My middle age patient complains of night sweats for several months, but she has had no weight loss and does not appear ill. What could I be missing?

Night sweats (NS) is a common patient complaint, affecting about a third of hospitalized patients on medical wards1.  Despite its long list of potential causes, direct relationship between the often- cited conditions and NS is usually unclear2, its cause may remain elusive In about a third to half of cases in the primary care setting, and its prognosis, at least in those >65 y of age, does not appear to be unfavorable 2,3.

Selected commonly and less frequently cited conditions associated with NS are listed (Table)2-9.  Although tuberculosis is one of the first conditions we think of when faced with a patient with NS, it should be emphasized that NS is not common in this disease (unless advanced) and is rare among hospitalized patients as a cause of their NS1,9.

In one of the larger study of adult patients seen in primary care setting, 23% reported pure NS and an additional 18% reported night and day sweats5; the prevalence of NS in both men and women was highest in 41-55 y age group. In multivariate analyses, factors associated with pure NS in women were hot flashes and panic attacks; in men, sleep disorders. 

Table. Selected causes of night sweats

Commonly cited Less frequently cited
Neoplastic/hematologic (eg, lymphoma, leukemia, myelofibrosis)

Infections (eg, HIV, tuberculosis, endocarditis)

Endocrine (eg, ovarian failure, hyperthyroidism, orchiectomy, carcinoid tumor, diabetes mellitus [nocturnal hypoglycemia], pheochromocytoma)

Rheumatologic (eg, giant cell arteritis)

Gastroesophageal reflux disease

B-12 deficiency

Pulmonary embolism

Drugs (eg, anti-depressants, SSRIs, donepezil [Aricept], tacatuzumab)

Sleep disturbances (eg, obstructive sleep apnea)

Panic attacks/anxiety disorder

Obesity

Hemachromatosis

Diabetes insipidus

References

  1. Lea MJ, Aber RC, Descriptive epidemiology of night sweats upon admission to a university hospital. South Med J 1985;78:1065-67.
  2. Mold JW, Holtzclaw BJ, McCarthy L. Night sweats: A systematic review of the literature. J Am Board Fam Med 2012; 25-878-893.
  3. Mold JW, Lawler F. The prognostic implications of night sweats in two cohorts of older patients. J Am Board Fam Med 2010;23:97-103.
  4. Mold JW, Holtzclaw BJ. Selective serotonin reuptake inhibitors and night sweats in a primary care population. Drugs-Real World Outcomes 2015;2:29-33.
  5. Mold JW, Mathew MK, Belgore S, et al. Prevalence of night sweats in primary care patients: An OKPRN and TAFP-Net collaborative study. J Fam Pract 2002; 31:452-56.
  6. Feher A, Muhsin SA, Maw AM. Night sweats as a prominent symptom of a patient presenting with pulmonary embolism. Case reports in Pulmonology 2015. http://dx.doi.org/10.1155/2015/841272
  7. Rehman HU. Vitamin B12 deficiency causing night sweats. Scottish Med J 2014;59:e8-11.
  8. Murday HK, Rusli FD, Blandy C, et al. Night sweats: it may be hemochromatosis. Climacteric 2016;19:406-8.
  9. Fred HL. Night sweats. Hosp Pract 1993 (Aug 15):88.
My middle age patient complains of night sweats for several months, but she has had no weight loss and does not appear ill. What could I be missing?

When should I suspect spontaneous coronary artery dissection in my patient with chest pain?

Spontaneous coronary artery dissection (SCAD) is defined as the separation of the walls of the coronary artery.1 It is thought that hemorrhage into the false lumen can result in compression of the true lumen, leading to ischemia. Although its exact incidence is unknown, SCAD has been estimated to account for up to 35% of myocardial infarctions in women younger than 50 y of age.2-3

SCAD is often associated with acute chest pain with presentations ranging from acute coronary syndrome (ACS) to sudden cardiac death.1,4 Diagnosis is typically accomplished with coronary angiography and, increasingly, newer modalities such as optical coherence tomography, intravascular ultrasound, and cardiac CT angiography.1

Clinical features that should raise suspicion of SCAD are shown (Table)5. Among many risk factors, myocardial infarction in younger women and the absence of traditional cardiovascular risk factors or lack of typical atherosclerotic lesions in coronary arteries should be potential flags for the possibility of SCAD.

