How can I distinguish cardiac asthma from typical bronchial asthma?

Certain clinical features of cardiac asthma, defined as congestive heart failure (CHF) associated with wheezing, may be useful in distinguishing it from bronchial asthma, particularly in older patients with COPD (1-3).
• Paroxysmal nocturnal dyspnea associated with wheezing
• Presence of rales or crackles, ascites or other signs of CHF
• Poor response to bronchodilators and corticosteroids
• Formal pulmonary function test with bronchoprovocation demonstrating minimal methacholine response.

 
Cardiac asthma is not uncommon. In a prospective study of patients 65 yrs of age or older (mean age 82 yrs) presenting with dyspnea due to CHF, cardiac asthma was diagnosed in 35% of subjects. Even in non-elderly patients, cardiac asthma has been reported in 10-15% of patients with CHF (2).

 
The mechanism(s) underlying cardiac asthma is likely multifactorial. Pulmonary edema and pulmonary vascular congestion have traditionally been considered as key factors either through edema in the interstitial fluid of bronchi squeezing the bronchiolar lumen or by externally compressing the entire airway structure and the bronchiole wall. Reflex bronchoconstriction involving the vagus nerve, bronchial hyperreactivity, systemic inflammation, and airway remodeling may also play a role (1,3). 

 
Treatment of choice for cardiac asthma typically includes diuretics, nitrates and morphine, not bronchodilators or corticosteroids (1,3). 

 
Bonus Pearl: Did you know that the term “cardiac asthma” was first coined by the Scottish physician, James Hope, way back in 1832 to distinguish it from bronchial asthma!

 

References
1. Litzinger MHJ, Aluen JKN, Cereceres R, et al. Cardiac asthma: not your typical asthma. US Pharm. 2013;38:HS-12-HS-18. https://www.uspharmacist.com/article/cardiac-asthma-not-your-typical-asthma
2. Jorge S, Becquemin MH, Delerme S, et al. Cardiac asthma in elderly patients: incidence, clinical presentation and outcome. BMC Cardiovascular Disorders 2007;7:16. https://www.ncbi.nlm.nih.gov/pubmed/17498318
3. Tanabe T, Rozycki HJ, Kanoh S, et al. Cardiac asthma: new insights into an old disease. Expert Rev Respir Med 2012;6(6), 00-00. https://www.ncbi.nlm.nih.gov/pubmed/23234454

 

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How can I distinguish cardiac asthma from typical bronchial asthma?

My patient with COPD exacerbation on corticosteroids has an elevated white blood cell and neutrophil count. How can I tell if his elevated neutrophil count is caused by the corticosteroids or an acute infection?

The most helpful lab data favoring corticosteroid-induced granulocytosis (CIG) is the absence of a shift to the left in the peripheral WBC (ie, no more than 6% band forms) and toxic granulation.1 Although the total WBC itself is less helpful, experimental studies have reported a mean maximum neutrophil counts 2.4 times the base line after IV injection of hydrocortisone (200 mg) 2, and a mean increase of 4,000 neutrophils/mm3 after prednisone (20-80 mg). 3

Several possible mechanisms for CIG revolving around altered neutrophil characteristics and dynamics have been proposed4, including

  • Reduced egress from blood into tissues
  • Demargination from vascular endothelial surfaces
  • Delayed apoptosis
  • Enhanced release from the bone marrow.

An experimental animal study reported that only 10% of CIG is related to bone marrow release of neutrophils with the rest related to demargination (61%) and reduced egress from blood or delayed apoptosis (29%).4 This study may explain why high percentage of band forms would not be expected in CIG.

References

  1. Shoenfeld Y, Gurewich Y, Gallant LA, et al. Prednisone-induced leukocytosis: influence of dosage, method, and duration of administration on the degree of leukocytosis. Am J Med 1981;71:773-78. Link
  2. Bishop CR, Athens JW, Boggs DR, et al. Leukokinetic studies: A non-steady-state kinetic evaluation of the mechanism of cortisone-induced granulocytosis. J Clin Invest 1986;47:249-60. https://www.ncbi.nlm.nih.gov/pubmed/5638121
  3. Dale DC, Fauci AS, Guerry DuPont, et al. Comparison of agents producing a neutrophilic leukocytosis in man. J Clin Invest 1975;56:808-13. PDF
  4. Nakagawa M, Terashma T, D’yachkova YD, et al. Glucocorticoid-induced granulocytosis: Contribution of marrow release and demargination of intravascular granulocytes. Circulation 1998;98:2307-13. PDF

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My patient with COPD exacerbation on corticosteroids has an elevated white blood cell and neutrophil count. How can I tell if his elevated neutrophil count is caused by the corticosteroids or an acute infection?

