In my patient with a serious infection, when should I worry about a primary immunodeficiency disorder?

You may consider a primary immunodeficiency disorder (PID) when 2 or more of the following “warning signs” are present: 1

  • ≥ 4 ear infections in 1 year
  • ≥ 2 serious sinus infections in 1 year
  • ≥ 2 pneumonias in 1 year
  • Recurrent, deep skin or organ abscesses
  • Persistent thrush in mouth or persistent fungal infection on the skin
  • ≥ 2 deep-seated infections, including septicemia
  • ≥ 2 months on antibiotics with little effect
  • Need for IV antibiotics to clear infections
  • Failure of an infant to gain weight or grow normally
  • Family history of primary immunodeficiency

Other infectious conditions that may be a clue to PID include those in unusual locations (eg, pneumococcal arthritis) or caused by unusual pathogens (eg, Pneumocystis jirovecii).

Among non-infectious conditions, history of granulomas in multiple organs, early-onset eczema refractory to therapy, and autoimmunity (eg, autoimmune cytopenias, autoimmune thyroiditis, celiac disease, vitiligo, type I diabetes mellitus) may also be potential clues.2

But before you embark on searching for PID,  rule out local barrier disorders of the skin or mucosa (eg, foreign body, bronchiectasis, cystic fibrosis) and secondary causes of immunodeficiency (eg, HIV), syndromes of protein loss/deficiency (eg, cirrhosis, nephrotic syndrome, malnutrition), splenectomy, malignancy, and medications (eg, steroids, chemotherapy, tumor necrosis factor inhibitors).2

Final Fun Fact: Did you know that PID affects 1 in 1,200 people in the US? 3


  1. Arkwright PD, Gennery AR. Ten warning signs of primary immunodeficiency: a new paradigm is needed for the 21st century. Ann N Y Acad Sci 2011; 1238:7-14
  2. Hausmann O, Warnatz K. Immunodeficiency in adults a practical guide for the allergist. Allergo J Int. 2014; 23: 261–268
  3. Boyle JM, Buckley RH. Population prevalence of diagnosed primary immunodeficiency diseases in the United States. J Clin Immunol 2007; 27:497


Contributed by Yousef Badran, MD, Mass General Hospital, Boston, MA.

In my patient with a serious infection, when should I worry about a primary immunodeficiency disorder?

Can a seizure cause abnormalities on the brain MRI?

Yes it can, and the MRI abnormalities could represent seizure’s effects on the brain, not the seizure’s structural cause. Seizure-related MRI changes are often associated with status epilepticus, but have also been reported in complex partial status epilepticus.1,2

T2-weighted MRI images may show increased signal intensity at the cortical gray matter, subcortical white matter, or hippocampus. The MRI changes are unilateral about one-half of the cases, while in about 8% of patients leptomeningeal contrast-enhancement may be observed. Partial simple and complex seizures are associated with hippocampal involvement.3

The increased signal intensity following seizures is thought to be due to increased metabolism at the epileptogenic area, which in turn results in increased oxygen consumption, hypoxia, hypercarbia, lactic acidosis, and ultimately vasodilation and edema.

Reversibility of MRI changes following seizures has been noted between 15 and 150 days (average, 62 days). A structural abnormality is more likely the cause of a seizure when the MRI changes do not resolve during this period.3 Therefore, seizure-induced brain-MRI abnormalities remain a diagnosis of exclusion.


  1. Kim JA, Chung JI, Yoon PH, et al. Transient MR signal changes in patients with generalized tonicoclonic seizure or status epilepticus: periictal diffusion-weighted imaging. Am J Neuroradiol 2001; 22:1149–1160
  2. Henry TR, Brunberg DI, Pennell PB, et al. Focal cerebral magnetic resonance changes associated with partial status epilepticus. Epilepsia 1994; 35:35–41
  3. Cianfoni A, Caulo M, Cerase A, et al. Seizure-induced brain lesions: a wide spectrum of variably reversible MRI abnormalities. Eur J Radiol. 2013; 82(11):1964-72.


