Pembrolizumab-associated anti-MDA5 dermatomyositis in a patient with lung cancer: a first case report.

We report the first case of anti-melanoma differentiation-associated gene 5 (MDA5)-positive dermatomyositis as a systemic immune-related adverse event in a 64-year-old man receiving pembrolizumab to treat advanced lung cancer. The patient experienced hypothyroidism, myalgia, skin involvement, dyspnoea and diarrhoea. Laboratory tests revealed raised inflammatory markers, hypercreatinekinasemia and anti-MDA5 autoantibodies. Electroneuromyography and pathognomonic signs on physical examination confirmed the diagnosis of pauci-myopathic dermatomyositis. Pembrolizumab was discontinued and immunosuppressive therapy led to rapid and progressive improvement, with complete remission of dermatomyositis. This case report widens the spectrum of systemic immune-related adverse events associated with pembrolizumab.

The importance of caregivers for patients with advanced basal cell carcinoma treated with hedgehog-pathway inhibitors: an observational prospective study.

Oral targeted therapy with hedgehog pathway inhibitors has revolutionized the standard of care for patients with advanced basal cell carcinoma (BCC). These patients are frail and elderly, have various comorbidities, and receive pharmacological polytherapy. Moreover, adverse events may have a significant impact on therapeutic adherence, which must be managed by the clinician. We evaluated the impact of caregivers on the treatment of patients with advanced BCC in terms of continuation of therapy over time. All patients included in this observational prospective study had histologically confirmed metastatic or locally advanced BCC (LaBCC) and were treated with hedgehog pathway inhibitors from January 2016 to December 2021 at the Department of Dermatology at the University of Florence, Italy. The collected patient data included: age, sex, BCC site and area of spread; number of cycles, dose, duration and tolerability of therapy; marital status (single, divorced, married/living with a partner, widow/widower); and information such as living with someone, and the presence of any caregivers. Of the 34 patients included, 33 had LaBCC and one metastatic BCC. There were 11 females (32.4%) and 23 males (67.6%). Patients who were married or living with a caregiver -tolerated therapy better than single patients who lived alone. Indeed, patients with married/live-in caregivers and/or those with an adequate caregiver experienced greater therapeutic adherence and tolerance of adverse events. Given the greater therapeutic adherence of patients with live-in caregivers as partners, it is essential to consider patients' marital status. It is advisable to involve the caregiver early on, and there should be a training discussion on the various possible adverse events and the best way to mitigate them. Therapeutic success is linked not only to patients being informed but also to training of caregivers.

Presentation and progression of MPO-ANCA interstitial lung disease.

The association between MPO-ANCA-associated vasculitis (AAV) and interstitial lung disease (ILD) has been well established. Pulmonary fibrosis may coexist with, follow, or even precede the diagnosis of AAV, and its presence adversely affects the prognosis. The optimal approach to investigating ANCA in patients with ILD remains a subject of ongoing debate. Here we aim to describe presentation and progression of MPO-ANCA ILD. We conducted a retrospective evaluation of a cohort of individuals diagnosed with MPO-ANCA ILD, with or without accompanying renal impairment, at the Immunology and Cell Therapy Unit, Careggi University Hospital, Florence, Italy, between June 2016 and June 2022. Clinical records, imaging studies, pathologic examinations, and laboratory test results were collected. Among the 14 patients identified with MPO-ANCA ILD, we observed a significant association between MPO-ANCA titers assessed at the time of ILD diagnosis and renal involvement. Renal impairment in these cases often manifested as subclinical or slowly progressive kidney damage. Interestingly, complement C3 deposits were consistently found in all renal biopsy specimens, thereby suggesting the potential for novel therapeutic targets in managing renal complications associated with MPO-ANCA ILD. The presentation of MPO-ANCA vasculitis as ILD can be the first and only clinical manifestation. MPO-ANCA levels at ILD diagnosis could warn on the progression to renal involvement in patients with MPO-ANCA ILD, hence caution is needed because renal disease can be subclinical or smoldering.

Disseminated nocardiosis and anti-GM-CSF antibodies.