Does my patient about to undergo immunosuppressive therapy need antiviral prophylaxis even if she tests positive for hepatitis B surface antibody?

The presence of hepatitis B surface antibody (HBsab) in patients who also test positive for core antibody does not necessarily confer full protection against hepatitis B virus (HBV) reactivation during immunosuppression (incidence 4.3%). 1 This is because despite having HBsab and no HB surface antigen,  a small portion of patients continue to have detectable HBV DNA in the serum and are therefore at risk of reactivation during severe immunosuppression. 2

In fact, the American Gastroenterological Association recommends against using anti-HBs status to guide antiviral prophylaxis in anti-HBc-positive patients. 1

Overall, antiviral prophylaxis may reduce the risk of HBV reactivation by 87% (C.I. 70%-94%). Antiviral drugs with a high barrier to resistance (eg, entecavir) are preferred over lamivudine.

Immunosuppressants often requiring HBV prophylaxis include: 1-3

  • B cell-depleting agents (eg, rituximab, ofatumumab)
  • Anthracycline derivatives (eg, doxorubicin, epirubicin)
  • Prednisone (4 weeks or more)
  • Tumor necrosis factor inhibitors (eg, etanercept, adalimumab, certolizumab, infliximab)
  • Other cytokine or integrin inhibitors (eg, abatacept, ustekinumab, natalizumab, vedolizumab)

Traditional immunosuppressive agents such as azathioprine, 6-mercaptopurine and methotrexate are often considered “low-risk” and do not generally require prophylaxis. 1

Fun Fact: Did you know that hepatitis B virus is very old and probably originated in birds when dinosaurs roamed the earth? 4

References

  1. Reddy KR, Beavers KL, Hammond SP, et al. American Gastroenterological Association Institute Guideline on the prevention and treatment of hepatitis B virus reactivation during immunosuppressive drug therapy. Gastroenterology 2015;148:215-19. https://www.ncbi.nlm.nih.gov/pubmed/25447850
  2. Gigi E, Georgiou T, Mougiou D, et al. Hepatitis B reactivation in a patient with rheumatoid arthritis with antibodies to hepatitis B surface antigen treated with rituximab. HIPPOKATRIA 2013;17:91-93. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3738290/
  3. Kim EB, Kim DS, Park SJ, et al. Hepatitis B virus reactivation in a surface antigen-negative and antibody-positive patient after rituximab plus CHOP chemotherapy. Cancer Res Treat 2008;40:36-38. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2699087/
  4. Suh A, Brosius J, Schmitz J, et al. The genome of a Mesozoic paleovirus reveals the evolution of hepatitis B virus. Nature Communications 2013; Article no. 1791. http://www.nature.com/articles/ncomms2798
Does my patient about to undergo immunosuppressive therapy need antiviral prophylaxis even if she tests positive for hepatitis B surface antibody?

What is the utility of bedside skin-fold test in diagnosing Cushing’s syndrome?

Skin atrophy is a common feature of Cushing’s syndrome (CS), a hypercortisol state,  with multiple studies reporting radiographic evidence of reduced skin thickness in this condition1,2.

Measurement of skin thickness on the dorsal aspect of the 2nd or 3rd proximal phalanges on the non-dominant hand by using ECG calipers to pinch together a fold of skin has also been reported to assess skin atrophy in CS, with thickness less than 18 mm correlating strongly with CS3,4; the minimal subcutaneous fat at this location allows for a more accurate measurement of skin thickness.

However, caution should be exercised in interpreting the results of this study. Specifically, some overlap was observed between normal controls and patients with CS.  In addition, the study population was limited to women of reproductive age presenting with oligomenorrhea and hirsutism for at least 2 years, a subset of patients that may account for only 40% of cases with CS5,6.  Further studies are clearly needed to determine the clinical utility of the skin-fold test in patients suspected of CS.

References

  1. Sheppard RH, Meema HE. Skin thickness in endocrine disease. A roentgenographic study. Ann Intern Med 1967;66:531-9.
  2. Ferguson JK, Donald RA, Weston TS, et al. Skin thickness in patients with acromegaly and Cushing’s syndrome and response to treatment. Clin Endocrinol (Oxf) 1983;18:347-53.
  3. Corenblum B, Kwan T, Gee S, et al. Bedside assessment of skin-fold thickness: A useful measurement for distinguishing Cushing’s disease from other causes of hirsutism and oligomenorrhea. Arch Intern Med. 1994;154:777-781.
  4. Loriaux DL. Diagnosis and differential diagnosis of Cushing’s syndrome. N Engl J Med 2017;376:1451-9.
  5. Lindholm J, Juul S, Jorgensen JOL, et al: Incidence and late prognosis of Cushing’s syndrome: a population-based study. J Clin Endocrinol Metab 2001;86:117–123.
  6. Lado-Abeal J, Rodriguez-Arnao J, Newell-Price JD, et al. Menstrual abnormalities in women with Cushing’s disease are correlated with hypercortisolemia rather than raised circulating androgen levels. J Clin Endocrinol Metab. 1998;83:3083-8.

