Thursday, February 02, 2023

Autonomic dysfunction as a cause of cardiovascular disease


This free full text review focuses on neurodegenerative synucleinopathies and briefly, in addition, touches on other disorders such as POTS, vasovagal syncope and inappropriate sinus tachycardia.

Synucleinopathies result from misfolded protein aggregates of α-synuclein. The normal function of α-synuclein in the nervous system is not well understood.

The synucleinopathies are parkinson disease, lewy body dementia, pure autonomic failure and multiple system atrophy. Any of these disorders can be accompanied by autonomic dysfunction.

Orthostatic hypotension, supine hypertension, or both may occur. All of the long-term consequences of hypertension may be associated with the supine hypertension seen in autonomic dysfunction. Use of a short acting antihypertensive administered at night is a suggested treatment strategy.

Nucleic acid testing for viral pathogens in community-acquired pneumonia


The American thoracic Society has published a guideline for this in the American Journal of Respiratory and Critical Care Medicine. These are soft recommendations based on low-level evidence.

The guideline does not address influenza or covid.  For influenza, the IDSA community-acquired pneumonia guidelines recommend influenza PCR testing during flu season (in preference to antigen testing ). The  guidelines did not address covid-19 as there was insufficient data at the time of the literature review.

The guideline calls for viral PCR panel testing in the following groups of patients: those with neutropenia, those undergoing active cancer therapy, those with a transplant history, those with advanced HIV,  those with a history of chronic immunosuppression including systemic corticosteroids, and those whose community-acquired pneumonia is classified as severe.

Criteria for severity overlap with some of those just mentioned and include the presence of septic shock or need for mechanical ventilation. Absent these two conditions three of the following minor criteria denote severity: impaired respiratory physiology in the form of either a respiratory rate greater than 30 or a PO2 to Fio2 ratio below 250, multilobar infiltrates, altered mental status, BUN greater than 20, white blood cell count less than 4,000, platelet count less than 100,000,  hypothermia less than 36.8 centigrade or hypotension requiring aggressive fluid resuscitation.

Could aspergillus be hiding out in your critically ill patient?


An issue from the American Journal of respiratory and Critical Care Medicine contains two articles and a related an editorial addressing this subject.

This study looked for evidence of aspergillus infection in patients diagnosed with VAP:

Rationale: Aspergillus infection in patients with suspected ventilator-associated pneumonia remains uncharacterized because of the absence of a disease definition and limited access to sensitive diagnostic tests.

Objectives: To estimate the prevalence and outcomes of Aspergillus infection in adults with suspected ventilator-associated pneumonia.

Methods: Two prospective UK studies recruited 360 critically ill adults with new or worsening alveolar shadowing on chest X-ray and clinical/hematological parameters supporting suspected ventilator-associated pneumonia. Stored serum and BAL fluid were available from 194 nonneutropenic patients and underwent mycological testing. Patients were categorized as having probable Aspergillus infection using a definition comprising clinical, radiological, and mycological criteria. Mycological criteria included positive histology or microscopy, positive BAL fluid culture, galactomannan optical index of 1 or more in BAL fluid or 0.5 or more in serum.

Measurements and Main Results: Of 194 patients evaluated, 24 met the definition of probable Aspergillus infection, giving an estimated prevalence of 12.4% (95% confidence interval, 8.1–17.8). All 24 patients had positive galactomannan in serum (n = 4), BAL fluid (n = 16), or both (n = 4); three patients cultured Aspergillus sp. in BAL fluid. Patients with probable Aspergillus infection had a significantly longer median duration of critical care stay (25.5 vs. 15.5 d, P = 0.02). ICU mortality was numerically higher in this group, although this was not statistically significant (33.3% vs. 22.8%; P = 0.23).

Conclusions: The estimated prevalence for probable Aspergillus infection in this geographically dispersed multicenter UK cohort indicates that this condition should be considered when investigating patients with suspected ventilator-associated pneumonia, including patient groups not previously recognized to be at high risk of aspergillosis.

Another study in the same issue looked at the prevalence of aspergillus in patients on mechanical ventilation with covid-19. They found it in over 20% of patients.

The accompanying editorial cited additional evidence all of which suggests that aspergillus infection is under-diagnosed in critically ill patients.

Patients need not be immunosuppressed in the traditional sense although the use of corticosteroids, even short-term, is a major risk factor. The main use of corticosteroids  was for treatment of COPD exacerbations.

Antimicrobial resistance in critically ill patients


This review focuses mainly on gram-negative bacteria. Although it approaches the problem in light of the covid-19 pandemic it has general applicability.

First a few definitions.

ESKAPE microorganisms : Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa and Enterobacter spp

Enterobacterales: new term for enterobacteriaceae

MDR: resistant to at least one antibiotic in three or more categories

XDR (extensive drug-resistant): resistant to at least one antibiotic in all but two or fewer categories

PDR (pan drug-resistant): resistant to all antibiotics

Difficult to treat resistant pathogens: resistant to front line agents and requiring second-line agents of greater toxicity and often lower efficacy (eg aminoglycosides, colistin).