Infections that are unusually severe or caused by opportunistic pathogens are a hallmark of primary immunodeficiency (PID). Anti-cytokine autoantibodies (ACA) are an emerging cause of acquired immunodeficiency mimicking PID. Nocardia spp. are Gram-positive bacteria generally inducing disseminated infections in immunocompromised patients, but seldom also occurring in apparently immunocompetent hosts. Anti-GM-CSF autoantibodies are associated with autoimmune pulmonary alveolar proteinosis (PAP). In those patients, an increased incidence of disseminated nocardiosis and cryptococcosis has been observed. It is unclear whether the PAP or the autoantibodies predispose to the infection. We report an apparently immunocompetent woman presenting with disseminated nocardiosis without any evidence of PAP. Clinical data and radiological images were retrospectively collected. Lymphocyte populations were analyzed by flow cytometry. Anti-GM-CSF autoantibodies were measured by ELISA. A 55-year-old otherwise healthy woman presented with cerebral and pulmonary abscesses. Personal and familial history of infections or autoimmunity were negative. After extensive examinations, a final diagnosis of disseminated nocardiosis was made. Immunologic investigations including neutrophilic function and IFN-γ/IL-12 circuitry failed to identify a PID. Whole-exome sequencing did not find pathogenic variants associated with immunodeficiency. Serum anti-GM-CSF autoantibodies were positive. There were no clinical or instrumental signs of PAP. Trimethoprim-sulfamethoxazole and imipenem were administered, with progressive improvement and recovery of the infectious complication. We identified anti-GM-CSF autoantibodies as the cause of disseminated nocardiosis in a previously healthy and apparently immunocompetent adult. This case emphasizes the importance of including ACA in the differential diagnosis of PID, especially in previously healthy adults. Importantly, anti-GM-CSF autoantibodies can present with disseminated nocardiosis without PAP.

Optimization of the diagnosis and characterization of gibberellin-regulated protein sensitization: An Italian cohort study.

BACKGROUND: Pru p 7 was the first gibberellin-regulated protein (GRP) to be identified as a food allergen as the basis of a pollen food allergy syndrome. OBJECTIVE: To clinically and biologically characterize a group of patients with suspected allergy to Pru p 7 to optimize the diagnostic workup of GRP sensitization. METHODS: Allergy to Pru p 7 was suspected in the presence of a systemic allergic reaction to plant food, positive skin prick test results for cypress pollen and lipid-transfer protein-enriched peach extract, and absence of Pru p 3-specific immunoglobulin E. Controls were patients with food allergies, patients sensitized to Pru p 3, and patients with cypress allergy without food allergy. Diagnostic workup included skin tests, basophil activation test, Western blot, and single and multiplex assays. RESULTS: In total, 23 patients and 14 controls were enrolled. The most implicated food was peach (91.3%). Approximately 70% of patients reacted to multiple foods. Mueller 4 reactions were 8.7%. In 26.1% of cases, a cofactor triggered the reaction. The basophil activation test results were positive for rPru p 7 in 87% of the patients. Specific immunoglobulin E to Pru p 7 was detected in 95.7% by singleplex and in 73.9% by multiplex assays in patients with suspected allergies; 73.9% of them also reacted to cypress pollen GRP (Cup s 7) in Western blot analysis. CONCLUSION: Patients with Pru p 7-Cup s 7 allergy in our cohort confirm a mild-to-severe clinical syndrome characterized by pollen and food allergy. The diagnosis may benefit from the proposed selection criteria that can be used as preliminary steps to further characterize the cross-reactive GRP sensitization.

Bendamustine impairs humoral but not cellular immunity to SARS-CoV-2 vaccination in rituximab-treated B-cell lymphoma-affected patients.

Background: Patients with B-cell lymphoma are a fragile category of subjects, particularly exposed to infections and characterized by an impaired vaccination response due to the disease itself and, even more, to the chemotherapy regimen. For this reason, extensive knowledge of the immune response status of these subjects is of fundamental importance to obtain possible indications for a tailored immunization strategy. Methods: We enrolled two cohorts of patients with B-cell lymphoma under rituximab treatment or 3-24 months after treatment. In all patients, we evaluated both humoral and cellular immunological memory toward SARS-CoV-2, after standard vaccination and upon one booster dose. Results: We observed no Spike-specific IgG production in patients (n = 25) under anti-CD20 treatment, whereas patients (n = 16) vaccinated after the completion of chemotherapy showed a higher humoral response. Evaluating SARS-CoV-2-specific T-cell response, we found that patients in both cohorts had developed robust cellular immunity after vaccination. Of the 21 patients (51%) that experienced a breakthrough SARS-CoV-2 infection, only six patients developed severe disease. Interestingly, these six patients had all been treated with rituximab plus bendamustine. Notably, we observed that Spike-specific IgG levels in patients treated with rituximab plus bendamustine were absent or lower compared with those in patients treated with rituximab plus other chemotherapy, whereas Spike-specific T-cell response was not different based on chemotherapy regiment. Discussion: Our results show that, in patients with B-cell lymphoma under rituximab therapy, anti-SARS-CoV-2 mRNA vaccination induces a weak or absent humoral response but a consistent T-cell response. In addition, chemotherapy regimens with bendamustine further reduce patients' ability to mount a Spike-specific humoral response even after a long time period from chemotherapy discontinuation. These results provide evidence that different chemotherapeutics display different immunosuppressive properties that could be taken in to account in the choice of the right drug regimen for the right patient. Moreover, they question whether immunocompromised patients, particularly those treated with bendamustine, need interventions to improve vaccine-induced immune response.