Contributed by Sagar Raju, Medical Student, Harvard Medical School

What is the utility of bedside skin-fold test in diagnosing Cushing’s syndrome?

When should I consider Pneumocystis jirovecii pneumonia (PCP) prophylaxis in my non-HIV patient?

The most significant risk factor for PCP prophylaxis is defect in cell-mediated immunity including high-dose glucocorticoid (HDGC, ≥20 mg of prednisone daily) treatment1.  A systematic review concluded that at a PCP rate of 6.2% in control groups, PCP prophylaxis with trimethoprim/sulfamethoxazole (TMP/STX) is highly effective (85% risk reduction) in non-HIV patients with acute leukemia or solid organ/autologous bone marrow  transplantation (number needed to treat 19)2.

Other Indications for PCP prophylaxis include1:

  1. HDGC treatment for ≥1month plus another cause of immunocompromise.
  2. Combination of immunosuppressive drugs, such as tumor-necrosing factor- α inhibitors plus HDGC or other immunosuppression.
  3. Polymyositis/dermatomyositis with interstitial pulmonary fibrosis on glucocorticoids.
  4. Certain primary immunodeficiencies (eg idiopathic CD4-lymphopenia, hyper-IgM syndrome).
  5. Granulomatosis with polyangiitis (Wegener’s) on methotrexate and HDGC
  6. Rheumatologic diseases on HDGC and a second immunosuppressive drug
  7. T-cell depleting agents (eg, fludarabine)
  8. Severe malnutrition

TMP/STX may be given either as double-strength 3x/week or single-strength daily1,2.

 

References

  1. Anevlavis S, Kaltsas K, Bouros D. Prophylaxis for pneumocystis pneumonia (PCP) in non-HIV infected patients. PNEUMON 2012;25, October-December.
  2. Stern A, Green H, Paul M, Leibovici L. Prophylaxis for pneumocystis pneumonia (PCP) in non-HIV immunocompromised patients (Review). Cochrane data of Systematic Reviews 2014, issue 10. DOI: 10.1002/14651858.CD005590.pub3. 
When should I consider Pneumocystis jirovecii pneumonia (PCP) prophylaxis in my non-HIV patient?

My patient with autoimmune hepatitis has been on less than 20 mg of prednisone daily for the past month and now complains of dyspnea. What is the dose of prednisone that should make me worry about Pneumocystis jirovecii pneumonia (PCP) in her?

The risk of infection in patients on glucocorticoids (GCs) is likely determined not only by the dose and duration of treatment but also by the nature of the underlying disease requiring GC therapy (eg, asthma, autoimmune disease, malignancy),   use of additional immunosuppressants, as well as individual host sensitivity to the effects of GCs1,2.  For these reasons, it is often difficult to determine how much GCs will be too much for a specific patient when discussing opportunistic infections such as PCP in patients without HIV infection.

In patients with an autoimmune disease such as ours, as little as 12 mg/day of prednisone on presentation or as few as 5 days of GC therapy has been associated with PCP3.  Because the critical amount of immunosuppression necessary for PCP to cause disease is unclear4, and autoimmunity is often associated with T-cell dysregulation5, it is prudent to consider PCP in the differential of diagnosis of dyspnea (along with fever or pulmonary infiltrates if present) in this patient despite not receiving “high” doses of prednisone daily.  It is also important to remember that many cases of PCP occur during GC taper4.

 

References

  1. Lionakis MS, Kontoyiannis DP. Glucocorticoids and invasive fungal infections. Lancet 2003;362:1828-38.
  2. Youssef J, Novosad SA, Winthrop KL. Infection risk and safety of corticosteroids. Rheum Dis Clin N Am 2016; 42; 157-176.
  3. Yale SH, Limper AH. Pneumocystis carinii pneumonia in patients without acquired immunodeficiency syndrome: associated illness and prior corticosteroid therapy. Mayo Clin Proc 1996;71:5-13.
  4. Sepkowitz KA, Brown AE, Armstrong D. Pneumocystis carinii pneumonia without acquired immunodeficiency syndrome. Arch Intern Med 1995;1125-28.
  5. Arkwright PD, Abinun M, Cant AJ. Autoimmunity in human immunodeficiency diseases. Blood 2002;99:2694-2707.
My patient with autoimmune hepatitis has been on less than 20 mg of prednisone daily for the past month and now complains of dyspnea. What is the dose of prednisone that should make me worry about Pneumocystis jirovecii pneumonia (PCP) in her?

