Beware Adult Onset CGD in Subjects with Pulmonary or Extrapulmonary Granulomas but Negative AFB & Tuberculous Culture

 Chronic Granulomatous Disease (CGD) is rare and affects 1 in 200,000 live births. While 75% have the X-linked form (and thus presenting in boys) due to a protein subunit of NADPH oxidase called gp91phox, the rest have an autosomal recessive form due to other protein subunits of the same enzyme, namely p22phox, p47phox, and p67 phox. Of these, p47phox is the second commonest and can present during adulthood occasionally. The involved gene is that of NCF-1 (Neutrophil Cytosolic Factor-1). The average age for presentation of the X-linked form is 3 years, and for the autosomal recessive forms, 8 years.

When CGD presents in adulthood, it is often confused with tuberculosis due to a pulmonary involvement (the most commonly affected organ in CGD), and presence of granulomas on biopsy. These granulomas are however, non-necrotising, and obviously without detectable AFB and yield negative cultures for M.tuberculosis. They are therefore sometimes diagnosed as pulmonary sarcoidosis, given the geographical setting and demographics.

Sputum or bronchoscopic washings growing the following 6 genus in a subject with pulmonary granuloma should lead to a suspicion of CGD- Aspergillus, Candida, Staphylococcus, Serratia, Burkholderia or Nocardia.

These patients often have hyperglobulinemia, with raised Ig levels, but this is not invariable. 

CGD can affect other areas, and thus cause abscesses or cellulitis in the skin, gingivitis (but not periodontitis, unlike leucocyte adhesion defects) Crohn's like granulomas in the intestines, and spinal abscesses. Granulomas can cause obstructive lesions in the urogenital & GI tracts. Delayed wound healing is often a notable feature.

Unlike LAD, which can also rarely present in adulthood, the neutrophil count tends to be normal between infectious episodes. Just for context, there are two forms of LAD, including LAD-1, caused by a defect of CD18, which is a part of the heterodimeric beta-integrins, and LAD-2, caused by a defect in fucosylation, and thus an absence of Sialyl Lewis-X , the latter being necessary for neutrophils to roll on endothelial cells prior to adhesion and diapedesis. Subjects with LAD tend to have severe periodontitis and perpetually high neutrophil counts. LAD-2 is associated with developmental abnormalities such as stunted growth.

The most convenient diagnostic test for CGD is flow cytometry with Dihydrorhodamine 123. Absence of fluorescent staining indicates abrogation of oxidative burst in neutrophils, which is characteristic of CGD. An alternative test is the Nitroblue tetrazolium test (NBT).

The only curative treatment is allogeneic BMT. Symptoms can be improved by treatment with gamma-interferon, and prophylactic administration of co-trimoxazole and itraconazole. Infective episodes should be treated with specific antibiotics.

Why Extensive Training May Not Help You Run Faster

Practice makes perfect. Right? Not always, it would seem.

I have often wondered why, despite running daily, I have not been able to improve my times. I would be classed as middle to long distance runner, averaging 6 miles daily during weekdays and 9.5 miles on weekends. In the spring of 2020, I thought I had hit a sweet spot, consistently running the longer weekend distance at between 73 and 75 minutes. At 54.5 years of age, that was a reasonable time.

But things went backwards in the autumn of that year, and this year I have struggled to get below 90 minutes for the 9.5 mile run.  In fact most runs have been in the mid to high 90s, with a few taking longer than 100 minutes.

Is this muscle fatigue, perhaps an inevitable consequence of the exercise addict's need to run daily? Or is it due to glycogen depletion?

The answer, it would seem lies elsewhere.

There are two broad categories of muscle fibres, the red, myoglobin rich, largely aerobic, mitochondria laden "slow" Type I fibre, and the larger, predominantly anaerobic, white, glycogen loaded "fast" Type II fibre, that predominantly use glycogen to generate its ATP. 

Type II fibres are further subdivided into Type IIA & Type IIB.

It seems that the determinant of the type of muscle fibre is the myosin heavy chain (MHC, not to be confused with Major Histcompatibility Complex) isotype. Thus Type I fibres are rich in MHC 1, type IIA in MHC 2A, and Type IIB in MHC 2X, also called MHC 2D.

You may well wonder what happened to MHC 2B and 2C? Well, MHC 2B is found in some ultrafast Type II fibres, mainly in cranial muscles, and MHC 2C is found in regenerating muscle fibres.

Biochemically, type I and type II fibres are distinguished by their ATPase staining and the speed of the sarcoplasmic reticulum (SR) in releasing calcium. Thus, Type I fibres stain for ATPase at low pH, while Type II fibres do so at an alkaline pH. Similarly Type II fibres possess SR that release Ca very quickly, while with Type I fibres, the release of Ca from SR is slower.

The distinction between Type IIA and Type IIB fibres is more than that of semantics. Type IIA has characteristics that are intermediate between Type I and Type IIB. Thus, they are versatile in being able to function as slow muscle fibres that serve sustained activity such as gaze, while, when called upon, they can also serve up the explosive speed of contraction, sustainable only for short periods, that epitomises Type IIB fibres. 

Muscle fibres can be "pure" and contain just MHC1 or 2A or 2X, but they can also be hybrid- ie. contain MHC1 & 2A, or 2A&2X, or all three, ie. MHC1, 2A &2X. 

Using immunohistochemical staining, long distance elite runners have a higher proportion of  MHC1 fibres than non-runners, roughly equivalent amounts of MHC2A, and almost no MHC2X fibres. Similarly, non-runners tend to have more hybrid MHC fibres in general than runners, which suggests that hybrid fibres can change their composition depending on the workload imposed on them.

Type I fibres are high maintenance. They tend to be smaller, have larger blood supply and higher oxygen consumption. Type II fibres are larger, but consume low oxygen, and at least the IIB fibres are relatively less used, "standing by" for the relatively less frequent occasions when explosive power is required.

A muscle fibre owes its "type" or allegiance to the alpha motor neuron that innervates it. Thus a motor unit (comprised of all the muscle fibres innervated by a particular motor neurone) will always innervate the same type of muscle fibres. Thus a motor unit can be classified as Fast twitch (F) or Slow twitch (S). The F units are further classified as Fatigue resistant (FR) or Fast fatiguing (FF). When there is denervation and cross re-enervation, the muscle fibres take on the characteristics of the "new" motor neurone. Thus S units can turn into FR or FF on cross-reinnervation and so on.

It follows from the above that with training, entire motor units change their character (as individual muscle fibres are unable to do so, being dictated by the motor unit they are part of). Thus, with prolonged training, FF units can change into FR and FR into S. Change in the other direction happens with deconditioning.

And herein, I believe lies my predicament. I believe that my FF units have slowly transitioned into FR and FR units into S units. Glycogen depletion would not be germane to this, as it would only affect the FF motor units, which are comprised principally of Type IIB muscle fibres. While the S units and FR units are fatigue resistant and ideal for long distance running, the muscle fibres they innervate are smaller, and lack the speed of FF units.