Image credit: sciencerfvideo – stock.adobe.com

Final diagnosis
Tuberculosis meningitis in an immuno-competent White man without epidemiologic risk factors for tuberculosis.

History of present illness
A 71-year-old man was admitted after presenting with cold-like symptoms for the past 3 weeks. He experienced rhinorrhea, congestion, cough, and a mild headache that had worsened over the past 1 week and was associated with light sensitivity.

His wife also reported worsening confusion, babbling speech, and lethargy over the past few days, as well as fevers at home.

Medical history
The patient’s history was notable for hypertension, aortic stenosis, and atrial flutter.

Key medications
Prior to hospitalization, he was taking amiodarone and apixaban.

Epidemiological history
He works as a masonry contractor and has been exposed to various environmental elements, although he has had no specific recent exposures. He was born in the suburbs of Philadelphia, Pennsylvania, and has lived his entire life there. He denies having lived or worked in rural areas. He has traveled internationally to Western Europe but has never lived abroad. He traveled to Ohio 1 month prior but otherwise has not traveled outside the Philadelphia area. He has had no significant contact with animals.

Physical examination
On admission, the patient was confused and disoriented. He was unable to answer questions or contribute to the history. His temperature was 101.9 °F. His heart rate was 61 beats per minute, blood pressure was 145/72 mm Hg, respiration rate was 18 breaths per minute, and oxygen saturation level was 100% on room air. Upon examination, he had no nuchal rigidity. Overall, he appeared ill. He had an audible systolic murmur and clear lung fields bilaterally. There were no notable rashes. He was confused and lethargic, opening his eyes to verbal stimuli but otherwise not interactive.

Studies
He had an HIV screen and a syphilis antibodies screen, both of which had negative results. Blood cultures collected were also negative. The results from his comprehensive metabolic panel and complete blood cell count with differential diagnosis were normal. Findings of a CT angiography of the head and neck were unremarkable. A chest, abdomen, and pelvis CT showed a punctate 4-mm left upper lobe pulmonary nodule. An MRI of the brain showed no intracranial mass, infarction, or hemorrhage. His respiratory panel was positive for parainfluenza. A CT of the sinuses showed right maxillary sinus disease. Results from a lumbar puncture showed a white blood cell (WBC) count of 563/ μL (normal range, 0-5 cells/uL), with 27% neutrophils, 72% lymphocytes, and 1% monocytes; a red blood cell count (RBC) of 158/μL; a glucose level of 10 mg/dL (normal range, 40-70 mg/dL); and a protein level of 237 mg/dL (normal range, 0-45 mg/dL); no opening pressure was recorded. Results from a meningitis-encephalitis panel were negative. Other pertinent negative testing results included cerebrospinal fluid (CSF), herpes simplex virus 1 and 2, cryptococcal antigen, Venereal Disease Research Laboratory test, JC polyoma virus, varicella-zoster virus, and West Nile virus immunoglobulin G antibodies. Results from a cytology of CSF were negative for malignant cells. Findings from a repeat lumbar puncture showed a WBC of 2/μL, RBC of 50/μL, glucose level of 50 mg/dL, and protein level of 33 mg/dL.

Clinical course
Upon his initial presentation, the patient was started on intravenous vancomycin, ceftriaxone, ampicillin, and acyclovir. He was also started on doxycycline for possible tick-borne illness. His fevers waxed and waned, and his mental status progressively worsened; this prompted a repeat CT of the head, which showed enlarging ventricles. He underwent an external ventricular drain placement. He had a positive result on his QuantiFERON-TB Gold In-Tube test despite having no epidemiologic history or known tuberculosis exposures. His antibiotics were discontinued after results for CSF cultures and a tick-borne illness workup came back negative.

Diagnostic procedures and results
Results from the patient’s CSF acid-fast bacteria (AFB) stain were negative. A Cepheid GeneXpert MTB/RIF polymerase chain reaction (PCR) assay run on CSF detected Mycobacterium tuberculosis (MTB) DNA. He underwent bronchoalveolar lavage with AFB cultures that were positive and MTB-PCR positive. His CSF fluid cultures grew AFB, identified as an MTB complex.

