as our case series shows, a high level of suspicion is needed by the treating physician to diagnose HSE early in patients presenting with new neurological symptoms following WBRT.

CARs—A New Perspective to HCMV Treatment

Human cytomegalovirus (HCMV), by primary infection or reactivation, represents a great risk for immune-suppressed or compromised patients. In immunocompetent humans, the immune system suppresses the spread of HCMV during an infection, resulting in a mostly asymptomatic or mild course of the disease, whereas in immune suppressed patients, the compromised host immune response cannot control the viral infection. Multiple viral immunomodulatory mechanisms additionally contribute to immune evasion. Use of chimeric antigen receptors (CARs), a treatment strategy adapted from cancer immunotherapy, is investigated for possible application to combat HCMV and other infections in immunocompromised patients. The administration of CAR+ T-cells directed against HCMV antigens can bypass viral immune evasion and may complement existing treatment methods. This review gives a short overview of HCMV, the obstacles of current treatment options as well as a brief introduction to CARs and the current research situation on CAR+ T-cells against HCMV.

Low-Coverage Whole Genome Sequencing of Cell-Free DNA From Immunosuppressed Cancer Patients Enables Tumor Fraction Determination and Reveals Relevant Copy Number Alterations.

Cell-free DNA (cfDNA) analysis is a minimally invasive method that can be used to detect genomic abnormalities by directly testing a blood sample. This method is particularly useful for immunosuppressed patients, who are at high risk of complications from tissue biopsy. The cfDNA tumor fraction (TF) varies greatly across cancer type and between patients. Thus, the detection of molecular alterations is highly dependent on the circulating TF. In our study, we aimed to calculate the TF and characterize the copy number aberration (CNA) profile of cfDNA from patients with rare malignancies occurring in immunosuppressed environments or immune-privileged sites. To accomplish this, we recruited 36 patients: 19 patients with non-Hodgkin lymphoma (NHL) who were either human immunodeficiency virus (HIV)-positive or organ transplant recipients, 5 HIV-positive lung cancer patients, and 12 patients with glioma. cfDNA was extracted from the patients’ plasma and sequenced using low-coverage whole genome sequencing (LC-WGS). The cfDNA TF was then calculated using the ichorCNA bioinformatic algorithm, based on the CNA profile. In parallel, we performed whole exome sequencing of patient tumor tissue and cfDNA samples with detectable TFs. We detected a cfDNA TF in 29% of immune-suppressed patients (one patient with lung cancer and six with systemic NHL), with a TF range from 8 to 70%. In these patients, the events detected in the CNA profile of cfDNA are well-known events associated with NHL and lung cancer. Moreover, cfDNA CNA profile correlated with the CNA profile of matched tumor tissue. No tumor-derived cfDNA was detected in the glioma patients. Our study shows that tumor genetic content is detectable in cfDNA from immunosuppressed patients with advanced NHL or lung cancer. LC-WGS is a time- and cost-effective method that can help select an appropriate strategy for performing extensive molecular analysis of cfDNA. This technique also enables characterization of CNAs in cfDNA when sufficient tumor content is available. Hence, this approach can be used to collect useful molecular information that is relevant to patient care.

A Case Report on Mucormycosis in Non-Diabetic, Non-Covid Recovered Patient with no History of Steroid use

Rhino cerebral orbital mucormycosis is an aggressively spreading fungal infection caused by filamentous fungi of the Mucoraceae family and is found to be more prone in patients with comorbidities that include: uncontrolled diabetes mellitus, immune-suppressed patients, iron and aluminum overload, chronic steroid therapy, severe trauma, and protein-energy malnutrition.&#x0D; A 51year old male patient was admitted to the hospital with a complaint of headache and intermittent fever. The patient had no history of diabetes or denovo hypertension. Based on the analysis of histopathological and radiological investigations, the patient was diagnosed with mucormycosis. The patient furthermore underwent an endoscopic surgical debridement followed by standard treatment including antifungal antibiotic(amphotericin-B) and azole antifungals (posaconazole) along with symptomatic treatment. Though the patient was given all possible therapy available, no improvement was seen in the patient's condition (poor prognosis).

Oncolytic Virotherapy for Cancer: Clinical Experience.

Oncolytic viruses are a new class of therapeutics which are largely in the experimental stage, with just one virus approved by the FDA thus far. While the concept of oncolytic virotherapy is not new, advancements in the fields of molecular biology and virology have renewed the interest in using viruses as oncolytic agents. Backed by robust preclinical data, many oncolytic viruses have entered clinical trials. Oncolytic viruses that have completed some levels of clinical trials or are currently undergoing clinical trials are mostly genetically engineered viruses, with the exception of some RNA viruses. Reolysin, an unmodified RNA virus is clinically the most advanced oncolytic RNA virus that has completed different phases of clinical trials. Other oncolytic viruses that have been studied in clinical trials are mostly DNA viruses that belong to one of the three families: herpesviridae, poxviridae or adenoviridae. In this review work we discuss recent clinical studies with oncolytic viruses, especially herpesvirus, poxvirus, adenovirus and reovirus. In summary, the oncolytic viruses tested so far are well tolerated, even in immune-suppressed patients. For most oncolytic viruses, mild and acceptable toxicities are seen at the currently defined highest feasible doses. However, anti-tumor efficacies of oncolytic viruses have been modest, especially when used as monotherapy. Therefore, the potency of oncolytic viruses needs to be enhanced for more oncolytic viruses to hit the clinic. Aiming to achieve higher therapeutic benefits, oncolytic viruses are currently being studied in combination with other therapies. Here we discuss the currently available clinical data on oncolytic viruses, either as monotherapy or in combination with other treatments.