Clonally expanded PD-1-expressing T cells are enriched in synovial fluid of juvenile idiopathic arthritis patients.

Juvenile idiopathic arthritis (JIA) is the most common chronic rheumatic condition in childhood. The disease etiology remains largely unknown; however, a key role in JIA pathogenesis is surely mediated by T cells. T-lymphocytes activity is controlled via signals, known as immune checkpoints. Delivering an inhibitory signal or blocking a stimulatory signal to achieve immune suppression is critical in autoimmune diseases. However, the role of immune checkpoints in chronic inflammation and autoimmunity must still be deciphered. In this study, we investigated at the single-cell level the feature of T cells in JIA chronic inflammation, both at the transcriptome level via single-cell RNA sequencing and at the protein level by flow cytometry. We found that despite the heterogeneity in the composition of synovial CD4+ and CD8+ T cells, those characterized by PD-1 expression were clonally expanded tissue-resident memory (Trm)-like cells and displayed the highest proinflammatory capacity, suggesting their active contribution in sustaining chronic inflammation in situ. Our data support the concept that novel therapeutic strategies targeting PD-1 may be effective in the treatment of JIA. With this approach, it may become possible to target overactive T cells regardless of their cytokine production profile.

Musculin does not modulate the disease course of Experimental Autoimmune Encephalomyelitis and DSS colitis.

Previous evidences show that Musculin (Msc), a repressor member of basic helix-loop-helix transcription factors, is responsible in vitro for the low responsiveness of human Th17 cells to the growth factor IL-2, providing an explanation for Th17 cells rarity in inflammatory tissue. However, how and to what extent Musculin gene can regulate the immune response in vivo in an inflammatory context is still unknown. Here, exploiting two animal models of inflammatory diseases, the Experimental Autoimmune Encephalomyelitis (EAE) and the dextran sodium sulfate (DSS)-induced colitis, we evaluated the effect of Musculin gene knock-out on clinical course, performing also a deep immune phenotypical analysis on T cells compartment and an extended microbiota analysis in colitis-sick mice. We found that, at least during the early phase, Musculin gene has a very marginal role in modulating both the diseases. Indeed, the clinical course and the histological analysis showed no differences between wild type and Msc knock-out mice, whereas immune system appeared to give rise to a regulatory milieu in lymph nodes of EAE mice and in the spleen of DSS colitis-sick mice. Moreover, in the microbiota analysis, we found irrelevant differences between wild type and Musculin knock-out colitis-sick mice, with a similar bacterial strains' frequency and diversity after the DSS treatment. This work strengthened the idea of a negligible Msc gene involvement in these models.

Anti-RuvBL1/2 Autoantibodies Detection in a Patient with Overlap Systemic Sclerosis and Polymyositis.

Anti-RuvBL1/2 autoantibodies have recently been detected in patients with systemic sclerosis (SSc) and scleromyositis overlap syndromes. These autoantibodies exhibit a distinct speckled pattern in an indirect immunofluorescent assay on Hep-2 cells. We report the case of a 48 year old man with facial changes, Raynaud's phenomenon, puffy fingers, and muscle pain. A speckled pattern on Hep-2 cells was identified, but the conventional antibody testing was negative. Based on the clinical suspicion and the ANA pattern, further testing was sought demonstrating anti-RuvBL1/2 autoantibodies. Hence, a review of the English literature was performed to define this newly emerging clinical-serological syndrome. With the one here reported, a total of 52 cases have been described to date (December 2022). Anti-RuvBL1/2 autoantibodies are highly specific for SSc and are associated with SSc/PM overlaps. Apart from myopathy, gastrointestinal and pulmonary involvement are frequently observed in these patients (94% and 88%, respectively).

