When do we start antiretroviral therapy in HIV patients with opportunistic infections?

On Monday and Wednesday, Megan and Jack presented cases of patients with uncontrolled/newly diagnosed HIV who presented with PJP pneumonia.  One question that came up was, when do we start antiretroviral therapy (ART) in these patients?

For the most part, the answer is immediately.  Early ART initiation results in less AIDS progression and death with little increase in adverse events.  An RCT published in 2009 in PLoS ONE evaluated almost 300 subjects who presented with either an AIDS-defining opportunistic infection (OI) OR serious bacterial infection (BI) + CD4 < 200 (1).  People were randomized either to immediate start of ART or deferred start after treatment of OI was completed.  The breakdown of infections among patients was: 63% PJP, 12% cryptococcal meningitis, and 12% bacterial infections.  The study found that 14% of patients in the early arm had progression of disease or died, compared to 24% of patients in the deferred arm.  Median time to ART was 12 days after OI treatment in the early arm and 45 days after OI treatment in the deferred arm.  Rates of confirmed immune reconstitution inflammatory syndrome (IRIS) were at 5.7% for the early arm and 8.5% for the deferred arm and was not statistically significant.

The primary exception to starting immediately is in a patient with cryptococcal meningoencephalitis.  The trial described above was not powered to look solely at patients with cryptococcal meningitis, and other trials looking at early versus delayed initiation of ART in patients with cryptococcal CNS disease consistently lower rates of survival and increased rates of IRIS with early initiation (2-4).  ART is also frequently delayed in the setting of other CNS opportunistic infections (ex. CNS tuberculosis) although evidence is less robust here.

Takeaway: Initiate ART immediately in patients presenting with opportunistic infections (especially PJP) EXCEPT for those who have CNS cryptococcal disease, and consider delaying in other CNS infections such as tuberculosis.  Have a low threshold to send a serum cryptococcal antigen in patients with HIV before starting ART, particularly those with neurological symptoms.

References:

  1. Zolopa A, Andersen J, Powderly W, et al. Early antiretroviral therapy reduces AIDS progression/death in individuals with acute opportunistic infections: a multicenter randomized strategy trial. PLoS ONE. 2009;4(5):e5575.
  2. Makadzange AT, Ndhlovu CE, Takarinda K, et al. Early versus delayed initiation of antiretroviral therapy for concurrent HIV infection and cryptococcal meningitis in sub-saharan Africa. Clin Infect Dis. 2010;50(11):1532-8.
  3. Boulware DR, Meya DB, Muzoora C, et al. Timing of antiretroviral therapy after diagnosis of cryptococcal meningitis. N Engl J Med. 2014;370(26):2487-98.
  4. Bisson GP, Molefi M, Bellamy S, et al. Early versus delayed antiretroviral therapy and cerebrospinal fluid fungal clearance in adults with HIV and cryptococcal meningitis. Clin Infect Dis. 2013;56(8):1165-73.

When should we think about diffuse alveolar hemorrhage and how do we treat it?

On Monday, Jackie presented a case of a middle aged woman with anti-phospholipid syndrome who presented with cough and dyspnea and was ultimately diagnosed with diffuse alveolar hemorrhage (DAH).


When should we consider diffuse alveolar hemorrhage on the differential? (1)

DAH is usually acute onset but can sometimes have a stuttering course over weeks.  The most common symptoms are cough (hemoptysis is present in about 2/3 of cases), fever, and dyspnea.  There are usually diffuse or patchy opacities on CXR and diffuse GGOs +/- consolidations on CT chest.  Patients usually have a hemoglobin drop on lab check.  DAH can be diagnosed on bronchoalveolar lavage if serial lavage aliquots become progressively bloodier.

Three different types of disease processes can lead to DAH, reflected in the histology: pulmonary capillaritis, bland pulmonary hemorrhage, and diffuse alveolar damage (the histologic companion to acute respiratory distress syndrome).  Thinking through these categories is helpful in determining the treatment course, as we’ll see below, but it also helps you reason through who is at risk of developing DAH.  Pulmonary capillaritis can be a complication of systemic vasculitis, rheumatic disease, and various drugs.  Bland hemorrhage is usually related to bleeding disorders or blood thinners, although it can also be associated with elevated left ventricular end diastolic pressures and some connective tissue disorders.