#11: Metronidazole for the Treatment of Norovirus in Transplant Recipients

Abstract Background Norovirus is a common cause of gastroenteritis in both immunocompetent and immunocompromised hosts. In transplant recipients, it can lead to prolonged shedding and chronic diarrhea. Treatment with nitazoxanide, oral immunoglobulin, or mammalian target of rapamycin (mTOR) inhibitors have shown varying degrees of benefit in small studies. The commensal gastrointestinal bacterial flora may influence the pathogenesis of norovirus infection. Metronidazole is often used to modulate gastrointestinal flora, and improvement of an HIV patient with suspected Giardia infection subsequently identified to have norovirus suggested a possible use of this drug for other immune-suppressed patients with norovirus infection. Methods Solid-organ or stem cell transplant recipients testing positive for norovirus in stool from July 2014 to March 2019 were identified from the medical record. Patient characteristics, laboratory data, and medications were systematically reviewed to identify factors associated with clinical improvement. Results Thirty-eight patients met inclusion criteria. Almost 75% of the patients were male. Almost 80% of the patients were solid-organ transplant recipients: 40% heart, 24% kidney, and 15% liver. There were 85 positive norovirus tests among the 38 patients. Of these, 14 involved coinfections with another potential pathogen: 11 with adenovirus, 2 with Clostridioides difficile, and 1 with cytomegalovirus. In 25 of the 85 positive norovirus tests, nitazoxanide was given. Clinical improvement was documented in 15 of these episodes (60%), while no improvement was observed in 10 (40%). Eight positive tests were treated with metronidazole alone, with documented improvement observed during 6 (75%) courses. In 9 additional episodes, metronidazole was given within a week of the test result and 2 of these had improvement. When other antibiotics were used concurrently with metronidazole, 78% of episodes (7/9) did not lead to clinical response. Changes in immunosuppression were used for the treatment of 6 episodes, leading to clinical improvement in 5. Conclusion Metronidazole treatment was associated with clinical improvement of norovirus gastroenteritis in transplant recipients at rates similar to those seen with nitazoxanide therapy. Reduction in immunosuppression also led to clinical improvement but in situations where that cannot be done safely, metronidazole may be an alternative to nitazoxanide. In this cohort, metronidazole was only used as a therapy after nitazoxanide, suggesting that a trial of metronidazole as rescue therapy in comparison to a repeat course of nitazoxanide after the initial failure of nitazoxanide is justified.

PD-1 inhibition therapy for advanced cutaneous squamous cell carcinoma: a retrospective analysis from the University of Southern California.

Approximately 5% of patients with cutaneous squamous cell carcinoma (CSCC) may develop recurrent or metastatic disease. The management of such cases is challenging and requires multi-disciplinary care. Immunotherapy using PD-1 inhibition was approved to treat unresectable or metastatic CSCC in 2018. Given limited data regarding clinical outcomes outside of published trials, we describe our experience using this therapy. We retrospectively reviewed all patients treated with PD-1 inhibition as therapy for locally advanced, regionally metastatic or distant metastatic CSCC at the University of Southern California. Clinicopathological characteristics, treatment data using PD-1 inhibitors, and outcomes were assessed. Among 26 patients treated with PD-1 inhibition, the objective response rate was 42.3%, with 19.2% of patients having partial response and 23.1% having complete response to therapy. The median progression-free survival was 5.4months. Median tumor mutational burden (TMB) was higher among responders compared to non-responders (60 vs. 9 Mut/Mb, p = 0.04). Primary CSCC tumor location on the head/neck was also associated with response to PD-1 inhibition (p = 0.04). Two patients with mutations affecting mismatch repair deficiency were noted to have complete response to treatment. No other variables were associated with treatment outcomes. PD-1 inhibition produces durable responses among patients with advanced or metastatic CSCC. PD-1 inhibition therapy is well tolerated, but patients should be monitored closely for immune-related adverse events, particularly frail or immune-suppressed patients. Further investigation of potential biomarkers to help identify patients who will derive the most benefit from this therapeutic option is needed.

The Risk and Impact of COVID-19 Pandemic on Immunosuppressed Patients: Cancer, HIV, and Solid Organ Transplant Recipients.

Toward the end of the year 2019, there was the eruption of an acute respiratory syndrome, which is widely referred as coronavirus disease (COVID-19) from Wuhan, Hubei Province. The disease causes a range of respiratory illnesses, which are fatal. The COVID-19 disease has spread globally and has significantly impacted the health delivery systems, travel regulations, and economic activities and has posed and upsurge of responsibilities for the frontline healthcare workers. Due to the nature of the COVID-19 disease, it has typically caused complications which include pneumonia, multiple organ dysfunction together with renal failure, and acute respiratory distress syndrome. As of date, there is no approved vaccine or treatment for COVID-19 though there are ongoing research studies to formulate a treatment. COVID-19 is highly contagious, and the risk of infection is higher for patients with immunesuppressed patients than regular patients. The immunesuppressed conditions include cancer, HIV, and patients with solid organ transplants (SOT). This paper aims to review the risk and impact of COVID-19 on immunesuppressed patients, with a focus on cancer, HIV, and patients with SOT and the essence of special parameters for their care and management. Despite the fatal effects of this global pandemic, the findings of this study indicate the high risk which immunosuppressed patients have to contract the disease; thus, the governments and health delivery systems have to offer them extra support and treatment.