Fourth Dose of mRNA COVID-19 Vaccine Transiently Reactivates Spike-Specific Immunological Memory in People Living with HIV (PLWH).

Background: People Living With HIV (PLWH), with advanced disease, lower CD4+ T cell counts or an unsuppressed HIV viral load can have a suboptimal vaccine response. For this reason, in the current COVID-19 pandemic, they represent a prioritized population for the SARS-CoV-2 fourth (or second booster) vaccine dose. This work aims to investigate the effects of a second booster on the reactivation of the spike-specific humoral and cell-mediated immune responses in PLWH. Methods: A total of eight PLWH, who received a fourth dose of the original mRNA vaccines were enrolled. They were evaluated before and then 7 days, 1 month and 2 months after the injection. The humoral response was assessed via a chemiluminescent immunoassay. Immunophenotyping and the functional evaluation of the SARS-CoV-2-specific cellular immune responses were performed via flow cytometry. Results: Anti-spike IgG levels were above the cut-off value for all subjects at all timepoints. The spike-specific CD4+ T cell response was reactivated one week after the fourth vaccine dose, and on average declined at two months post-vaccination. A similar trend was observed for the spike-specific B cells. A low percentage of spike-specific CD4+ T cells was activated by the B.1.1.529 BA.1 Omicron-spike mutated peptides, and the majority of these cells were reactive to the conserved portions of the spike protein. Similarly, the majority of the spike-specific memory B cells were able to bind both Wuhan and Omicron-spike entire protein. Conclusions: Spike-specific adaptive immune responses are transiently reactivated in PLWH following the fourth mRNA vaccine dose. The breadth of the immune responses to the mutated spike protein provides insight on the possible cross-reactivity for the SARS-CoV-2 variants of concern (VOCs).

Therapeutical Targets in Allergic Inflammation.

From the discovery of IgE to the in-depth characterization of Th2 cells and ILC2, allergic inflammation has been extensively addressed to find potential therapeutical targets. To date, omalizumab, an anti-IgE monoclonal antibody, and dupilumab, an anti-IL-4 receptor α monoclonal antibody, represent two pillars of biologic therapy of allergic inflammation. Their increasing indications and long-term follow-up studies are shaping the many different faces of allergy. At the same time, their limitations are showing the intricate pathogenesis of allergic diseases.

Long-term SARS-CoV-2 Asymptomatic Carriage in an Immunocompromised Host: Clinical, Immunological, and Virological Implications.

PURPOSE: SARS-CoV-2 infection in immunocompromised hosts is challenging, and prolonged viral shedding can be a common complication in these patients. We describe the clinical, immunological, and virological course of a patient with eosinophilic granulomatosis with polyangiitis, who developed the status of long-term asymptomatic SARS-CoV-2 carrier for more than 7 months. METHODS: Over the study period, the patient underwent 20 RT-PCR tests for SARS-CoV-2 detection on nasopharyngeal swabs. In addition, viral cultures and genetic investigation of SARS-CoV-2 were performed. As for immunological assessment, serological and specific T-cell testing was provided at different time points. RESULTS: Despite the patient showing a deep drug-induced B and T adaptive immunity impairment, he did not experience COVID-19 progression to severe complications, and the infection remained asymptomatic during the follow-up period, but he was not able to achieve viral clearance for more than 7 months. The infection was finally cleared by SARS-CoV-2-specific monoclonal antibody treatment, after that remdesivir and convalescent plasma failed in this scope. The genetic investigations evidenced that the infection was sustained by multiple viral subpopulations that had apparently evolved intra-host during the infection. CONCLUSION: Our case suggests that people with highly impaired B- and T-cell adaptive immunity can prevent COVID-19 progression to severe complications, but they may not be able to clear SARS-CoV-2 infection. Immunocompromised hosts with a long-term infection may play a role in the emergence of viral variants.

Clinical and Immunological Features of SARS-CoV-2 Breakthrough Infections in Vaccinated Individuals Requiring Hospitalization.