Treatment and follow-up
The patient was started on rifampin, isoniazid, pyrazinamide, ethambutol, and dexamethasone. His mental status remained unchanged, and his treatment team held goals-of-care discussions with his family. His family decided to transition him to comfort-directed care, and he died.

Discussion
Tuberculous meningitis (TBM) is a severe and potentially life-threatening form of meningitis caused by the bacterium MTB. TBM is particularly prevalent in regions with high rates of tuberculosis, such as parts of sub-Saharan Africa and Southeast Asia, but it can also occur in individuals with compromised immune systems or those who are not adequately treated for pulmonary tuberculosis. Cases in immunocompetent individuals without appropriate risk factors are exceedingly rare.¹ The onset of TBM is often insidious, with symptoms gradually worsening over weeks to months; neck stiffness is typically absent, which contributes to difficulty in diagnosing the disease.² Early initiation of antitubercular treatment is a strong predictor of survival from TBM, making early diagnosis crucial in these patients.

Diagnosis of TBM typically involves a combination of clinical evaluation, imaging studies, CSF analysis, and microbiological tests to identify MTB. Although an AFB culture remains the gold standard, testing is often timely and requires more than 2 weeks for results. Ziehl- Neelsen staining can provide rapid results but has a low sensitivity of 10% to 20%.²

The World Health Organization has endorsed the GeneXpert MTB/RIF PCR testing for diagnosis of extrapulmonary tuberculosis.² This modality allows the detection of MTB DNA and rifampin resistance in various bodily fluids, including CSF, within 2 hours. Although the GeneXpert MTB/RIF PCR test is significantly better than AFB staining, sensitivity remains imperfect and false negatives can occur. Research into more effective diagnostic tools and treatment regimens is an important area of focus in the fight against this challenging disease. Additionally, TBM should remain on the differential diagnosis for patients who present with subacute meningitis and a negative infectious workup despite lacking appropriate risk factors or an immunocompetent state.

References

1.Khanna SR, Kralovic SM, Prakash R. Tuberculous meningitis in an immunocompetent host: a case report. Am J Case Rep. 2016;17:977-981. https://doi.org/10.12659/ajcr.900762

2.Méchaï F, Bouchaud O. Tuberculous meningitis: challenges in diagnosis and management. Revue Neurologique. 2019;175(7):451-457.
doi:10.1016/j.neurol.2019.07.007

Contagion: There has been data to demonstrate cefteroline response in community acquired bacterial pneumonia can be as early as 72 hours. What is the clinical significance of this and what does that mean for hospital discharge and the potential economic impact?

Sakoulas: The faster a patient improves, the sooner they can be discharged, potentially transitioning to an oral agent or even completing therapy altogether, depending on their circumstances. We’re now moving toward shorter therapy durations for straightforward community-acquired pneumonia, typically five to seven days. So, if a patient has already received three or four days of antibiotics in the hospital, they may not even need an oral antibiotic upon discharge. This minimizes exposure to additional medications.

Quick response time is critical, not only for discharge but also because patients who respond more rapidly tend to have a lower risk of readmission. Slow responders—those who are still not improving significantly after four or five days—are more likely to be readmitted. This ties back to the analogy of a slippery surface: if a car is still sliding after the brakes are applied, it’s likely to encounter more problems stopping. In the same way, shortening a patient’s response time may reduce their likelihood of readmission.

We see a similar concept with endocarditis. For example, if a patient undergoes valve replacement surgery and their cultures are negative at the time, their prognosis is generally better than if they have a positive culture during surgery, which also extends their required treatment duration.

Although readmission rates are heavily influenced by comorbidities, it remains to be studied whether a more aggressive approach with patients who have comorbidities could shorten their response time and, ultimately, reduce their chances of readmission. Nonetheless, it’s logical to aim for faster recovery to facilitate earlier discharge, benefitting both patient outcomes and hospital efficiency.

Contagion: What are some of the other risk factors for readmission?