Rates of infections due to ESBL producing organisms and carbapenemase producing organisms are rising. K. pneumoniae carbapenemase (KPC) producing bacteria are the ones predominant in the United States. The New Delhi Metallo-beta-lactamase (NDM) and the OXA-48 carbapenemase are rising in importance.

Acinetobacter is a complex and rising concern. From the review:

Finally,A. baumannii complex frequently causes nosocomial infections, particularly in ICUs where the incidence has increased over time. The SENTRY program evaluated the frequency of cases and anti-microbial susceptibility profiles of the A. baumannii collection from medical centers registered in this program [13]. This study showed that these isolates were recovered mainly from patients with pneumonia and bloodstream infections and evidenced reduced susceptibility to most antimicrobials tested. In all regions, colistin was the most active agent followed by minocycline.

Despite this seemingly grim picture the pipeline seems to have kept up with these trends reasonably well. Newer agents include:

Ceftolozane and tazobactam (Zerbaxa) Enhanced pseudomonas activity; activity against ESBL organisms but significant resistance rates; no activity against carbapenemase producing bacteria. (If used for intra abdominal infections coadministration of metronidazole is required).

Ceftazidime–avibactam (Avycaz) and imipenem–relebactam (Recarbrio) are active against most carbapenemase producing bacteria.

Not mentioned were fosfomycin (not yet available in IV form in the US) and omadacycline (Nuzyra). Omadacycline, though expected to be bacteriostatic, has an impressive spectrum. From another paper:

Omadacycline maintains activity against difficult-to-treat pathogens, including methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant enterococci (VRE), Enterobacteriaceae that produce extended-spectrum β-lactamases (ESBLs) and carbapenemases, and multidrug-resistant (resistant to greater than or equal to 3 classes of agents) strains of Acinetobacter spp. and Stenotrophomonas maltophilia (2).

ANCA testing in eosinophilic granulomatosis with polyangiitis (EGPA)


The American Journal of Respiratory and Critical Care Medicine published a consensus statement on the use of ANCA testing in patients with eosinophilic granulomatosis with polyangiitis  (EGPA,formerly Churg Strauss syndrome).  The article serves is a helpful update and review on some aspects of EGPA.

First some Basics about the ANCA test. The two main types have two different nomenclatures of designation depending on the assay used. In the ELISA test, which uses specific antigens, the two antibodies are proteinase three (pr3) and myeloperoxidase (MPO).  These correlate mainly (and there are some exceptions) with the immunofluorescent patterns of C and P ANCA respectively.

What about disease associations? Granulomatosis with polyangiitis (formerly known as Wegener's granulomatosis) is generally associated with C ANCA. Microscopic polyangiitis (MPA) is generally associated with P ANCA. The same is true of pauci immune  renal limited vasculitis. These categories are not absolute.

When it comes to EGPA it's a little more complex. Only 40% or so of patients with EGPA are ANCA  positive and the predominant pattern is ANCA P.  Test characteristics of ANCA for GPA,  MPA and renal limited vasculitis are pretty good. This, as is evident from the above, is not the case for EGPA.

Now on to the paper.

Despite the poor test characteristics the consensus panel recommends testing on all patients or suspected EGPA patients because it may point to the correct diagnosis and has implications for disease phenotype. Here's the specific recommendation, from the abstract of the paper:

MPO-ANCA should be tested with antigen-specific immunoassays in any patient with eosinophilic asthma and clinical features suggesting EGPA, including constitutional symptoms; purpura; polyneuropathy; unexplained heart, gastrointestinal, or kidney disease; and/or pulmonary infiltrates or hemorrhage. A positive MPO-ANCA result contributes to the diagnostic workup for EGPA. Patients with MPO-ANCA–associated EGPA have vasculitis features, such as glomerulonephritis, neuropathy, and skin manifestations, more frequently than patients with ANCA-negative EGPA. However, the presence of MPO-ANCA is neither sensitive nor specific enough to identify whether a patient should be subclassified as having “vasculitic” or “eosinophilic” EGPA. At present, ANCA status cannot guide treatment decisions, that is, whether cyclophosphamide, rituximab, or mepolizumab should be added to conventional glucocorticoid treatment. In EGPA, monitoring of ANCA is only useful when MPO-ANCA was tested positive at disease onset.

According to the paper there are some important clinical correlations. EGPA patients who are anca positive tend more to have a vasculitic  manifestations such as glomerulonephritis, neuropathy, pulmonary Hemorrhage and skin lesions. Those who are negative tend more toward the infiltrative aspects of the disease which translates into cardiac involvement and pulmonary granulomas.

Treatment decisions are made more on clinical grounds than on the basis of the ANCA test. Again, from the paper:

Glucocorticoids  are  the  cornerstone  of  therapy  for  EGPA.  Additional  immunosuppressive agents  (e.g.,  cyclophosphamide)  should  be  prescribed  for  patients  with  life-  and/or  organ-threatening manifestations, such as heart disease, glomerulonephritis, alveolar hemorrhage or mononeuritis  multiplex,  and  can  be  considered  for  selected  patients  with  glucocorticoid dependence  or  recurrent  disease  [51].