Takeaway: Suspect DAH when a patient with specific risk factors (elevated bleeding risk, rheumatologic disease, or systemic vasculitis) presents with dyspnea, a hemoglobin drop, and diffuse GGOs/opacities on imaging.  The presence of hemoptysis is helpful but this symptom can be absent in many cases.


How do we treat DAH 2/2 pulmonary capillaritis?

Patients who present with DAH that is presumed 2/2 pulmonary capillaritis should be pulsed with glucocorticoids.  The choice of additional immunosuppressive therapy differs depending on the underlying disease, but usually involves cyclophosphamide, rituximab, and/or plasma exchange.  Most of the evidence for treating DAH 2/2 pulmonary capillaritis comes from patients with ANCA-associated vasculitis, mixed cryoglobinemia, and SLE and is extrapolated to other causes of capillaritis.

A randomized controlled trial published last month in NEJM evaluated the efficacy of plasma exchange and two different dosing regimens of glucocorticoids in severe ANCA-associated vasculitis, either with diffuse pulmonary hemorrhage or severe kidney involvement (2).  There were 4 treatment arms: plasma exchange + standard dose steroids, plasma exchange + reduced dose steroids, no plasma exchange + standard dose steroids, and no plasma exchange + reduced dose steroids.  All patients in the trial received induction therapy with either cyclophosphamide or rituximab (>80% got cyclophosphamide) and high dose IV methylprednisolone for 1-3 days.  Notably, only about 8-9% of participants in each arm had severe pulmonary hemorrhage.  Rates of the primary composite outcome (death from any cause and end stage kidney disease) were similar and non-inferior in all groups.

Takeaway: Treat DAH 2/2 capillary capillaritis with pulse dose steroids and usually an additional immunosuppressive agent (most evidence is with cyclophosphamide) if severe disease.  IVIG and plasma exchange can be considered in severe cases as well, although plasma exchange may not be effective in severe ANCA-associated vasculitis.

References:

  1. https://www.uptodate.com/contents/mixed-cryoglobulinemia-syndrome-treatment-and-prognosis?sectionName=Dosing%20of%20glucocorticoids&search=dah%20pearls&topicRef=4341&anchor=H3895751587&source=see_link#H3895751587
  2. Walsh M, Merkel PA, Peh CA, et al. Plasma Exchange and Glucocorticoids in Severe ANCA-Associated Vasculitis. N Engl J Med. 2020;382(7):622-631.

 

Recent Updates in HTN

This week, we’re highlighting a couple of recent papers on treatment of hypertension which have come up in discussions.


The first is the Hygia Chronotherapy Trial (1) which was published in October of 2019 in the European Heart Journal.  It was a multi-center, randomized controlled trial in Spain that evaluated whether taking anti-hypertensives at bedtime or upon awakening was better for cardiovascular disease risk reduction in adults with essential hypertension.  In short, patients taking the medications at bedtime had a much lower hazard ratio for the composite primary outcome of cardiovascular death, MI, coronary revascularization, heart failure, and stroke (HR 0.55).  All of the individual components of the primary outcome were also significant, including CV death alone (HR 0.44).  There are certainly limitations to this trial: it was non-blinded and it was unclear why the analyses were adjusted, since randomization usually washes out confounders and renders adjusting analyses unnecessary.

Takeaway: Despite the limitations, the effects of this intervention are very robust and given the minimal risks in taking anti-hypertensives at night (except for maybe diuretics), it makes sense to ask patients to take their blood pressure medications at night.


The second is an observational cohort study just published in JAMA IM last week comparing cardiovascular outcomes and safety of hydrochlorothiazide versus chlorthalidone (2).  They used multiple databases to study over 700,000 patients and used propensity scoring to try to control for confounders and match the two groups.  The authors found that there were no significant differences in the risk of MI, hospitalized HF, or stroke, but chlorthalidone was associated with much higher rates of electrolyte abnormalities (hypokalemia, hazard ratio, and hyponatremia) and renal disease.  Important to note that the median “at risk,” or exposure, period was only 92 days. The overall exposure period in this study was short and there may not have been enough follow up time to show cardiovascular benefit.  This is also an observational cohort study which is prone to bias — patients who were higher risk at baseline may have been prescribed chlorthalidone by providers who believe in its benefit over HCTZ.