Sakoulas: Age is definitely a major factor, especially for those over 65, as it increases risk for nearly everything. Other main risk factors include structural lung disease, diabetes, and heart disease, which can impact respiratory function. Among these, diabetes is particularly notable. A well-controlled diabetic is very different from a patient with a hemoglobin A1c in the double digits; the latter is functionally neutropenic, making bacterial infections especially challenging to manage.

Contagion: what should be the plan for discharge so you don’t see readmission for these individuals?

Sakoulas: This is always a challenge. The goal is to cover as much ground as possible with therapy while the patient is a captive audience in the hospital. By using the most potent therapy available during their hospital stay, we hope to prevent infection from spreading, which may reduce complications and follow-up needs once they leave.

Additionally, there’s value in optimizing antibiotic dosing, especially for specific populations. For instance, a recent study at our hospital found that obesity is a risk factor for outpatient parenteral antimicrobial therapy (OPAT) failure and readmissions. Unfortunately, many antibiotic dosing studies have not adequately addressed the obese population. A study published in AC earlier this year (April) provided insights into more appropriate dosing strategies for obese patients. This is worth exploring because these patients may not be receiving enough of the drug to effectively treat the infection.

In summary, ensuring appropriate dosing—especially for obese patients—and using the most potent therapy possible, along with strong follow-up care, can help address issues early and potentially prevent a small problem from escalating into one that requires hospitalization.

The conversation was edited for grammar and clarity.

Contagion: As we are heading into seasonal respiratory virus season, what are you seeing in your own practice and region of the country in this regard, and how should clinicians be preparing to combat a resurgence in COVID 19 and the early onset of respiratory season?

Sakoulas: I’m based in Southern California, working as an ID physician. What we’re noticing here is a slight uptick in flu cases. In fact, as of this time of year, we’re seeing about three times more flu cases than we had at the same point last year. This suggests we might be in for a heavier flu season than usual, at least based on early indicators. Typically, our flu season peaks in January. In Southern California, it’s quite predictable—flu activity often surges right after the holiday season. People travel, visit family, return home, and then around January 5th, it’s as if a fire is lit.

We also had a COVID bump in August, which mirrored trends across much of the country, though it was far less severe than what we saw during the pandemic years. We had some hospitalizations, but most were incidental.

For clinicians, the main preparation is staying informed and encouraging patient vaccination. We now have vaccines for influenza, COVID, and RSV. RSV vaccines are recommended for anyone over 60 or for anyone at high risk over 75. Encouraging vaccination is really the most effective tool we have since the therapeutic options for viral infections are limited. Although some treatments show statistically significant effects in studies, the clinical impact often seems minor.

In short, with viral infections, prevention through vaccination is key. We as healthcare providers are mandated to get vaccinated, and ideally, the best time to do so is now.

Contagion: For pneumonia patients with lung function related comorbidities—such as COPD or structural lung disease, smokers, over age 65, asthma—who are these most challenging patients and why?

Sakoulas: Older patients present unique challenges, especially those with structural lung disease. Anytime there’s an infection or problem in the lungs, entering that illness with a compromised organ system makes it significantly more challenging. This is mainly because they have limited respiratory reserve. When someone with underlying health issues gets an illness, even a minor one, it can affect them much more severely than a healthier person. Additionally, these patients often receive frequent antibiotic treatments due to repeated exacerbations and ongoing care needs. Frequent antibiotic use increases the risk of antibiotic resistance, which, in turn, makes them more susceptible to infections by unusual organisms that are less common in straightforward cases of community-acquired pneumonia.

Contagion: What are the clinical considerations you are thinking about in your treatment management?

Sakoulas: When it comes to pneumonia—and, really, most infections—it often comes down to two main factors: comorbidities and severity of illness. Stopping an infection is a bit like stopping a car. Your level of sickness can be thought of as your speed, while your comorbidities are like the type of surface you’re on. If you have multiple comorbidities, it’s like driving on an icy downhill road; if you’re very sick, it’s as if you’re moving at a high speed. These are the two factors I explain to patients and students when discussing how we assess infection risks and make treatment decisions.

For example, if a patient has multiple comorbidities or has been on prior antibiotics, we need to make specific treatment decisions. However, if a younger patient with no major risk factors becomes severely ill—such as requiring ICU admission or ventilation within the first 24 to 48 hours of hospitalization—I start to consider staph pneumonia, particularly during the respiratory season we discussed earlier.