BACKGROUND AND PURPOSE: Waning immunity and the surge of SARS-CoV-2 variants are responsible for breakthrough infections, i.e., infections in fully vaccinated individuals. Although the majority of vaccinated infected subjects report mild or no symptoms, some others require hospitalization. The clinical and immunological features of vaccinated hospitalized COVID-19 patients are currently unknown. METHODS: Twenty-nine unvaccinated and 36 vaccinated hospitalized COVID-19 patients were prospectively enrolled and clinical and laboratory data were gathered. Immunophenotyping of leukocytes' subsets, T and B cell SARS-CoV-2-specific responses were evaluated via flow cytometry. Anti-IFN-α autoantibodies were measured via ELISA. RESULTS: Despite vaccinated patients were older and with more comorbidities, unvaccinated subjects showed higher levels of pro-inflammatory markers, more severe disease, and increased mortality rate. Accordingly, they presented significant alterations in the circulating leukocyte composition, typical of severe COVID-19. Vaccinated patients displayed higher levels of anti-Spike IgGs and Spike-specific B cells. Of all participants, survivors showed higher levels of anti-Spike IgGs and Spike-specific CD4+ T cells than non-survivors. At hospital admission, 6 out of 65 patients (9.2%) displayed high serum concentrations of autoantibodies targeting IFN-α. Remarkably, 3 were unvaccinated and eventually died, while the other 3 were vaccinated and survived. CONCLUSION: Despite more severe pre-existing clinical conditions, vaccinated patients have good outcome. A rapid activation of anti-SARS-CoV-2-specific immunity is fundamental for the resolution of the infection. Therefore, prior immunization through vaccination provides a significant contribution to prevention of disease worsening and can even overcome the presence of high-risk factors (i.e., older age, comorbidities, anti-IFN-α autoantibodies).

Variants Disrupting CD40L Transmembrane Domain and Atypical X-Linked Hyper-IgM Syndrome: A Case Report With Leishmaniasis and Review of the Literature.

X-linked hyper-IgM (XHIGM) syndrome is caused by mutations of the CD40LG gene, encoding the CD40L protein. The clinical presentation is characterized by early-onset infections, with profound hypogammaglobulinemia and often elevated IgM, susceptibility to opportunistic infections, such as Pneumocystis jirovecii pneumonia, biliary tract disease due to Cryptosporidium parvum, and malignancy. We report a 41-year-old male presenting with recurrent leishmaniasis, hypogammaglobulinemia, and myopathy. Whole-exome sequencing (WES) identified a missense variant in the CD40LG gene (c.107T>A, p.M36K), involving the transmembrane domain of the protein and a missense variant in the carnitine palmitoyl-transferase II (CPT2; c.593C>G; p.S198C) gene, leading to the diagnosis of hypomorphic XHIGM and CPT2 deficiency stress-induced myopathy. A review of all the previously reported cases of XHIGM with variants in the transmembrane domain showcased that these patients could present with atypical clinical features. Variants in the transmembrane domain of CD40LG act as hypomorphic generating a protein with a lower surface expression. Unlike large deletions or extracellular domain variants, they do not abolish the interaction with CD40, therefore preserving some biological activity.

SARS-CoV-2 Spike-Specific CD4+ T Cell Response Is Conserved Against Variants of Concern, Including Omicron.

Although accumulating data have investigated the effect of SARS-CoV-2 mutations on antibody neutralizing activity, less is known about T cell immunity. In this work, we found that the ancestral (Wuhan strain) Spike protein can efficaciously reactivate CD4+ T cell memory in subjects with previous Alpha variant infection. This finding has practical implications, as in many countries only one vaccine dose is currently administered to individuals with previous COVID-19, independently of which SARS-CoV-2 variant was responsible of the infection. We also found that only a minority of Spike-specific CD4+ T cells targets regions mutated in Alpha, Beta and Delta variants, both after natural infection and vaccination. Finally, we found that the vast majority of Spike-specific CD4+ T cell memory response induced by natural infection or mRNA vaccination is conserved also against Omicron variant. This is of importance, as this newly emerged strain is responsible for a sudden rise in COVID-19 cases worldwide due to its increased transmissibility and ability to evade antibody neutralization. Collectively, these observations suggest that most of the memory CD4+ T cell response is conserved against SARS-CoV-2 variants of concern, providing an efficacious line of defense that can protect from the development of severe forms of COVID-19.

SARS-CoV-2 infection and vaccination trigger long-lived B and CD4+ T lymphocytes with implications for booster strategies.