Takeaway:  There was previously little direct evidence that HCTZ specifically improves cardiovascular outcomes.  The ALLHAT trial in 2002 (3) studied chlorthalidone, not HCTZ, and the 2017 AHA/ACC guidelines suggest chlorthalidone as the preferred thiazide diuretic.  This paper suggests that chlorthalidone has a worse side effect profile and may not have the benefits over hydrochlorothiazide that we previously believed, but a follow up RCT is needed!


References:

  1. Hermida RC, Crespo JJ, Domínguez-sardiña M, et al. Bedtime hypertension treatment improves cardiovascular risk reduction: the Hygia Chronotherapy Trial. Eur Heart J. 2019;
  2. Hripcsak G, Suchard MA, Shea S, et al. Comparison of Cardiovascular and Safety Outcomes of Chlorthalidone vs Hydrochlorothiazide to Treat Hypertension. JAMA Intern Med. 2020
  3. Major outcomes in high-risk hypertensive patients randomized to angiotensin-converting enzyme inhibitor or calcium channel blocker vs diuretic: The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). JAMA. 2002;288(23):2981-97.

Moffitt week in review 2/18-21

On Tuesday, we discussed a case of a patient with a history of multiple myeloma who presented with worsening HFpEF and was found to have suspected cardiac amyloidosis.

We discussed a differential dx for low voltage ECG, and first of all reminded ourselves how to define “low voltage”:

  • Amplitudes of all QRS complexes in limb leads are < 5 mm  — OR –
  • Amplitudes of all QRS complexes in the precordial leads are < 10 mm

For the approach to a low voltage ECG, we broke this down into 2 buckets: (1) things that get between electrodes and the heart and (2) abnormalities of the myocardium itself:

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On Wednesday, Alex shared a case of a patient with recent prolonged hospitalization with multiple immune-related adverse events associated with immune checkpoint blockade, who was now presenting with pneumonia with parapneumonic effusion.

We discussed some of the organ-specific adverse events associated w checkpoint blockade, noting that the most commonly seen organs involved in these adverse events are:

  • Skin (dermatitis)
  • GI (enteritis/colitis/hepatitis)
  • Endocrine organs (thyroiditis, hypophysitis, primary adrenal insufficiency)

Have questions about immune-related adverse events? So do we, and so do a lot of people, apparently. This NEJM review from 2018 (https://www.nejm.org/doi/full/10.1056/NEJMra1703481) focuses on 10 questions that we often encounter when caring for this expanding patient population! Check out the summary table below:

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On Thursday, Anna presented the case of a patient who had a liver transplant more than 10 years ago with a complicated subsequent course. This patient had chronic rejection requiring multiple immunosuppressants (recently on all 4 of everolimus, sirolimus, mycophenolate and prednisone) and had multiple infectious complications including CMV retinitis, and cryptococcal meningitis. He was now presenting with weeks of fevers, malaise and generalized weakness.

We discussed a helpful approach to a decompensation in a patient with a history of a solid organ transplant:

  1. Infectious complications of immunosuppression
  2. Malignant complication of immunosuppression (transplant patients on chronic immunosuppression are at higher risk for multiple malignancies including lymphoproliferative disorders)
  3. Toxicity of immunosuppression (e.g. renal toxicity and neuro toxicity related to calcineurin inhibitors cyclosporine and tacrolimus)
  4. Rejection of the transplanted organ
  5. Progression of the underlying disease that led to the transplant in the first place

Our patient developed acute one-sided weakness in the hospital, and had an abnormal NCHCT w hypodensity in the thalamus and hyperdensity in the frontal lobe. Further w/u including MRI, LP, and eventually brain led to the diagnosis of a primary CNS post-transplant lymphoproliferative disorder (PTLD).

A couple of pertinent bits of info about PTLD:

  • The incidence in solid organ transplant recipients is ~ 1% at 10 years. This varies by type of transplant and by degree of immunosuppression

Who is at highest risk?

  • patients with marked immunosuppression
  • EBV positive patients

When does it occur?

  • 80% of these malignancies occur in first year after transplant (likely related to high degree of immunosuppression during that time)

How does it present? If there is no lymphadenopathy, can we rule it out?

  • Presentation is highly variable depending on areas involved – often associated with non-specific symptoms such as fever, weight loss and fatigue
  • More than half present with with extranodal masses – these can be in the CNS (as in our patient), in the transplanted organ or elsewhere

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On Friday at ambulatory report, Arturo presented a young woman with a history of type 1 diabetes and steatohepatitis who presented with diffuse bony pain and unexplained ecchymoses.