The conversation was edited for grammar and clarity.

Longhorn Vaccines and Diagnostics has developed a promising new sepsis vaccine utilizing a composite peptide approach that targets three major toxins: lipopolysaccharide (LPS), lipoteichoic acid (LTA), and peptidoglycan. Designed to prevent sepsis and improve the effectiveness of existing antibiotics, this vaccine may also hold potential for treating a range of inflammatory diseases such as Alzheimer’s, Parkinson’s, heart disease, and cancer. The vaccine’s antibodies are being engineered for an extended half-life, increasing their potential for longer-lasting efficacy.

Jeff Fischer, MBA, co-founder and president of Longhorn Vaccines, emphasized the significance of this breakthrough. “Sepsis prevention has always been something we’ve been working toward, and I think our composite peptide approach has brought us closer to that success.

The vaccine combines LPS, LTA, and peptidoglycan into a single, composite peptide. This combination uniquely addresses both gram-positive and gram-negative bacterial infections, which are major contributors to sepsis. Fischer explained the difficulties with past approaches: “At that time, we were focusing on a component of the bacterial cell wall called lipoteichoic acid (LTA), which is found on gram-positive bacteria. One of the challenges with this approach was that it only covered gram-positive species, while gram-negative bacteria are also a major cause of sepsis.”

In the 1980s, research on LPS—a toxin from gram-negative bacteria—had failed in clinical trials, but Fischer’s team was able to combine LPS and LTA into one vaccine. Adding peptidoglycan, a common component in both types of bacteria, strengthened the approach. Fischer elaborated, “We were able to combine LPS and LTA into a single vaccine, and there was another key factor that gave us confidence: adding peptidoglycan, a component of the cell wall found in both gram-positive and gram-negative bacteria. Peptidoglycan is released during bacterial cell death and the process of infection, contributing to inflammation that can lead to sepsis.”

This composite peptide vaccine has the potential to reduce sepsis-related inflammation by targeting the three main toxins involved. According to Fischer, “By combining LTA, LPS, and peptidoglycan into a composite peptide vaccine, we were able to target the three main toxins that contribute to sepsis-related inflammation. The antibodies generated by this vaccine not only reduced the toxins but also helped kill the bacteria. With this approach, we felt we had an opportunity not just to treat sepsis after it occurred but potentially to prevent it altogether.”

The vaccine may also help tackle the growing challenge of antibiotic resistance. Fischer noted, “This approach also allows us to use fewer antibiotics, which is significant given the growing issue of antibiotic resistance. In fact, this vaccine may make current antibiotics, which have become less effective, more effective again—by working in conjunction with the antibodies to clear the bacteria and the circulating toxins.”

As the research progresses, Fischer and his team are uncovering broader implications for the vaccine. The same toxins—LPS, LTA, and peptidoglycan—are implicated in a variety of inflammatory diseases, which are associated with conditions like Alzheimer’s, Parkinson’s, heart disease, and certain cancers. Fischer shared his thoughts on the broader impact: “As we’ve continued our research and explored the idea of clearing these toxins, we’ve realized that LPS, LTA, and peptidoglycan may be implicated in many other significant diseases due to the inflammation they cause. Because these toxins are constantly released when bacteria enter the bloodstream, whether from the gut or urinary tract infections, they contribute to systemic inflammation throughout the body.”

Fischer believes the approach could be a powerful tool for treating a wide array of inflammatory diseases. “The key advantage is that the body has no use for these toxins, so by eliminating them, there’s no real threat to the host. We’re not downregulating something essential or cutting back on beneficial inflammation, such as cytokines that help fight infection. Instead, we’re naturally downregulating the immune response by removing the toxins that are driving excessive inflammation.”

Longhorn Vaccines is moving forward with the development of this innovative vaccine. Fischer concluded, “We’re very excited about this work and are moving it forward as quickly as possible. We hope to have more data to share with the scientific community soon.”

Part 1 of our interview with Fischer on their universal influenza vaccine approach here: New Peptide Vaccine for Universal Influenza Protection