BACKGROUNDImmunization against SARS-CoV-2, the causative agent of COVID-19, occurs via natural infection or vaccination. However, it is currently unknown how long infection- or vaccination-induced immunological memory will last.METHODSWe performed a longitudinal evaluation of immunological memory to SARS-CoV-2 up to 1 year after infection and following mRNA vaccination in naive individuals and individuals recovered from COVID-19 infection.RESULTSWe found that memory cells are still detectable 8 months after vaccination, while antibody levels decline significantly, especially in naive individuals. We also found that a booster injection is efficacious in reactivating immunological memory to spike protein in naive individuals, whereas it was ineffective in previously SARS-CoV-2-infected individuals. Finally, we observed a similar kinetics of decay of humoral and cellular immunity to SARS-CoV-2 up to 1 year following natural infection in a cohort of unvaccinated individuals.CONCLUSIONShort-term persistence of humoral immunity, together with the reduced neutralization capacity versus the currently prevailing SARS-CoV-2 variants, may account for reinfections and breakthrough infections. Long-lived memory B and CD4+ T cells may protect from severe disease development. In naive individuals, a booster dose restored optimal anti-spike immunity, whereas the needs for vaccinated individuals who have recovered from COVID-19 have yet to be defined.FUNDINGThis study was supported by funds to the Department of Experimental and Clinical Medicine, University of Florence (Project Excellence Departments 2018-2022), the University of Florence (project RICTD2122), the Italian Ministry of Health (COVID-2020-12371849), and the region of Tuscany (TagSARS CoV 2).

Quality of life in patients with allergic and immunologic skin diseases: in the eye of the beholder.

Allergic and immunologic skin diseases negatively impact the quality of life (QoL) of affected patients with detrimental consequences. Nonetheless, in everyday clinical practice the evaluation of QoL is often overlooked. Considering the increasing prevalence of atopic dermatitis, allergic contact dermatitis, hereditary angioedema, cutaneous mastocytosis, and urticaria, it is essential to determine the effects of allergic and immunologic skin diseases on QoL. A joint meeting (GET TOGETHER 2021) of the Italian Society of Allergology, Asthma and Clinical Immunology (SIAAIC) and the Italian Society of Allergological, Occupational and Environmental Dermatology (SIDAPA) aimed to summarize the features of the main QoL tools used in these diseases and to describe the extent of QoL impairment as well as the impact of treatments on QoL, particularly biologic therapies. The assessment of QoL in patients with allergic and immunologic skin diseases relies on generic, organ-specific and disease-specific questionnaires. While generic and organ-specific questionnaires allow comparison between different diseases, disease-specific questionnaires are designed and validated for specific cohorts: the QoL Index for Atopic Dermatitis (QoLIAD) and the Childhood Atopic Dermatitis Impact Scale (CADIS) in atopic dermatitis, the ACD-11 in allergic contact dermatitis, the Angioedema QoL Questionnaire (AE-QoL) and the Hereditary Angioedema QoL questionnaire (HAE-QoL) in hereditary angioedema, the Mastocytosis QoL Questionnaires (MCQoL e MQLQ) in cutaneous mastocytosis, and the Chronic Urticaria QoL questionnaire (CU-Q2oL) in urticaria. Among the many factors that variably contribute to QoL impairment, pruritus can represent the leading cause of patient discomfort. Biologic therapies significantly ameliorate QoL in atopic dermatitis, hereditary angioedema, mastocytosis and chronic urticaria. In general, adequate management strategies are essential for improving QoL in patients with allergic and immunologic skin diseases.

Hallmarks of immune response in COVID-19: Exploring dysregulation and exhaustion.

One and half year following the occurrence of COVID-19 pandemic, significant efforts from laboratories all over the world generated a huge amount of data describing the prototypical features of immunity in the course of SARS-CoV-2 infection. In this Review, we rationalize and organize the main observations, trying to define a "core" signature of immunity in COVID-19. We identified six hallmarks describing the main alterations occurring in the early infection phase and in the course of the disease, which predispose to severe illness. The six hallmarks are dysregulated type I IFN activity, hyperinflammation, lymphopenia, lymphocyte impairment, dysregulated myeloid response, and heterogeneous adaptive immunity to SARS-CoV-2. Dysregulation and exhaustion came out as the trait d'union, connecting abnormalities affecting both innate and adaptive immunity, humoral and cellular responses.