Although the optimal management of SCAD is unclear, conservative therapy with aspirin, clopidogel and beta-blockers has often been recommended5 .  Percutaneous coronary intervention (PCI) carries a risk of worsening the dissection or causing additional dissections in such patients1. Revascularization is often reserved for those with hemodynamic instability, persistent ischemia, sustained ventricular tachycardia or fibrillation, or left main dissection.1,5

Table. Clinical features that raise suspicion of SCAD5 ______________________________________________________________________________________________________________
Myocardial infarction in young women (especially age ≤ 50 y)
Absence of traditional cardiovascular risk factors
Little or no evidence of typical atherosclerotic lesions in coronary arteries
Peripartum state
History of fibromuscular dysplasia
History of relevant connective tissue disorder (eg, Marfan’s syndrome, Ehler Danlos syndrome)
History of relevant systemic inflammation (incl. SLE, IBD, sarcoidosis, polyarteritis nodosa)
Precipitating stress events caused by emotional or intense physical factors ______________________________________________________________________________________________________________
SLE: Systemic lupus erythematosus; IBD: Inflammatory bowel disease (eg, Crohn’s, ulcerative colitis).

References

  1. Saw J, Mancini GB, Humphries KH. Contemporary Review on Spontaneous Coronary Artery Dissection. J Am Coll Cardiol 2016;68:297-312.
  2. Rashid HN, Wong DT, Wijesekera H, et al. Incidence and characterisation of spontaneous coronary artery dissection as a cause of acute coronary syndrome – a single-centre Australian experience. Int J Cardiol 2016;202:336-8.
  3. Nakashima T, Noguchi T, Haruta S, et al. Prognostic impact of spontaneous coronary artery dissection in young female patients with acute myocardial infarction: a report from the Angina Pectoris-Myocardial Infarction Multicenter Investigators in Japan. Int J Cardiol 2016;207:341-8.
  4. Lettieri C, Zavalloni D, Rossini R, et al. Management and long-term prognosis of spontaneous coronary artery dissection. Am J Cardiol 2015;116:66-73.
  5. Yip A, Saw J. Spontaneous coronary artery dissection-A review. Cardiovasc Diagn Ther 2015;5:37-48. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4329168/pdf/cdt-05-01-037.pdf

Contributed by Mahesh Vidula, MD, Mass General Hospital, Boston, MA.

When should I suspect spontaneous coronary artery dissection in my patient with chest pain?

How should I interpret a positive urine pneumococcal antigen when my suspicion for pneumococcal disease is very low?

The popular urine pneumococcal antigen (UPA) (based on the C-polysaccharide of Streptococcus pneumoniae cell wall) has been a valuable diagnostic tool in diagnosing invasive pneumococcal infections, but may be associated with up to nearly 10% rate of false-positivity in hospitalized patients1.  Three factors have often been cited as the  cause of false-positive UPA results: a. Nasopharyngeal carriage; b.Prior invasive pneumococcal infection and;  c. Pneumococcal vaccination.

Among adults with nasopharyngeal carriage of S. pneumoniae, particularly those with HIV infection, 12-17% of positive UPA tests may be false-positive1. In patients with recent invasive pneumococcal disease, UAP may remain positive in over 50% of patient at 1 month and about 5% at 6 months1,2.

Among persons receiving the 23-valent polysaccharide pneumococcal vaccine (PPV), over 20% may have a positive UPA up to 30 hours following immunization, some potentially longer1.  In fact, the manufacturer of UPA assay recommends that UPA not be obtained within 5 days of receiving PPV. There is reason to believe that conjugated pneumococcal vaccine may be associated with the same phenomenon3.

So in a hospitalized patient with low suspicion for pneumococcal disease but a positive UAP, it would be wise to first exclude the possibility of PPV administration earlier during hospitalization before the sample was obtained1,4.