We discussed an approach to abnormal bleeding, including running through the categories of blood, vWF and vessel wall. Check out this schema courtesy of Rabih Geha.

Based on the work-up Arturo had already pursued in clinic, we were most suspicious for a vessel wall problem. We’ll leave you with another beautiful schema courtesy of Rabih!

Does the concern for colon cancer preclude the use of anti-TNF agents for IBD?

This week, Teddy presented a case of a middle aged man who presented with a couple weeks of bloody diarrhea.  He was diagnosed with colocolonic intussuseption and presumptive ulcerative colitis (UC), with high concern for occult colon cancer.  We discussed indications for colectomy in UC and the link between TNF-alpha antagonists and increased risk of malignancy.


What are indications for surgical intervention and colectomy in patients with UC?

  • Patients who develop life-threatening complications (perforation, life-threatening GI bleed, and toxic megacolon) require immediate surgery
  • Patients with fulminant colitis unresponsive to glucocorticoids and an anti-TNF agent should also be considered for urgent surgery

Treatment induced immunosuppression with anti-TNF agents has long been thought to lead to an increased risk of malignancy.  A 2006 JAMA systematic review of RCTs looking at anti-TNF therapy for rheumatoid arthritis found a odds ratio for malignancy of 3.3 (1).  When looking specifically at IBD, the few studies looking specifically at cancer risk have found no evidence of excess risk related to anti-TNF exposure, but follow up in these studies has been short (all < 2 years).  Most recently, a 2014 JAMA cohort study with more than 56,000 patients found no increased risk of cancer with a 3.7 year median follow up (2).


Takeaway: Risks of prescribing anti-TNF agents to patients with IBD and increased risk of malignancy may be overblown.  That being said, more studies studying patients over longer periods of follow-up and at higher accumulated doses of the drugs need to be done.

References:

  1. Bongartz T, Sutton AJ, Sweeting MJ, Buchan I, Matteson EL, Montori V. Anti-TNF antibody therapy in rheumatoid arthritis and the risk of serious infections and malignancies: systematic review and meta-analysis of rare harmful effects in randomized controlled trials. JAMA. 2006;295(19):2275-85)
  2. Nyboe Andersen N, Pasternak B, Basit S, et al. Association between tumor necrosis factor-α antagonists and risk of cancer in patients with inflammatory bowel disease. JAMA. 2014;311(23):2406-13

Should patients presenting with an upper GI bleed have nasogastric lavage?

Today in GI report, Andy presented a case of a young man with longstanding aspirin use and weeks of abdominal pain and N/V who was found to have a hemoglobin of 4.

We discussed the utility of nasogastric (NG) tube lavage in the setting of suspected UGIB.  Evidence is mixed and studies have not shown definitive evidence that it improves outcomes.  An RCT published in 2015 compared NG placement w/ aspiration and lavage vs no NG placement in patients presenting with UGIB.  The presence of coffee grounds or red blood in the NG aspirate did not change physician assessments and all patients underwent endoscopy.  There were no differences in re-bleeding rates or mortality.

Rockey DC, Ahn C, De melo SW. Randomized pragmatic trial of nasogastric tube placement in patients with upper gastrointestinal tract bleeding. J Investig Med. 2017;65(4):759-764.

On the other hand, NG lavage can be really helpful in differentiating between an UGIB and LGIB.  When trying to determine if a bleed is coming from above, the presence of blood or coffee grounds on NG lavage has a sensitivity of 44%, specificity of 95%, and PLR of 9.6.  Important to note that this is specific but not sensitive so the absence of blood or coffee grounds does NOT rule out UGIB.  Additionally, the presence of bright red blood on lavage can mean that the bleed is more severe and needs more urgent evaluation with endoscopy (positive LR 3.1).

Srygley FD, Gerardo CJ, Tran T, Fisher DA. Does this patient have a severe upper gastrointestinal bleed?. JAMA. 2012;307(10):1072-9.

Takeaway:  Most patients presenting with active UGIB should go to endoscopy and NG lavage will likely not change management.  However, when unclear, the presence of blood or coffee grounds on NG lavage can be helpful in differentiating between an UGIB and LGIB.  Along with other signs and symptoms, the presence of bright red blood on lavage can be also be helpful in determining if the patient has a severe UGIB and needs more urgent endoscopy.