Contributed by Johan H.L. Boneschansker, MD, Mass General Hospital, Boston, MA.

Can a seizure cause abnormalities on the brain MRI?

Is prolactin level useful in determining whether my patient with loss of consciousness suffered a seizure?

It depends on the timing of your patient’s presentation!

It is generally held that serum prolactin level peaks within 10-20 min after a generalized tonic-clonic or complex partial seizure and returns to baseline within 2-6 h. Even then, its sensitivity is no more than 50%-60% for these types of seizures.  Elevated PL is also seen in 60%-80% of patients with syncope.1

A report by the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology (2006) concluded that “elevated serum prolactin assay, when measured in the appropriate clinical setting at 10-20 min after a suspected event, is a useful adjunct for the differentiation of generalized tonic-clonic or complex partial seizure from psychogenic non-epileptic seizure among adults or older children (Level B).2 

In contrast, reports of PL increasing for up to 6 h after epileptic seizure or not reaching baseline for 12-18 h can also be found in the literature.3

Although the mechanism for elevation of PL in certain seizures is unknown,  one hypothesis proposes that prolactin is secreted due to the interference with the inhibitory control of hypothalamus by the electrical perturbation of this part of the brain.4  


  1. Nass RD, Sassen R, Elger CE. The role of postictal laboratory blood analyses in the diagnosis and prognosis of seizures. Seizure 2017;47:51-65.
  2. Chen DK, So YT, Fisher RS. Is prolactin a clinically useful measure of epilepsy? Epilepsy Currents 2006;6:78-79.
  3. Siniscalchi A, Gallelli L, Mercuri NB, et al. Serum prolactin levels in repetitive temporal epileptic seizures. Eur Rev Med Pharmacol Sci 2008;12:365-368.
  4. Collins WCJ, Lanigan O, Callaghan N. Plasma prolactin concentrations following epileptic and pseudoseizures. J Neurol Neurosurg Psych 1983; 46:505-8.


Is prolactin level useful in determining whether my patient with loss of consciousness suffered a seizure?

The urine antigen for Legionella in my patient with severe community-associated pneumonia is negative. How well does it rule out Legionella pneumonia?

Not as well as you might think!

Legionella urine antigens are 60%-80% sensitive (>99% specific) for detecting L. pneumophila serogroup 1 which accounts for about 70%-80% of Legionnaire’s disease (LD) in the US1; there are at least 15 serogroups.2 So as many as 40% or more LD may be missed by urine antigen testing alone. 2 Urine antigen can be excreted as early 3 days after the onset of symptoms and can persist for >300 days which may present a problem in diagnosing a current illness in patients with recurrent pneumonia. 2 One study reported lowest sensitivity (80%) for antigen testing during days 4 to 7 days of symptoms.3Other means of looking for Legionella include culture of respiratory samples for L. pneumophila which can detect all types of Legionella species (sensitivity 20%-80%) but has a lengthy turnaround time. Paired antibody testing may also be performed (sensitivity 70%-80%) in undiagnosed cases of severe pneumonia. 1Take home point: Don’t depend totally on urine antigen testing to rule out LD.

Final fun fact: Did you know that legionellae survive in the aquatic environment by parasitizing free-living protozoa?


  1. CDC. Legionellosis: United States, 2000-2009. MMWR 2011;60:1083-86.
  2. Fields BS, Benson RF, Besser RE. Legionella and Legionnaire’s disease: 25 years of investigation. Clin Micro Rev 2002;15:506-26.  
  3. Kohler RB, Zimmerman SE, Wilson E, et al. Onset and duration of urinary antigen excretion in Legionnaire’s disease. J Clin Microbiol 20:605-7.
The urine antigen for Legionella in my patient with severe community-associated pneumonia is negative. How well does it rule out Legionella pneumonia?

Should I use qSOFA to screen for severe infections in my non-ICU patient?