 

References

  1. Ryscavage PA, Noskin GA, Bobb A, et al. Incidence and impact of false-positive urine pneumococcal antigen testing in hospitalized patients. S Med J 2011;104:293-97.
  2. Andre F, Prat C, Ruiz-Manzano J, et al. Persistence of Streptococcus pneumoniae urinary antigen excretion after pneumococcal pneumonia. Eur J Clin Microbiol Infect Dis 2009;28:197-201.
  3. Navarro D, Garcia-Maset Leonor, Gimeno C, et al. Performance of the Binax NOW Streptococcus pneumoniae urinary assay for diagnosis of pneumonia in children with underlying pulmonary diseases in the absence of acute pneumococcal infection. J Clin Microbiol 2004; 42: 4853-55.
  4. Song JY, Eun BW, Nahm MH. Diagnosis of pneumococcal pneumonia: current pitfalls and the way forward. Infect Chemother 2013;45:351-66.

 

How should I interpret a positive urine pneumococcal antigen when my suspicion for pneumococcal disease is very low?

How should I interpret a positive result for serum cryoglobulins?

Cryoglobulins (CGs) are immunoglobulins that precipitate in the blood under cold conditions (<37◦ C) and redissolve upon warming1.  The term “cryoglobulinemia” is commonly used to describe patients with a systemic inflammatory syndrome that is often associated with small-to-medium vessel vasculitis due to cryoglobulin-containing immune complexes. Although some patients with cryoglobulinemia may be asymptomatic, most present with a range of diseases characterized by fatigue, arthralgia, skin rashes or necrosis, purpura, neuropathy, bowel wall ischemia and/or glomerulonephritis and kidney failure.

Wintrobe and Buell are credited for first describing cryglobulinemia in 1933 when assessing a patient who ultimately was found to have multiple myeloma2. Since then the spectrum of diseases associated with CG has expanded to also include seemingly disparate conditions such as hepatitis C, autoimmune disorders and monoclonal gammopathy of undetermined significance (MGUS).  A commonly cited classification scheme for CG is shown (Table)3.   It should be emphasized that some CGs may not fit neatly into this scheme.

In our patient, the positive CG serum test should be interpreted in the clinical context in which it was obtained while searching for risk factors as well as signs and symptoms that may be associated with cryoglobulinemia.

 

Table. Classification of cryoglobulinemia

Category Description Examples
Type I Isolated monoclonal immunoglobulin, either IgM or IgG (less commonly IgA or free immunoglobulin light chains Multiple myeloma, Waldenström’s macroglobulinemia, monoclonal gammopathy of undetermined significance (MGUS)
Type II Mixture of monoclonal IgM and polyclonal IgG Hepatitis C, HIV, other viral infections
Type III Polyclonal mixture IgM and IgG Autoimmune disorders, hepatitis C

References

  1. Takada S, Shimizu T, Hadano Y, et al. Cryoglobulinemia (review). Mol Med Rep 2012;6:3-8
  2. Wintrobe MM, Buell MV. Hyperproteinemia associated with multiple myeloma. Bull Johns Hopkins Hosp 52: 156-165, 1933
  3. Brouet JC, Clauvel JP, Danon F, et al. Biological and clinical significance of cryoglobulins. Am J Med 1974; 57:775-88.

 

Contributed by Kirstin Scott, Medical Student, Harvard Medical School

How should I interpret a positive result for serum cryoglobulins?

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?

Is diabetes mellitus (DM) an independent risk factor for venous thromboembolism (VTE)?

Although DM was originally thought to be an independent risk factor for DM1,2, more recent data suggest otherwise.

A population-based study involving residents of Olmsted County, Minnesota, calculated the incidence of VTE among patients with DM over a 25-year period and found it to be higher than that of controls .   However, in the same study, after controlling for hospitalization for major surgery or medical illness and nursing home confinement, no association between DM and VTE was found2  .  

A recent systematic review and meta-analysis of case-control and cohort studies involving over 1 million patients found no significant association between DM and VTE when controlled for common risk factors (eg, obesity, sedentary life style, smoking, hypertension, or dyslipidemia)3.  The authors concluded that DM and its complications are not independent risk factors for incident VTE.  