What is the connection between cirrhosis and adrenal insufficiency (AI)?

The reported prevalence of AI in patients with liver disease varies widely (30-60%)1. However, there is no consensus on how to define AI in such patients, nor is the methodology for its evaluation standardized. 

A common criticism is the frequent reliance on total, not free, serum cortisol in cirrhosis which may overestimate the prevalence of AI because cortisol is bound to corticosteroid binding globulin and albumin, commonly found at lower concentrations in cirrhosis. However, even when based on measuring free cortisol, AI is found in 12%-29% of clinically stable cirrhotic patients1.

 Secondary AI due to hypothalamic-pituitary dysfunction has been reported in Child-Pugh class A, B, and C patients (42%, 69%, and 80%, respectively)2. The mechanism of AI in cirrhosis is unclear, but low serum cholesterol in cirrhosis leading to lack of substrate for steroidogenesis, and increased levels of circulating endotoxin and pro-inflammatory cytokines impairing the hypothalamic-pituitary-adrenal axis have been postulated1.

 

References

  1. Fede G, Spadaro L, Purrello F. Review: adrenal insufficiency in liver disease. J Liver 2014;3:1. https://www.ncbi.nlm.nih.gov/pubmed/22234976
  2. Zietz, B, Lock, G, Plach, B, et al. Dysfunction of the hypothalamic-pituitary-glandular axes and relation to Child-Pugh classification in male patients with alcoholic and virus-related cirrhosis. Eur J Gastroenterol Hepatology 2003;15:495-501. https://www.ncbi.nlm.nih.gov/pubmed/12702906
What is the connection between cirrhosis and adrenal insufficiency (AI)?

Should my patient with chronic obstructive pulmonary disease (COPD) who emigrated from Latin America over 20 years ago undergo testing for Strongyloides infection (SI)?

Worldwide prevalence of SI may be as high as 100 million people, with an increasing number seen in developed countries among immigrants (including those from Latin America), refugees, and travelers. “Autoinfection” by Strongyloides allows it to complete its life cycle between the GI tract and the lung without leaving the host, and is often associated with chronic asymptomatic infection in the immunocompetent persons1.

Immunocompromised patients, however, particularly those treated with corticosteroids (including systemic courses as short as 6 days, or local injection)  are at increased risk of developing an accelerated form of autoinfection due to SI, also known as  hyperinfection syndrome (HIS)1,2.  HIS has been reported as late as 64 years after leaving an endemic  area!1.   When Strongyloides larvae disseminate away from the lung or GI tract into other organs (e.g. brain) the mortality rate may approach 100%, if untreated.

Due to the potential complications associated with untreated SI, particularly in the immunocompromised , routine screening of anyone with a potential Strongyloides-exposure history (irrespective of symptoms or years since exposure) has been advocated1,3.  In our patient with COPD, screening for asymptomatic SI by a highly sensitive test (eg serology) should be considered (as early as possible if corticosteroids are being considered for treatment of his COPD).  Some have also advocated empiric treatment with ivermectin in “at risk patients” in whom testing is not feasible or practical1,4.

 

References

  1. Mejia R, Nutman TB. Screening, prevention, and treatment for hyperinfection syndrome and disseminated infections caused by Strongyloides stercoralis. Curr Opin Infect Dis 2012;25:458-463.
  2. Keiser PB, Nutman TB. Strongyloides stercoralis in the immunocompromised population. Clin Microbiol Rev 2004;17:208-217.
  3. CDC. Strongyloides. http://www.cdc.gov/parsites/strongyloides/helath_professionals/ , accessed September 20, 2016.
  4. Santiago M, Leitão B. Prevention of strongyloides hyperinfection syndrome: a rheumatologic point of view. Eur J Intern Med 2009;20:744-748.
Should my patient with chronic obstructive pulmonary disease (COPD) who emigrated from Latin America over 20 years ago undergo testing for Strongyloides infection (SI)?

What is the significance of Howell-Jolly bodies in the peripheral smear of my patient with a spleen who presents with pneumonia?

Howell-Jolly bodies (HJBs, Figure) are often indicative of asplenia (either post-splenectomy or congenital absence) or hyposplenism associated with a variety of conditions, including  sickle cell disease, autoimmune disorders, celiac disease, inflammatory bowel disease (particularly ulcerative colitis), HIV, cirrhosis, primary pulmonary hypertension, splenic irradiation, amyloidosis, sarcoidosis, bone marrow transplantation, and high-dose corticosteroid therapy1-4.