Sepsis-3 qSOFA criteria—systolic BP ≤100 mg Hg, altered mental state, and RR≥22, with ≥2 considered positive— should NOT be used as either a screening or diagnostic tool for sepsis until properly designed prospective studies validate its utility.1

An important issue with qSOFA is its poor sensitivity for identifying patients with sepsis and its complications.  In a retrospective study of over 30,000 hospitalized patients suspected of infection in the emergency department or hospital wards, qSOFA ≥2 had a sensitivity of only 54% and specificity of 67% for in-hospital mortality or ICU transfer vs a much higher sensitivity of 91% but lower specificity of 13% for SIRS ≥2. Interestingly, most patients in this study met qSOFA criteria only 5 h before the studied outcome vs 17 h for SIRS ≥2 criteria.2

In another retrospective study of over 15,000 patients presenting to the Emergency Department with suspected infection, qSOFA ≥2 had a sensitivity of  49% and a specificity of 79% for hospital mortality vs  84% and 35% for SIRS≥2, and 65% and 74% for “severe sepsis” (Sepsis-2), respectively.3

So, using qSOFA alone to decide who needs prompt management of their infection (eg, blood cultures, serum lactate, antibiotics, fluids) may delay timely intervention in a substantial proportion of patients with infection that may become complicated by ICU transfer or death.  As is usually the case in medicine, it pays to look at the entire picture!


  1. Machado FR, Nsutebu E, AbDulaziz S, et al. Sepsis 3 from the perspective of clinicians and quality improvement initiatives. J Crit Care 2017:40: 315-17.
  2. Churpek MM, Synder A, Han X, et al. Quick sepsis-related organ failure assessment, systemic inflammatory response syndrome, and early warning scores for detecting clinical deterioration n infected patients outside the intensive care unit. Am J Respir Crit Care Med 2017; 195: 906-11.
  3. Lembke K, Parashar S, Simpson S. Sensitivity and specificity of SIRS, qSOFA, and severe sepsis for mortality of patients presenting to the emergency department with suspected infection. Chest Annual Meeting, Toronto, October 29, 2017.
Should I use qSOFA to screen for severe infections in my non-ICU patient?

My patient with aortic sclerosis has a loud systolic ejection murmur. What is the exact mechanism of this murmur?

We usually blame cardiac murmurs on the “turbulence” caused by blood flowing past an irregular valve surface but, believe it or not, how the murmur is created has been a matter of controversy. 1-4

For sure, murmurs are generated by disturbance of laminar blood flow (ie, turbulence) but over the years many have argued that turbulence per se fails to produce adequate acoustic force to be audible at the chest wall.2 Although challenged by some,1  the concept of “vortex shedding” borrowed from fluid dynamics is fascinating and has been proposed as a potential explanation.

Per this theory, just as a boulder causes a stream to separate and generate vortices, valves (particularly when abnormal) also create vortices. As the vortices are shed near the valve, they leave in their place relatively calm wakes which are then rapidly filled by flowing blood, creating the sound of a murmur.  

Two important variables in this theory are velocity and viscosity. When the velocity of blood flow increases substantially as in high cardiac output states (eg, fever, pregnancy), vortex shedding and the intensity of the murmur also increase. Similar phenomenon may be expected when the blood viscosity is lowered (eg, in anemia).



  1. Sabbah HN, Stein PD. Turbulent blood flow in humans: Its primary role in the production of ejection murmurs. Circ Res 1976;38: 513-24.
  2. Alpert MA, Systolic murmurs. In Walker HK, Hall WD, Hurst JW. Clinical methods: The history, physical, and laboratory examinations. 3rd ed. Butterworths, Boston, 1990.
  3. Bruns D. A general theory of the causes of murmurs in the cardiovascular system. Am J Med 1959;27:360-74.
  4. Guntheroth WG. Innocent murmurs: A suspect diagnosis in non-pregnant adults. Am J Cardiol 2009;104:735-7.
My patient with aortic sclerosis has a loud systolic ejection murmur. What is the exact mechanism of this murmur?