Zion Ambulatory Report: Alcohol Use, AKI, GI Bleed, and More!

Thanks so much to our attending guest star, Lily Kornbluth, for presenting such a complicated and rich case on Tuesday morning. We discussed a 34yoM who initially presented to re-establish primary care and along the way reviewed an approach to a new patient visit, differentiation of AKI from CKD, evaluation of lower GI bleed in the outpatient setting, and diagnosis and management of alcoholic hepatitis. There were so many learning points – I’ll try to summarize the most salient of them here!

Approach to a New Patient Visit

  • We’ve previously reviewed an approach to a new patient visit with a healthy young person. Briefly, elicit your patient’s goals and values and focus on components of well-being, aka all those health-related behaviors and social history components we often don’t have time for.
    • Tom Goslinga shared that he uses a smartphrase .hpihealthy as a prompt with these patients. Feel free to borrow it!
  • In this patient, his history of heavy alcohol use was especially important. What many patients might consider “social drinking” is actually “at-risk drinking,” and it’s important to at least identify it.
    • The USPSTF recommends screening all adult patients >18yo.
    • Consider screening with a single question: “How many times in the past year have you had more than 4 (women) / 5 (men) drinks in a day?” 
      • Any answer >1 is considered at-risk drinking and warrants further discussion.

AKI vs CKD, Which Is It?

  • This patient had a creatinine of 2 on his baseline labs but no recent priors for comparison. So was it an AKI or CKD and how can we tell? 
    • First, look for electrolyte derangements that might suggest a more acute change vs hyperphosphatemia and anemia that would suggest a more chronic condition.
    • Consider adding on an intact PTH (iPTH). In a prospective study of 122 patients, an elevated PTH was found to have a sensitivity of 88% and a specificity of 89%. 
    • Use renal ultrasound to evaluate renal length and echogenicity.
  • Getting a sense of trend also helps, so have your patient return for repeat labs within a short interval.

Evaluation of GI Bleed in the Outpatient Setting

  • Don’t hesitate to contact your specialist directly to facilitate urgent follow up.
    • Page the inpatient consult pager, call the clinic, or reach out via MyChart or email to an attending.
  • Remember that referring directly for an EGD and/or colonoscopy may lead to certain therapeutic interventions. However, if no lesion requiring intervention is identified during the procedure, you won’t necessarily get further follow up/recommendations for ongoing management if you don’t ask.
  • This patient was found to have bleeding internal hemorrhoids, which may have been an early clue to the presence of more severe liver disease given their association with portal hypertension.

Detection and Management of Alcoholic Hepatitis (AH)

  • Several months later, this patient presented with new jaundice and was diagnosed with alcoholic hepatitis.
  • AH should be suspected in a patient with acute-onset jaundice and AST elevation on a background of heavy alcohol use. 
    • The thresholds for amount and duration of alcohol use are not known but generally >3 drinks/day for women and >4 drinks/day for men over a period of >5 years. Diagnosis 
    • Associated features include malaise, tender hepatomegaly, and other signs of decompensation (ascites, encephalopathy, bacterial infection, variceal bleeding).
    • Labs typically show Tbili >3, AST >50 but <400 with AST/ALT ratio of >1.5.
  • DDx includes biliary obstruction, viral hepatitis, autoimmune hepatitis, and Wilson’s disease, so evaluation should be targeted at ruling out these processes. 
  • Use Maddrey’s Discriminant Function (MDF) and MELD score to predict severity and assess need for treatment.
    • Check out this prior post by Max Brondfield at the VA for more on MDF in AH. 
    • Though steroid treatment for alcoholic hepatitis remains controversial, clinical practice guidelines still recommend their use in severe cases unless big contraindications exist given a slight trend toward short-term mortality benefit.
  • Note that most of these patients, particularly those with severe AH and/or evidence of decompensation, will require inpatient admission to expedite workup and trend labs. 

And a final fun fact: Hepatopetal refers to the flow of blood toward the liver through the portal vein (normal) and derives from the Ancient Greek ‘hepar’ meaning ‘liver’ and Latin ‘petere’ meaning ‘to seek.’ This is in contrast to hepatofugal (aka non-forward portal flow/NFPF), which refers to venous flow from the periphery toward the porta and backwards along the portal vein. Hepatofugal flow can be seen on ultrasound in patients with cirrhosis and portal hypertension.

References