Patients with pneumonia and HJBs on peripheral smear may be hyposplenic and at risk of potentially serious infections, predominantly caused by encapsulated bacteria eg, Streptococcus pneumoniae, Haemophilus influenzae and Neisseria meningitidis3.  Such patients should be immunized against these organisms, including sequential receipt of both conjugated and polysaccharide pneumococcal vaccines3,5.

HJBs are nuclear remnants in circulating mature red blood cells which are usually pitted by the spleen under normal physiological conditions. 

Final Fun Pearl:  Did you know that  HJBs were named after Henry Howell, an American physiologist who pioneered the use of heparin as an anti-coagulant and Justin Jolly, a French hematologist who was among the first to film mitotic activity in cells?

howelljollymgh

Figure. Howell-Jolly body in an RBC. Photo courtesy of Michael S. Abers, MD

 

References

  1. Di Sabatino, A, Carsetti R, Corazza G. Post-splenectomy and hyposplenic states. Lancet 2011;378:86–97. https://www.ncbi.nlm.nih.gov/pubmed/21474172
  2. Brousse, V, Buffet P, Rees D. The spleen and sickle cell disease: the sick(led) spleen. Br J Haematol 2014;166: 165–176. https://www.ncbi.nlm.nih.gov/pubmed/24862308
  3. Mathew H, Dittus C, Malek A, Negroiu A. Howell-Jolly bodies on peripheral smear leading to the diagnosis of congenital hyposplenism in a patient with septic shock. Clin Case Rep 2015;3:714-717. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4551333
  4. Ryan FP, Smart RC, Holdsworth CD, et al. Hyposplenism in inflammatory bowel disease 1978;19:50-55. https://www.ncbi.nlm.nih.gov/pubmed/624506
  5. Kuchar E, Miśkiewicz K , Karlikowska M. A review of guidance on immunization in persons with defective or deficient splenic function. Br J Haematol 2015; 171:683-94.  http://onlinelibrary.wiley.com/doi/10.1111/bjh.13660/full

Contributed by Katarzyna Orlewska, Medical Student, Warszawski Uniwersytet Medyczny, Poland

What is the significance of Howell-Jolly bodies in the peripheral smear of my patient with a spleen who presents with pneumonia?

Should corticosteroids (CS) be routinely considered in the treatment of hospitalized patients with community-acquired pneumonia (CAP)?

A recent systematic review on the subject concluded that for hospitalized adults with CAP, systemic CS may reduce mortality by about ~3% (primarily in severe CAP), mechanical ventilation need by ~5%, and hospital stay by ~1 day (1). But determining who might benefit the most and at what CS dosage regimen without undue risk of side effects (e.g. hyperglycemia) may be tricky.  

A randomized control trial of patients with CAP on prednisone 50 mg daily x 7d (vs placebo) showed a significant shorter time to clinical stability (3 vs 4.4 d) and higher in-hospital hyperglycemia in the CS group (2).; this study was not powered to detect significant difference in mortality, however.  Less treatment failure with adjunctive CS but without impact on mortality was recently reported in a small study involving patients with serum CRP >150 mg/L (i.e. high inflammatory state) (3).

Fortunately, a multicenter trial (ESCAPe, Extended Steroid in CAP) is currently underway. In the meantime, before considering CS, we need to be confident of the diagnosis and severity of CAP, its potential adverse effects in individual patients, and the appropriateness of the antibiotic (s) on board.

 

References

1. Siemieniuk RAC, Meade MO, Alonso-Coello P, et al. Corticosteroid therapy for patients hospitalized with community-acquired pneumonia: a systematic review and meta-analysis. Ann Intern Med 2015;165:519-528. https://www.ncbi.nlm.nih.gov/pubmed/26258555

2. Blum CA, Nigro N, Briel M. Adjunct prednisone therapy for patients with community-acquired pneumonia: a multi-centre, double-blind randomized, placebo-controlled trial. Lancet 2015;385:1511-1518. http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(14)62447-8/abstract

3. Torres A, Sibila O, Ferrer M, et al. Effect of corticosteroids on treatment failure among hospitalized patients with severe community-acquired pneumonia and high inflammatory response: a randomized clinical trial. JAMA 2015;313:677-86. https://www.ncbi.nlm.nih.gov/pubmed/25688779

Should corticosteroids (CS) be routinely considered in the treatment of hospitalized patients with community-acquired pneumonia (CAP)?