Thus, it appears that much of the risk of DVT in DM may be related to its comorbidities and the need for hospitalization, surgery or nursing home stay.

References

  1. Petrauskiene V, Falk M, Waernbaum I, et al. The risk of venous thromboembolism is markedly elevated in patients with diabetes. Diabetologia 2005;48:1017-21. https://www.ncbi.nlm.nih.gov/pubmed/15778859
  2. Heit JA, Leibson CL, Ashrani AA, et al. Is diabetes mellitus an independent risk factor for venous thromboembolism? A population-based case-control study. Thromb Vasc Biol 2009; 29:1399-1405. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2735343/
  3. Gariani K, Mavrakanas T, Combescure C, et al. Is diabetes mellitus a risk factor for venous thromboembolism? A systematic review and meta-analysis of case-control and cohort studies. Eur J Intern Med 2016;28:52-58. https://www.ncbi.nlm.nih.gov/pubmed/26507303
Is diabetes mellitus (DM) an independent risk factor for venous thromboembolism (VTE)?

My previously healthy 25 year old patient is admitted because of an anaphylactic reaction 4 hours after having a hamburger. Could it really have been the hamburger?

Absolutely! It could be related to alpha-gal (galactose-alpha-1, 3-galactose) allergy (AGA), a condition found in thousands of Americans1.  AGA (also known as red meat or mammalian allergy) is a novel form of IgE-mediated anaphylaxis that typically occurs 3-6 hrs (not immediately) after ingestion of mammalian meat (beef, pork, lamb, bison, goat, vension); turkey, chicken, and fish do not contain alpha-gal1,2 . Another unique feature of AGA is that it seems to develop in adult life3.

What’s even more fascinating about AGA is its presumed causal relationship with prior bites of Amblyomma americanum (the lone star tick)4,5, found in many southern, midwestern and eastern states in the US (Figure).    The proposed mechanism of sensitization is that tick saliva contains alpha-gal (possibly from feeding on deer or other mammals), which causes production of IgE to this oligosaccharide5.  When mammalian meat (in our patient, a hamburger) is ingested by the sensitized individual, an anaphylactic  reaction may ensue.  The delay in reaction is thought to be due to the time it takes for alpha-gal to be absorbed from the gut4

The story doesn’t end here! Some medications contain alpha-gal due to inert ingredients such as gelatin or magnesium stearate of bovine sources. At least one report of anaphylaxis in a patient with AGA has been blamed on medications with bovine-derived magnesium stearate6.  Currently,  the FDA does not require manufacturers to disseminate this information, so when  in doubt, individual drug manufacturers should be contacted.

Next time you see an anaphylactoid reaction of unclear cause, think about alpha-gal as well!

 

lgmap-lone_star_tick

tick

Figure: Lone start tick and its distribution in USA (Courtesy of CDC).

References

  1. Van Nunen S. Galactose-alpha-1, 3-galactose, mammalian meat and anaphylaxis:a world-wide phenomenon? Curr Treat Options Allergy 2014;1:262-77.
  2. Kar I, Gong M, Muglia C, et al. Alpha-gal (mammalian meat) allergy: implications for pharmacists. Pharmacy Times, May 27, 2015.
  3. Commins SP, Platts-Mills TAE. Anaphylaxis syndromes related to a new mammalian cross-reactive carbohydrate determinant. J Allergy Clin Immunol 2009;124:652-57.
  4. Commins SP, Platts-Mills TA. Delayed anaphylaxis to red meat in patients with IgE specific for galactose alpha-1, 3-galactose (alpha-gal). Curr Allergy Asthma Res 2013;13:72-77.
  5. Steinke JW, Platts-Mills TAE, Commins SP. The alpha gal story: lessons learned from connecting the dots. J Allergy Clin Immunol 2015;135:589-97. This is a must read for anyone interested in the subject!
  6. Muglia C, Kar I, Gong M, et al. Anaphylaxis to medications containing meat byproducts in an alpha-gal sensitized individual. J Allergy Clin Immunol Pract 2015; 3: 796-97.
My previously healthy 25 year old patient is admitted because of an anaphylactic reaction 4 hours after having a hamburger. Could it really have been the hamburger?